Đang tải... (xem toàn văn)
(BQ) Part 1 book Marks'' essentials of medical biochemistry a clinical approach presents the following contents: Carbohydrate metabolism, lipid metabolism, nitrogen metabolism. Invite you to consult.
SECTION FIVE 21 Carbohydrate Metabolism Basic Concepts in the Regulation of Fuel Metabolism by Insulin, Glucagon, and Other Hormones CHAPTER OUTLINE I METABOLIC HOMEOSTASIS II MAJOR HORMONES OF METABOLIC HOMEOSTASIS III SYNTHESIS AND RELEASE OF INSULIN AND GLUCAGON A Endocrine pancreas B Synthesis and secretion of insulin C Stimulation and inhibition of insulin release D Synthesis and secretion of glucagon IV MECHANISMS OF HORMONE ACTION A Signal transduction by hormones that bind to plasma membrane receptors Signal transduction by insulin Signal transduction by glucagon B Signal transduction by cortisol and other hormones that interact with intracellular receptors C Signal transduction by epinephrine and norepinephrine KEY POINTS ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ Insulin and glucagon are the two major hormones that regulate fuel mobilization and storage Insulin and glucagon maintain blood glucose levels near 80 to 100 mg/dL despite varying carbohydrate intake during the day Glucose homeostasis is the maintenance of constant blood glucose levels If dietary intake of all fuels is in excess of immediate need, it is stored as either glycogen or fat Appropriately stored fuels are mobilized when demand requires Insulin is released in response to carbohydrate ingestion and promotes glucose utilization as a fuel and glucose storage as fat and glycogen Glucagon is decreased in response to a carbohydrate meal and elevated during fasting Glucagon promotes glucose production via glycogenolysis (glycogen degradation) and gluconeogenesis (glucose synthesis from amino acids and other noncarbohydrate precursors) Increased levels of glucagon relative to insulin also stimulate the release of fatty acids from adipose tissue Insulin secretion is regulated principally by blood glucose levels Glucagon release is regulated principally through suppression by glucose and by insulin Glucagon acts by binding to a receptor on the cell surface, which stimulates the synthesis of the intracellular second messenger, cAMP cAMP activates protein kinase A, which phosphorylates key regulatory enzymes, activating some and inhibiting others Insulin acts via a receptor tyrosine kinase and leads to the dephosphorylation of the key enzymes phosphorylated in response to glucagon 329 Lieberman_Ch21.indd 329 9/16/14 2:04 AM SECTION V ■ CARBOHYDRATE METABOLISM 330 THE WAITING ROOM Fatty acids provide an example of the influence that the level of a compound in the blood has on its own rate of metabolism The concentration of fatty acids in the blood is the major factor determining whether skeletal muscles will use fatty acids or glucose as a fuel (see Chapter 24) In contrast, hormones are (by definition) carriers of messages between their sites of synthesis and their target tissues Insulin and glucagon, for example, are two hormonal messengers that participate in the regulation of fuel metabolism by carrying messages that reflect the timing and composition of our dietary intake of fuels Epinephrine, however, is a fight-or-flight hormone that signals an immediate need for increased fuel availability Its level is regulated principally through the activation of the sympathetic nervous system A Glucose Insulin Liver Triglyceride synthesis Glycogen synthesis Active glycolysis B Liver Glucose Glucagon Epinephrine Glycogen degradation Gluconeogenesis FIG 21.1 Insulin and the insulin counterregulatory hormones A Insulin promotes glucose storage as triglyceride (TG) or glycogen B Glucagon and epinephrine promote glucose release from the liver, activating glycogenolysis and gluconeogenesis Cortisol will stimulate both glycogen synthesis and gluconeogenesis Lieberman_Ch21.indd 330 Deborah S returned to her physician for her monthly office visit She has been seeing her physician for over a year because of obesity and elevated blood glucose levels She still weighed 198 lb, despite trying to adhere to her diet Her blood glucose level at the time of the visit, hours after lunch, was 221 mg/dL (reference range ϭ 80 to 140) Deborah suffers from type diabetes, an impaired response to insulin Understanding the actions of insulin and glucagon are critical for understanding this disorder Connie C is a 46-year-old woman who months earlier began noting episodes of fatigue and confusion as she finished her daily prebreakfast jog These episodes were occasionally accompanied by blurred vision and an unusually urgent sense of hunger The ingestion of food relieved all of her symptoms within 25 to 30 minutes In the last month, these attacks have occurred more frequently throughout the day and she has learned to diminish their occurrence by eating between meals As a result, she has recently gained lb A random serum glucose level done at 4:30 PM during her first office visit was subnormal at 67 mg/dL Her physician, suspecting she was having episodes of hypoglycemia, ordered a series of fasting serum glucose, insulin, and c-peptide levels In addition, he asked Connie to keep a careful daily diary of all of the symptoms that she experienced when her attacks were most severe I METABOLIC HOMEOSTASIS Living cells require a constant source of fuels from which to derive adenosine triphosphate (ATP) for the maintenance of normal cell function and growth Therefore, a balance must be achieved between carbohydrate, fat, and protein intake; their rates of oxidation; and their rates of storage when they are present in excess of immediate need Alternatively, when the demand for these substrates increases, the rate of mobilization from storage sites and the rate of their de novo synthesis also require balanced regulation The control of the balance between substrate need and substrate availability is referred to as metabolic homeostasis The intertissue integration required for metabolic homeostasis is achieved in three principal ways: • The concentration of nutrients or metabolites in the blood affects the rate at which they are used or stored in different tissues • Hormones carry messages to individual tissues about the physiological state of the body and nutrient supply or demand • The central nervous system uses neural signals to control tissue metabolism, either directly or through the release of hormones Insulin and glucagon are the two major hormones that regulate fuel storage and mobilization (Fig 21.1) Insulin is the major anabolic hormone of the body It promotes the storage of fuels and the utilization of fuels for growth Glucagon is the major hormone of fuel mobilization Other hormones, such as epinephrine, are released as a response of the central nervous system to hypoglycemia, exercise, or other types of physiologic stress Epinephrine and other stress hormones also increase the availability of fuels (Fig 21.2) Glucose has a special role in metabolic homeostasis Many tissues (e.g., the brain, red blood cells, kidney medulla, exercising skeletal muscle) depend on glycolysis for all or a part of their energy needs As a consequence, these tissues 9/16/14 2:04 AM CHAPTER 21 ■ BASIC CONCEPTS IN THE REGULATION OF FUEL METABOLISM Insulin Blood fuel Dietary Fuels: • Carbohydrate • Fat • Protein Blood fuel Fuel stores + Growth Neuronal signals Glucagon + Stress hormones Blood fuel Fuel utilization ATP Cell function FIG 21.2 Signals that regulate metabolic homeostasis The major stress hormones are epinephrine and cortisol require uninterrupted access to glucose to meet their rapid rate of ATP use In the adult, a minimum of 190 g glucose is required per day, approximately 150 g for the brain and 40 g for other tissues Significant decreases of blood glucose below 60 mg/ dL limit glucose metabolism in the brain and elicit hypoglycemic symptoms (as experienced by Connie C.), presumably because the overall process of glucose flux through the blood–brain barrier, into the interstitial fluid, and subsequently into the neuronal cells is slow at low blood glucose levels because of the Km values of the glucose transporters required for this to occur (see Chapter 22) The continuous efflux of fuels from storage depots, during exercise, for example, is necessitated by the high amounts of fuel required each day to meet the need for ATP under these conditions Disastrous results would occur if even a day’s supply of glucose, amino acids, and fatty acids could not enter cells normally and were instead left circulating in the blood Glucose and amino acids would be at such high concentrations in the circulation that the hyperosmolar effect would cause progressively severe neurologic deficits and even coma The concentration of glucose and amino acids would rise above the renal tubular threshold for these substances (the maximal concentration in the blood at which the kidney can completely resorb metabolites), and some of these compounds would be wasted as they spilled over into the urine Nonenzymatic glycosylation of proteins would increase at higher blood glucose levels altering the function of tissues in which these proteins reside Triacylglycerols, present primarily in chylomicrons and very low density lipoproteins (VLDL) would rise in the blood, increasing the likelihood of atherosclerotic vascular disease These potential metabolic derangements emphasize the need to maintain a normal balance between fuel storage and fuel use II MAJOR HORMONES OF METABOLIC HOMEOSTASIS The hormones that contribute to metabolic homeostasis respond to changes in the circulating levels of fuels that, in part, are determined by the timing and composition of our diet Insulin and glucagon are considered the major hormones of metabolic homeostasis because they continuously fluctuate in response to our daily eating pattern They provide good examples of the basic concepts of hormonal regulation Certain features of the release and action of other insulin counterregulatory Lieberman_Ch21.indd 331 331 Hyperglycemia may cause a constellation of symptoms such as polyuria and subsequent polydipsia (increased thirst) The inability to move glucose into cells necessitates the oxidation of lipids as an alternative fuel As a result, adipose stores are used, and the patient with poorly controlled diabetes mellitus loses weight in spite of a good appetite Extremely high levels of serum glucose can cause a hyperosmolar hyperglycemic state in patients with type diabetes mellitus Such patients usually have sufficient insulin responsiveness to block fatty acid release and ketone body formation, but they are unable to significantly stimulate glucose entry into peripheral tissues The severely elevated levels of glucose in the blood compared with those inside the cell leads to an osmotic effect that causes water to leave the cells and enter the blood Because of the osmotic diuretic effect of hyperglycemia, the kidney produces more urine, leading to dehydration, which, in turn, may lead to even higher levels of blood glucose If dehydration becomes severe, further cerebral dysfunction occurs and the patient may become comatose Chronic hyperglycemia also produces pathological effects through the nonenzymatic glycosylation of a variety of proteins Hemoglobin A (HbA), one of the proteins that becomes glycosylated, forms HbA1c (see Chapter 7) Deborah S.’s high levels of HbA1c (12% of the total HbA, compared with the reference range of 4.7% to 6.4%) indicate that her blood glucose has been significantly elevated over the last 12 to 14 weeks, the half-life of hemoglobin in the bloodstream All membrane and serum proteins exposed to high levels of glucose in the blood or interstitial fluid are candidates for nonenzymatic glycosylation This process distorts protein structure and slows protein degradation, which leads to an accumulation of these products in various organs, thereby adversely affecting organ function These events contribute to the long-term microvascular and macrovascular complications of diabetes mellitus, which include diabetic retinopathy, nephropathy, and neuropathy (microvascular), in addition to coronary artery, cerebral artery, peripheral artery disease, and atherosclerosis (macrovascular) 9/16/14 2:04 AM 332 SECTION V ■ CARBOHYDRATE METABOLISM Liver Glycogen – + + – Protein + Glucose Fatty acids Amino acids VLDL Glucose + Fatty acids – + + Protein + CO2 Glycogen Skeletal muscle Triacylglycerols Adipocyte FIG 21.3 Major sites of insulin action in fuel metabolism VLDL, very low density lipoprotein; ᮍ, stimulated by insulin; ᮎ, inhibited by insulin Connie C.’s studies confirmed that her fasting serum glucose levels were below normal with an inappropriately high insulin level She continued to experience the fatigue, confusion, and blurred vision she had described on her first office visit These symptoms are referred to as the neuroglycopenic manifestations of severe hypoglycemia (neurologic symptoms resulting from an inadequate supply of glucose to the brain for the generation of ATP) Connie also noted the symptoms that are part of the adrenergic response to hypoglycemic stress Stimulation of the sympathetic nervous system (because of the low levels of glucose reaching the brain) results in the release of epinephrine, a stress hormone, from the adrenal medulla Elevated epinephrine levels cause tachycardia (rapid heart rate), palpitations, anxiety, tremulousness, pallor, and sweating In addition to the symptoms described by Connie C., individuals may experience confusion, light-headedness, headache, aberrant behavior, blurred vision, loss of consciousness, or seizures When severe or prolonged, death may occur Lieberman_Ch21.indd 332 hormones, such as epinephrine, norepinephrine, and cortisol, will be described and compared with insulin and glucagon Insulin is the major anabolic hormone that promotes the storage of nutrients: glucose storage as glycogen in liver and muscle, conversion of glucose to triacylglycerols in liver and their storage in adipose tissue, and amino acid uptake and protein synthesis in skeletal muscle (Fig 21.3) It also increases the synthesis of albumin and other proteins by the liver Insulin promotes the use of glucose as a fuel by facilitating its transport into muscle and adipose tissue At the same time, insulin acts to inhibit fuel mobilization Glucagon acts to maintain fuel availability in the absence of dietary glucose by stimulating the release of glucose from liver glycogen (see Chapter 23); by stimulating gluconeogenesis from lactate, glycerol, and amino acids (see Chapter 26); and, in conjunction with decreased insulin, by mobilizing fatty acids from adipose triacylglycerols to provide an alternate source of fuel (see Chapter 20 and Fig 21.4) Its sites of action are principally the liver and adipose tissue; it has no influence on skeletal muscle metabolism because muscle cells lack glucagon receptors The message carried by glucagon is that “Glucose is gone”; that is, the current supply of glucose is inadequate to meet the immediate fuel requirements of the body The release of insulin from the β-cells of the pancreas is dictated primarily by the level of glucose bathing the β-cells in the islets of Langerhans The highest levels of insulin occur approximately 30 to 45 minutes after a high-carbohydrate meal (Fig 21.5) They return to basal levels as the blood glucose concentration falls, approximately 120 minutes after the meal The release of glucagon from the α-cells of the pancreas, conversely, is controlled principally through a reduction of glucose and/or a rise in the concentration of insulin in blood, bathing the α-cells in the pancreas Therefore, the lowest levels of glucagon occur after a high-carbohydrate meal Because all of the effects of glucagon are opposed by insulin, the simultaneous stimulation of insulin release and suppression of glucagon secretion by a high-carbohydrate meal provides integrated control of carbohydrate, fat, and protein metabolism Insulin and glucagon are not the only regulators of fuel metabolism The intertissue balance between the use and storage of glucose, fat, and protein is also accom- 9/16/14 2:04 AM CHAPTER 21 ■ BASIC CONCEPTS IN THE REGULATION OF FUEL METABOLISM – Highcarbohydrate meal Liver Glycogen 333 + Glucose mg/dL 120 – + Fatty acids 100 Glucose 80 Amino acids 120 μU/mL Glucose Fatty acids Fatty acids + Triacylglycerols No effect 80 Insulin 40 Skeletal muscle 120 pg/mL Adipocyte FIG 21.4 Major sites of glucagon action in fuel metabolism ᮍ, pathways stimulated by glucagon; ᮎ, pathways inhibited by glucagon Glucagon 110 100 90 60 60 120 180 240 Minutes plished by the circulating levels of metabolites in the blood, by neuronal signals, and by the other hormones of metabolic homeostasis (epinephrine, norepinephrine, cortisol, and others) (Table 21.1) These hormones oppose the actions of insulin by mobilizing fuels Like glucagon, they are insulin counterregulatory hormones (Fig 21.6) Of all these hormones, only insulin and glucagon are synthesized and released in direct response to changing levels of fuels in the blood The release of cortisol, epinephrine, and norepinephrine is mediated by neuronal signals Rising levels of the insulin counterregulatory hormones in the blood reflect, for the most part, a current increase in the demand for fuel FIG 21.5 Blood glucose, insulin, and glucagon levels after a high-carbohydrate meal Table 21.1 Physiological Actions of Insulin and Insulin Counterregulatory Hormones Hormone Function Major Metabolic Pathways Affected Insulin • Promotes fuel storage after a meal • Promotes growth Glucagon • Mobilizes fuels • Stimulates glucose storage as glycogen (muscle and liver) • Stimulates fatty acid synthesis and storage after a high-carbohydrate meal • Stimulates amino acid uptake and protein synthesis • Activates gluconeogenesis and glycogenolysis (liver) during fasting • Activates fatty acid release from adipose tissue • Stimulates glucose production from glycogen (muscle and liver) • Stimulates fatty acid release from adipose issue • Stimulates amino acid mobilization from muscle protein • Stimulates gluconeogenesis to produce glucose for liver glycogen synthesis • Stimulates fatty acid release from adipose tissue Epinephrine Cortisol Lieberman_Ch21.indd 333 • Maintains blood glucose levels during fasting • Mobilizes fuels during acute stress • Provides for changing requirements during stress 9/16/14 2:04 AM 334 SECTION V ■ CARBOHYDRATE METABOLISM Low Blood Glucose Hypothalamic regulatory center Pituitary ACTH Autonomic nervous system ␣-Cells The message that insulin carries to tissues is that glucose is plentiful and can be used as an immediate fuel or can be converted to storage forms such as triacylglycerol in adipocytes or glycogen in liver and muscle Because insulin stimulates the uptake of glucose into tissues where it may be immediately oxidized or stored for later oxidation, this regulatory hormone lowers blood glucose levels Therefore, one of the possible causes of Connie C.’s hypoglycemia is an insulinoma, a tumor that produces excessive insulin Cortex Medulla Adrenal Cortisol Epinephrine Pancreas Norepinephrine Glucagon FIG 21.6 Major insulin counterregulatory hormones The stress of a low blood glucose level mediates the release of the major insulin counterregulatory hormones through neuronal signals Hypoglycemia is one of the stress signals that stimulates the release of cortisol, epinephrine, and norepinephrine Adrenocorticotropic hormone (ACTH) is released from the pituitary and stimulates the release of cortisol (a glucocorticoid) from the adrenal cortex Neuronal signals stimulate the release of epinephrine from the adrenal medulla and norepinephrine from nerve endings Neuronal signals also play a minor role in the release of glucagon Although norepinephrine has counterregulatory actions, it is not a major counterregulatory hormone III SYNTHESIS AND RELEASE OF INSULIN AND GLUCAGON A Endocrine Pancreas Whenever an endocrine gland continues to release its hormone in spite of the presence of signals that normally would suppress its secretion, this persistent inappropriate release is said to be “autonomous.” Secretory neoplasms of endocrine glands generally produce their hormonal product autonomously in a chronic fashion Autonomous hypersecretion of insulin from a suspected pancreatic β-cell tumor (an insulinoma) can be demonstrated in several ways The simplest test is to simultaneously draw blood for the measurement of both glucose and insulin at a time when the patient is spontaneously experiencing the characteristic adrenergic or neuroglycopenic symptoms of hypoglycemia During such a test, Connie C.’s glucose levels fell to 45 mg/dL (normal ϭ 80 to 100 mg/dL), and her ratio of insulin to glucose was far higher than normal The elevated insulin levels markedly increased glucose uptake by the peripheral tissues, resulting in a dramatic lowering of blood glucose levels In normal individuals, as blood glucose levels drop, insulin levels also drop Lieberman_Ch21.indd 334 Insulin and glucagon are synthesized in different cell types of the endocrine pancreas, which consists of microscopic clusters of small glands, the islets of Langerhans, scattered among the cells of the exocrine pancreas The α-cells secrete glucagon, and the β-cells secrete insulin into the hepatic portal vein via the pancreatic veins B Synthesis and Secretion of Insulin Insulin is a polypeptide hormone The active form of insulin is composed of two polypeptide chains (the A chain and the B chain) linked by two interchain disulfide bonds The A chain has an additional intrachain disulfide bond (Fig 21.7) Insulin, like many other polypeptide hormones, is synthesized as a preprohormone that is converted in the rough endoplasmic reticulum (RER) to proinsulin The “pre-” sequence, a short hydrophobic signal sequence at the N-terminal end, is cleaved as it enters the lumen of the RER Proinsulin folds into the proper conformation and disulfide bonds are formed between the cysteine residues It is then transported in microvesicles to the Golgi complex It leaves the Golgi complex in storage vesicles, where a protease removes the biologically inactive “connecting peptide” (C-peptide) and a few small remnants, resulting in the formation of biologically active insulin (see Fig 21.7) Zinc ions are also transported in these storage vesicles Cleavage of the C-peptide decreases the solubility of the resulting insulin, which then coprecipitates with zinc Exocytosis of the insulin storage vesicles from the cytosol of the β-cell into the blood is stimulated by rising levels of glucose in the blood bathing the β-cells Glucose enters the β-cell via specific glucose transporter proteins known as GLUT2 (see Chapter 22) Glucose is phosphorylated through the action of glucokinase to form glucose-6-phosphate, which is metabolized through glycolysis, the tricarboxylic acid 9/16/14 2:04 AM CHAPTER 21 ■ BASIC CONCEPTS IN THE REGULATION OF FUEL METABOLISM 335 20 Ala Leu Ser Gly Ala Gly Pro Pro Gln Gly Gly Leu Leu Gly C-Peptide Glu Leu Glu Val Gly Gln Ser 31 Gly Leu Val Gln Lys Gln Arg Leu Gly Asp Ile Val NH2 Asn Glu Phe A-Chain S Gln Glu Thr Gln S Gln Ser Ile Cys Ser Leu Tyr Arg Leu S Thr Lys 10 S Insulin Thr S Gly His Tyr Phe B-Chain Leu 10 30 Pro Cys Ser Arg Asn Cys Asn Glu Tyr S Cys Leu Ala 21 Cys Val His Glu COOH Glu Val Glu Gly Ala Leu Tyr Leu Val Cys 20 Arg Gly Phe FIG 21.7 Cleavage of proinsulin to insulin Proinsulin is converted to insulin by proteolytic cleavage, which removes the C-peptide and a few additional amino acid residues Cleavage occurs at the arrows (From Murray RK, et al Harper’s Biochemistry, 23rd Ed Stanford, CT: Appleton & Lange, 1993:560.) (TCA) cycle, and oxidative phosphorylation These reactions result in an increase in ATP levels within the β-cell (circle in Fig 21.8) As the β-cell [ATP]/[ADP] ratio increases, the activity of a membrane-bound, ATP-dependent Kϩ channel (KϩATP) is inhibited (i.e., the channel is closed) (circle in Fig 21.8) The closing of this channel leads to a membrane depolarization (as the membrane is normally hyperpolarized, see circle 3, Fig 21.8), which activates a voltage-gated Ca2ϩ channel that allows Ca2ϩ to enter the β-cell such that intracellular Ca2ϩ levels increase significantly (circle 4, Fig 21.8) The increase in intracellular Ca2ϩ stimulates the fusion of insulin containing exocytotic vesicles with the plasma membrane, resulting in insulin secretion (circle 5, Fig 21.8) Thus, an increase in glucose levels within the β-cells initiates insulin release Ca2+ + ⌬ [Ca2+] K+ Fusion and exocytosis Glucose – Insulin Glycolysis TCA cycle Oxidative phosphorylation ATP -Cell FIG 21.8 Release of insulin by the β-cells Details are provided in the text Lieberman_Ch21.indd 335 9/16/14 2:04 AM 336 SECTION V ■ CARBOHYDRATE METABOLISM A rare form of diabetes known as maturity-onset diabetes of the young (MODY) results from mutations in either pancreatic glucokinase or specific nuclear transcription factors MODY type is caused by a glucokinase mutation that results in an enzyme with reduced activity because of either an elevated Km for glucose or a reduced Vmax for the reaction Because insulin release depends on normal glucose metabolism within the β-cell that yields a critical [ATP]/[ADP] ratio in the β-cell, individuals with this glucokinase mutation cannot significantly metabolize glucose unless glucose levels are higher than normal Thus, although these patients can release insulin, they so at higher than normal glucose levels and are, therefore, almost always in a hyperglycemic state Interestingly, however, these patients are somewhat resistant to the long-term complications of chronic hyperglycemia The mechanism for this seeming resistance is not well understood Neonatal diabetes is an inherited disorder in which newborns develop diabetes within the first months of life The diabetes may be permanent, requiring lifelong insulin treatment, or transient The most common mutation leading to permanent neonatal diabetes is in the KCNJ11 gene, which encodes a subunit of the KϩATP channel in various tissues including the pancreas This is an activating mutation, which keeps the KϩATP channel open and less susceptible to ATP inhibition If the KϩATP channel cannot be closed, activation of the Ca2ϩ channel will not occur and insulin secretion will be impaired C Stimulation and Inhibition of Insulin Release Deborah S is taking a sulfonylurea compound known as glipizide to treat her diabetes The sulfonylureas act on the KϩATP channels on the surface of the pancreatic β-cells The KϩATP channels contain pore-forming subunits (encoded by the KCNJ11 gene) and regulatory subunits (the subunit to which sulfonylurea compounds bind encoded by the SUR1 gene) The binding of the drug to the sulfonylurea receptor closes Kϩ channels (as elevated ATP levels), which, in turn, increases Ca2ϩ movement into the interior of the β-cell This influx of calcium modulates the interaction of the insulin storage vesicles with the plasma membrane of the β-cell, resulting in the release of insulin into the circulation Measurements of proinsulin and the connecting peptide between the αand β-chains of insulin (C-peptide) in Connie C.’s blood during her hospital fast provided confirmation that she had an insulinoma Insulin and C-peptide are secreted in approximately equal proportions from the β-cell, but C-peptide is not cleared from the blood as rapidly as insulin Therefore, it provides a reasonably accurate estimate of the rate of insulin secretion Plasma C-peptide measurements could also be potentially useful in treating patients with diabetes mellitus because they provide a way to estimate the degree of endogenous insulin secretion in patients who are receiving exogenous insulin, which lacks the C-peptide Lieberman_Ch21.indd 336 The release of insulin occurs within minutes after the pancreas is exposed to a high glucose concentration The threshold for insulin release is approximately 80 mg glucose/dL Above 80 mg/dL, the rate of insulin release is not an all-or-nothing response but is proportional to the glucose concentration up to approximately 300 mg/ dL glucose As insulin is secreted, the synthesis of new insulin molecules is stimulated, so that secretion is maintained until blood glucose levels fall Insulin is rapidly removed from the circulation and degraded by the liver (and, to a lesser extent, by kidney and skeletal muscle), so that blood insulin levels decrease rapidly once the rate of secretion slows Several factors other than the blood glucose concentration can modulate insulin release The pancreatic islets are innervated by the autonomic nervous system, including a branch of the vagus nerve These neural signals help to coordinate insulin release with the secretory signals initiated by the ingestion of fuels However, signals from the central nervous system are not required for insulin secretion Certain amino acids also can stimulate insulin secretion, although the amount of insulin released during a high-protein meal is very much lower than that released by a high-carbohydrate meal Gastric inhibitory polypeptide (GIP) and glucagonlike peptide (GLP-1), gut hormones released after the ingestion of food, also aid in the onset of insulin release Epinephrine, secreted in response to fasting, stress, trauma, and vigorous exercise, decreases the release of insulin Epinephrine release signals energy utilization, which indicates that less insulin needs to be secreted, as insulin stimulates energy storage D Synthesis and Secretion of Glucagon Glucagon, a polypeptide hormone, is synthesized in the α-cells of the pancreas by cleavage of the much larger preproglucagon, a 160–amino acid peptide Like insulin, preproglucagon is produced on the RER and is converted to proglucagon as it enters the endoplasmic reticulum (ER) lumen Proteolytic cleavage at various sites produces the mature 29–amino acid glucagon (molecular weight 3,500) and larger glucagon-containing fragments (named glucagonlike peptides and 2) Glucagon is rapidly metabolized, primarily in the liver and kidneys Its plasma half-life is only about to minutes Glucagon secretion is regulated principally by circulating levels of glucose and insulin Increasing levels of each inhibit glucagon release Glucose probably has both a direct suppressive effect on secretion of glucagon from the α-cell as well as an indirect effect, the latter being mediated by its ability to stimulate the release 9/16/14 2:04 AM Glucose (mg/dL) Highprotein meal Nitrogen 90 85 Glucose 20 Insulin 10 Glucagon (pg/mL) 200 Glucagon 180 337 Insulin (U/mL) ␣-Amino nitrogen (mg/dL) CHAPTER 21 ■ BASIC CONCEPTS IN THE REGULATION OF FUEL METABOLISM 160 140 120 100 –60 60 120 180 240 Minutes FIG 21.9 Release of insulin and glucagon in response to a high-protein meal This figure shows the increase in the release of insulin and glucagon into the blood after an overnight fast followed by the ingestion of 100 g protein (equivalent to a slice of roast beef) Insulin levels not increase nearly as much as they after a high-carbohydrate meal (see Fig 21.5) The levels of glucagon, however, significantly increase above those present in the fasting state of insulin The direction of blood flow in the islets of the pancreas carries insulin from the β-cells in the center of the islets to the peripheral α-cells, where it suppresses glucagon secretion Conversely, certain hormones stimulate glucagon secretion Among these are the catecholamines (including epinephrine) and cortisol Many amino acids also stimulate glucagon release (Fig 21.9) Thus, the high levels of glucagon that would be expected in the fasting state not decrease after a high-protein meal In fact, glucagon levels may increase, stimulating gluconeogenesis in the absence of dietary glucose The relative amounts of insulin and glucagon in the blood after a mixed meal depend on the composition of the meal, because glucose stimulates insulin release and amino acids stimulate glucagon release However, amino acids also induce insulin secretion but not to the same extent that glucose does Although this may seem paradoxical, it actually makes good sense Insulin release stimulates amino acid uptake by tissues and enhances protein synthesis However, because glucagon levels also increase in response to a protein meal and the critical factor is the insulin to glucagon ratio, sufficient glucagon is released that gluconeogenesis is enhanced (at the expense of protein synthesis), and the amino acids that are taken up by the tissues serve as a substrate for gluconeogenesis The synthesis of glycogen and triglycerides is also reduced when glucagon levels rise in the blood IV MECHANISMS OF HORMONE ACTION For a hormone to affect the flux of substrates through a metabolic pathway, it must be able to change the rate at which that pathway proceeds by increasing or decreasing the rate of the slowest step(s) Either directly or indirectly, hormones affect the activity of specific enzymes or transport proteins that regulate the flux through a pathway Thus, ultimately, the hormone must either cause the amount of the substrate for the enzyme to increase (if substrate supply is a rate-limiting factor), change the conformation at the active site by phosphorylating the enzyme, change the concentration of Lieberman_Ch21.indd 337 Patients with type diabetes mellitus, such as Dianne A., have almost undetectable levels of insulin in their blood Patients with type diabetes mellitus, such as Deborah S., conversely, have normal or even elevated levels of insulin in their blood; however, the level of insulin in their blood is inappropriately low relative to their elevated blood glucose concentration In type diabetes mellitus, skeletal muscle, liver, and other tissues exhibit a resistance to the actions of insulin As a result, insulin has a smaller than normal effect on glucose and fat metabolism in such patients Levels of insulin in the blood must be higher than normal to maintain normal blood glucose levels In the early stages of type diabetes mellitus, these compensatory adjustments in insulin release may keep the blood glucose levels near the normal range Over time, as the β-cells’ capacity to secrete high levels of insulin declines, blood glucose levels increase, and exogenous insulin becomes necessary 9/16/14 2:04 AM 338 SECTION V ■ CARBOHYDRATE METABOLISM During the “stress” of hypoglycemia, the autonomic nervous system stimulates the pancreas to secrete glucagon, which tends to restore the serum glucose level to normal The increased activity of the adrenergic nervous system (through epinephrine) also alerts a patient, such as Connie C., to the presence of increasingly severe hypoglycemia Hopefully, this will induce the patient to ingest simple sugars or other carbohydrates, which, in turn, will also increase glucose levels in the blood Connie C gained lb before resection of her pancreatic insulinsecreting adenoma through this mechanism an allosteric effector of the enzyme, or change the amount of the protein by inducing or repressing its synthesis or by changing its turnover rate or location Insulin, glucagon, and other hormones use all of these regulatory mechanisms to regulate the rate of flux in metabolic pathways The effects mediated by phosphorylation or changes in the kinetic properties of an enzyme occur rapidly within minutes In contrast, it may take hours for induction or repression of enzyme synthesis to change the amount of an enzyme in the cell The details of hormone action were previously described in Chapter and are only summarized here A Signal Transduction by Hormones that Bind to Plasma Membrane Receptors Hormones initiate their actions on target cells by binding to specific receptors or binding proteins In the case of polypeptide hormones (such as insulin and glucagon) and catecholamines (epinephrine and norepinephrine), the action of the hormone is mediated through binding to a specific receptor on the plasma membrane The first message of the hormone is transmitted to intracellular enzymes by the activated receptor and an intracellular second messenger; the hormone does not need to enter the cell to exert its effects (In contrast, steroid hormones such as cortisol and the thyroid hormone triiodothyronine [T3] enter the cytosol and eventually move into the cell nucleus to exert their effects.) The mechanism by which the message carried by the hormone ultimately affects the rate of the regulatory enzyme in the target cell is called signal transduction The three basic types of signal transduction for hormones binding to receptors on the plasma membrane are (a) receptor coupling to adenylate cyclase which produces cyclic adenosine monophosphate (cAMP), (b) receptor kinase activity, and (c) receptor coupling to hydrolysis of phosphatidylinositol bisphosphate (PIP2) The hormones of metabolic homeostasis each use one of these mechanisms to carry out their physiological effect In addition, some hormones and neurotransmitters act through receptor coupling to gated ion channels (previously described in Chapter 8) SIGNAL TRANSDUCTION BY INSULIN Insulin initiates its action by binding to a receptor on the plasma membrane of insulin’s many target cells (see Fig 8.12) The insulin receptor has two types of subunits: the α-subunits to which insulin binds, and the β-subunits, which span the membrane and protrude into the cytosol The cytosolic portion of the β-subunit has tyrosine kinase activity On binding of insulin, the tyrosine kinase phosphorylates tyrosine residues on the β-subunit (autophosphorylation) as well as on several other enzymes within the cytosol A principal substrate for phosphorylation by the receptor, insulin receptor substrate (IRS-1), then recognizes and binds to various signal transduction proteins in regions referred to as SH2 domains IRS-1 is involved in many of the physiological responses to insulin through complex mechanisms that are the subject of intensive investigation The basic tissue-specific cellular responses to insulin, however, can be grouped into five major categories: (a) insulin reverses glucagon-stimulated phosphorylation, (b) insulin works through a phosphorylation cascade that stimulates the phosphorylation of several enzymes, (c) insulin induces and represses the synthesis of specific enzymes, (d) insulin acts as a growth factor and has a general stimulatory effect on protein synthesis, and (e) insulin stimulates glucose and amino acid transport into cells (Fig 21.10) Several mechanisms have been proposed for the action of insulin in reversing glucagon-stimulated phosphorylation of the enzymes of carbohydrate metabolism From the student’s point of view, the ability of insulin to reverse glucagon-stimulated phosphorylation occurs as if it were lowering cAMP and stimulating phosphatases that could remove those phosphates added by protein kinase A In reality, the mechanism is more complex and still not fully understood Lieberman_Ch21.indd 338 9/16/14 2:04 AM 608 INDEX Cyclooxygenase inhibition of, 443–444, 454 pathway, 440–444, 441f properties of, 444t CYP2E1, 383–385, 383f Cystathionase, 521, 523 deficiency of, 523–524 Cystathionine formation of, 521, 521f, 551–552, 551f serum levels, 523 Cystathionine β-synthase action of, 521–522 defect/deficiency, 523–525, 540–541, 552 Cystathioninuria, 521 Cysteine biosynthesis, 520–523, 520f, 521f degradation of, 523 structure of, 48f, 50–51 in urea cycle, 498 Cystic fibrosis (CF), case study, 208, 221–222, 222t, 496–497, 501–502, 501t Cystic fibrosis transmembrane conductance regulator (CFTR), 117, 128, 130, 208, 221 Cystine, 522 Cystinosis, 522 Cystinuria, 496, 498, 502, 522 Cytidine triphosphate (CTP), 562 Cytochrome b-c1 complex, 277 Cytochrome c, 277 Cytochrome oxidase, 280 Cytochrome P450 enzymes arachidonic acid metabolism and, 440, 441f drug interactions of, 384 in ethanol metabolism, 383–384, 383f free radical generation by, 287 induction of, 384 location of, 120 steroid hormone synthesis, 476, 477f structure of, 384f Cytochromes, 280, 280f Cytoplasm, 114 Cytosine base pairing of, 137, 137f degradation of, 565 methylation of, 195 nucleoside, 135t structure of, 135, 135f, 136f Cytoskeleton, 121 Cytosol, Cytosolic acetyl CoA, 435–436, 435f D Daily energy expenditure (DEE), 12–14, 13t DBH See Dopamine β-hydroxylase ddC See Dideoxycytidine ddI See Didanosine; Dideoxyinosine Death receptor pathway, 234–235, 235f Debrancher enzyme, 361–362, 362f, 364–365 DEE See Daily energy expenditure Dehydroepiandrosterone (DHEA), 478 Deletions, 181, 215 δ-ALA See δ-Aminolevulinic acid δ-ALA dehydratase, 537, 537f, 538f δ-ALA synthase, 537–538, 537f, 538f δ-Aminolevulinic acid (δ-ALA), 537–538, 538f Denaturation, protein, 72–73 Dental disease, case study, 298, 303, 309, 309t Deoxyribonuclease I (DNase I), 175 Deoxyribonucleic acid See DNA Deoxyribonucleotides, production of, 563–564 Deoxyribose from ribose, 563 structure of, 135f Deoxythymidine monophosphate (dTMP), 546–547, 547f Deoxyuridine monophosphate (dUMP), 546, 547f Lieberman_Subject_Index.indd 608 Deprenyl, 533 Dermatan sulfate, 399, 400f Desaturation of fatty acids, 438–439, 439f Dextrose, 36 DFP See Diisopropyl phosphofluoridate DHA See Docosahexaenoic acid DHAP See Dihydroxyacetone phosphate DHEA See Dehydroepiandrosterone DHFR See Dihydrofolate reductase DHPR See Dihydropteridine reductase Diabetes mellitus complications of, 420 diagnosis of, 29, 406 MODY, 98, 110t, 336, 341t neuroglycopenic symptoms, 415, 419–420 peripheral neuropathy, 376 type See Type diabetes mellitus type See Type diabetes mellitus Diabetic ketoacidosis (DKA), 22, 27, 29, 32–33, 43–44, 312, 325, 327, 406–407, 420t, 483, 492 Diabetic neuropathy, 420 Diabetic retinopathy, 420 Diacylglycerols, 40, 445, 446f, 449, 450f, 451 Didanosine (ddI), 150, 175 Dideoxycytidine (ddC), 175 Dideoxyinosine (ddI), 175 Dietary carbohydrates See Carbohydrates Dietary deficiency, vitamin, 86 Dietary fiber, 344, 350f, 351 Dietary fuels, 3–4, 4f, 5f Dietary requirements and guidelines, 14 carbohydrate, 14 essential fatty acids, 14–15 guidelines, 17 minerals, 16–17 protein, 15 essential amino acids, 15 nitrogen balance, 15–16 vitamins, 16 water, 17 xenobiotics, 17 Dietary therapy of elevated blood cholesterol, 458, 458t Diets, 12, 14 Diffusion, 117, 117f Digestion, 7, 7t Dihydrobiopterin, 523 Dihydrofolate (FH2), 546 Dihydrofolate reductase (DHFR), 546, 547f Dihydropteridine reductase (DHPR), 529 Dihydroxyacetone phosphate (DHAP) ether glycerolipids from, 451 from glycerol, 408, 408f, 410, 411f in glycolysis, 299, 300f, 445 1,25-Dihydroxy cholecalciferol (calcitriol), 479, 479f Diisopropyl phosphofluoridate (DFP), 90, 91f Dimethylallyl pyrophosphate from mevalonate, 460, 460f squalene from, 461, 461f Dimethyl glycine, 552, 552f Dinitrophenol (DNP), 284f Diphtheria, 184 Diploid, 140, 172 Disaccharidases, of intestinal brush border β-glycosidase, 349, 349f forms of, 348t glucoamylase, 347–348, 348f location within intestine, 349 membrane, 347–349, 348f, 349f sucrase–isomaltase, 348, 348f trehalase, 348–349, 349f Disaccharides of glycosaminoglycans, 399, 400f structure of, 37, 38f Dissociation constant (Kd), 67, 98 Dissociation of acids, 25, 25f Dissociation of water, 24 Disulfide bond, 50, 50f DKA See Diabetic ketoacidosis D-loop, tRNA, 171, 171f DNA cDNA, 157–158, 158f, 209 chemical synthesis of, 209–210 chromatin, 134, 140, 195 cloning of, 213–214, 214f damage leading to mutations chemical and physical alterations, 227–228 gain-of-function mutations, 228–229, 228f repair enzyme mutations, 229 differences in size between eukaryotic and prokaryotic DNA, 172–173, 174t gene expression See Gene expression genes See Genes genetic code, 178–180, 179t genome, 140–141 oxygen radical reactions with, 288 packing of, 139–140 polymorphisms, 215–218, 217f recombinant See Recombinant DNA techniques repair of, 155–156, 155f base excision repair, 156–157, 156f mismatch repair, 157, 157f nucleotide excision repair, 156, 156f transcription-coupled repair, 157 repetitive sequences, 172–173, 173f, 216–217, 217f sequencing of, 211–213, 212f structure of antiparallel strands, 137, 138f base-pairing, 137 bases, 135, 135f, 135t characteristics of DNA, 139, 139f chromosomes, 139–141, 140f, 141f determination of, 135–137, 135f, 136f double helix, 138–139, 138f location of DNA, 134–135 synthesis in eukaryotes, 152 cell cycle, 152, 152f DNA polymerase, 153 origin of replication, 152–153, 153f proteins involved in replication, 154t replication at ends of chromosomes, 154–155, 154f, 155f replication complex, 153–154, 153f, 154t synthesis in prokaryotes, 148, 148f base-pairing errors, 150–151 bidirectional replication, 148, 149f DNA ligase, 151, 151f DNA polymerase action, 149–150, 150f, 150t DNA unwinding, 149 replication fork, 151, 151f replication forks, 148, 149f RNA primer requirement, 151, 151f semiconservative replication, 148–149, 148f, 149f DNA-binding proteins, 60, 199–200 DNA chips, 217–218 DNA fingerprinting, case study, 208, 214, 217, 222 DNA ligase, 151, 151f DNA methylation, 195 DNA polymerases action of, 149–150, 150f, 150t eukaryotic, 153, 153f in PCR, 214–215, 215f DNase I See Deoxyribonuclease I DNP See Dinitrophenol Docosahexaenoic acid (DHA), 14 9/16/14 9:17 PM INDEX Dolichol phosphate, 396, 397f Domains, in tertiary structure, 64, 64f Dopamine, 34, 34f synthesis of, 530–532, 531f Dopamine β-hydroxylase (DBH), 531 Double helix, of DNA, 138–139, 138f Double minutes, 196 Double reciprocal plot, 98–99, 98f, 99f Downregulation, 128 Downstream events, 125 Downstream sequences, 164 Doxorubicin (Adriamycin), 139 dTMP See Deoxythymidine monophosphate dUMP See Deoxyuridine monophosphate Dystrophin, 116 E EBV See Epstein–Barr virus ECF See Extracellular fluid ECM See Extracellular matrix Edrophonium chloride, 123 EF1 See Elongation factor Eicosanoids, 14–15, 440 sources of, 440, 441f synthesis of, 440 overview, 441f pathways, 440–441, 441f prostaglandins, 440, 441f, 442–444, 442f, 443f thromboxanes, 440, 441f, 442–444, 443f Eicosapentaenoic acid (EPA), 14 eIF2 See Eukaryotic initiation factor Elastase, 497–498, 497f Electrochemical potential gradient, 277 Electrolytes, 16, 23, 23t Electronic strain, 84 Electron transfer flavoprotein–CoQ oxidoreductase (ETF-QO), 316–317 Electron-transfer flavoproteins (ETF), 279, 279f, 316–317 Electron transport chain, 278, 279f coenzyme Q, 279, 279f copper and reduction of oxygen, 279f, 280 energy yield from, 281 inhibition, 281, 281t NADH dehydrogenase, 278, 279f oxidative phosphorylation and, 276–277 Electrophiles, 89 Electrophoresis, 50, 57f Elements, 161 Elongation factor (EF1), 182–184, 182f, 183f Endocrine hormones, 6–7, 6f, 123, 123f Endocrine organ, adipose tissue as, 452–453 Endocrine pancreas, 334 Endocytosis, 117, 117f receptor-mediated, of lipoproteins, 471–472, 472f Endoglucosidase, 346 Endoglycosidases, 402 Endopeptidases, 497 Endoplasmic reticulum (ER), 119–120, 120f, 396, 397f Endoscopic retrograde cholangiopancreatography (ERCP), 431 Endothermic reactions, 243–245 Energetics, of TCA cycle, 263–265, 264f Energy See also Bioenergetics available to work, 242–245, 242f, 243f, 244t, 245f free energy change during reactions, 243, 244t from fuel oxidation, 250–253 transformations to work, 245–246 Energy balance, 254 Energy diagram, 81f, 85, 86f Energy yield of anaerobic glycolysis, 303 Lieberman_Subject_Index.indd 609 from electron transport chain, 281 of β-oxidation, 316 of ethanol oxidation, 385 Enoyl hydratase, 316 Enterohepatic circulation bile salts and, 426–427, 427f, 465, 465f folate deficiency and, 543 Enteropeptidase, 497f Enthalpy, 246 Entropy, 243 Enzyme regulation amount of enzyme, 107 regulated degradation, 108 regulated synthesis, 107–108 conformational changes, 102 in allosteric enzymes, 102–103, 103f from covalent modification, 103–104, 103f protein-protein interactions, 104–105 proteolytic cleavage, 105–107, 106f metabolic pathways, 108, 108f counterregulation of opposing pathways, 109 feedback regulation, 108f, 109 feed-forward regulation, 109 rate-limiting step, 108, 108f substrate channeling through compartmentation, 109 tissue isozymes, 109 reversible inhibition, 100 competitive inhibition, 100, 101f noncompetitive inhibition, 100–101, 101f simple product inhibition, 101 velocity and substrate concentration, 97 hexokinase isozymes, 99, 99f Lineweaver-Burk transformation, 98–99, 98f, 99f Michaelis-Menten equation, 97–98, 98f multisubstrate reactions, 100 rates of enzyme-catalyzed reactions, 100 Enzymes See also Coenzymes; specific enzymes catalysis, functional groups in, 85 amino acid side chains, 85, 86t coenzymes, 85–90 chymotrypsin, catalytic mechanism of, 81–84, 81f, 82f, 83f, 85f digestion by, enzyme-catalyzed reaction, 78 active site, 79, 79f substrate binding sites, 79–81, 80f transition state complex, 81, 81f inhibitors of, 90 covalent, 90, 91f heavy metals, 92 transition state analogues, 90–91, 92f, 93f optimum pH and temperature, 90 proteins as, EPA See Eicosapentaenoic acid Epigenetics, 195 Epimerases, 36 action of, 394 in pentose phosphate pathway, 379–380, 379f, 381f Epimerization, of UDP-glucose to UDP-galactose, 394 Epimers, 36, 36f galactose and glucose, 394 Epinephrine, 330, 332 cAMP and, 110 physiological actions, 333t, 334f in regulation of liver glycogen levels, 367–368 signal transduction, 340–341 skeletal muscle glycogenolysis, 364 structure of, 340f synthesis of, 530–532, 531f Epstein–Barr virus (EBV), 238 609 ER See Endoplasmic reticulum ERCP See Endoscopic retrograde cholangiopancreatography Erythromycin, 183, 185 Erythrose 4-phosphate, 380, 380f, 381f E (ejection) site, 182–185, 182f, 183f, 184f Essential amino acids, 15, 519, 519t Essential fatty acids, 14–15 Essential fructosuria, 375, 376 Esterases, 119, 426, 426f Estrogen HDL level increase from, 475 replacement therapy, 475 synthesis of, 477f, 478–479 ETF See Electron-transfer flavoproteins ETF-QO See Electron transfer flavoprotein–CoQ oxidoreductase Ethanol, 381–382 See also Alcoholism as dietary fuel, HDL level increase from, 475 metabolism of, 381–385, 383f, 384f NADH/NADϩ ratio and, 408 toxic effects of, 385–387, 386f oxidation of, 89, 94, 97, 100 phenobarbital interactions, 384 Ether glycerophospholipids, 448–449, 449f, 451 Ether lipids, 119 Euchromatin, 195 Eukaryotic cells cell components of cytoskeleton, 121 endoplasmic reticulum, 119–120, 120f Golgi complex, 120 lysosomes, 119 mitochondria, 118–119, 118f nucleus, 114, 119, 120f peroxisomes, 119 compartmentation in, 114–121 DNA synthesis in, 152 cell cycle, 152, 152f DNA polymerase, 153 origin of replication, 152–153, 153f replication at ends of chromosomes, 154–155, 154f, 155f replication complex, 153–154, 153f, 154t gene expression in, 193 availability of genes for transcription, 195–196 chromatin remodeling, 195, 195f DNA-binding proteins, structure of, 199–200 DNA methylation, 195 gene amplification, 196 gene deletions, 196 gene rearrangement, 195–196, 196f gene-specific regulatory proteins, 198–199 at multiple levels, 194–195 multiple regulators of promoters, 201–202, 201f posttranscriptional processing of RNA, 202 transcription factor regulation, 200–201 transcription factors, 198–199, 199f at transcription level, 196–202, 197f at translation level, 202–204, 202f, 203f plasma membrane of lipids, 115–116, 115f proteins, 115–116, 115f structure of, 114–115, 115f transport across, 117, 117f promoters, 164–166, 164f regulation of gene expression, 193 repetitive DNA sequences, 172–173, 173f structure of, 114, 114f, 115f 9/16/14 9:17 PM 610 INDEX Eukaryotic cells (continued) transcription in, 167 mRNA synthesis, 167–169, 167f, 168f, 169f rRNA synthesis, 169–170, 170f tRNA synthesis, 170–172, 171f, 172f Eukaryotic initiation factor (eIF2), 182 Exercise blood glucose levels during, 419 case study, 242, 245, 254, 255t, 258–259, 261, 264–265, 272, 272f, 298, 306, 309, 309t, 312, 316, 320, 326 glycogenolysis stimulation by, 368–369, 369f HDL level increase from, 475 Exergonic, 244 Exoglucosidase, 348 Exoglycosidases, 402 Exons, 167–169, 168f, 169f Exopeptidases, 498 Exothermic reactions, 243–245 Extracellular domains, membrane protein, 124 Extracellular fluid (ECF), 22, 22f Extracellular matrix (ECM), 398–399, 473–474, 474f collagen in, 70 Ezetimibe, 458, 469, 480 F F6P See Fructose 6-phosphate Fabry disease, 398 Facilitative diffusion, 117, 117f Factor VIII, 219 FAD See Flavin adenine dinucleotide Familial combined hyperlipidemia (FCH), 434, 445, 453–455 Familial hypercholesterolemia (FH), 473, 479–480, 480t Farnesyl pyrophosphate, 461, 461f Fasting state, amino acids metabolism in tissues, 570f, 571 release from skeletal muscle, 569, 570f basal state, 9, 10f blood glucose levels in gluconeogenesis stimulation, 417 glycogenolysis stimulation, 417 insulin and glucagon levels, 416 lipolysis stimulation, 417, 418f in starvation, 417–419, 419f fatty acid release from adipose triacylglycerols, 448, 448f fuel concentration changes, in prolonged fast, 12f fuel utilization by various tissues, 489t function of urea cycle during, 512 metabolic changes in brief fast, 9–11, 10f in prolonged fast, 11–12, 11f, 12f regulation of carbohydrate and lipid metabolism blood glucose levels, maintenance of, 487, 488f glucose and fatty acid use by muscle, 488–489 ketone body production by liver, 487–488 lipolysis in adipose tissue, 487, 489f starved state, 11, 11f tissue interrelationships during, 418f Fats as body fuel store, 4–6, 5t as dietary fuel, 4, 5f dietary recommendation, 424 Fat-soluble vitamin deficiency, 428 Fatty acids absorption of, 426–427 composition of human milk, 424 Lieberman_Subject_Index.indd 610 essential, 14–15, 439 during fasting, 12f as fuels, 312–313 β-oxidation of long-chain fatty acids, 316–319, 317f, 318f, 319f characteristics of, 313 fuel homeostasis role of, 324–326, 324f, 325f ω-oxidation, 321–322, 322f oxidation inhibition by malonyl CoA, 437–438, 438f oxidation of medium-chain fatty acids, 319 peroxisomal oxidation, 320–321, 321f regulation of β-oxidation, 319–320, 320f transport and activation of long-chain fatty acids, 313–316, 314f, 314t, 315f ketone bodies conversion from, 11 in micelles, 426 NADH/NADϩ ratio effect on metabolism, 385–386, 386f preferential utilization of, 325–326 regulation of metabolism, 330 release from adipose triacylglycerols, 447, 447f from chylomicrons, 430–431 in fasting state, 417, 418f saturated, 38, 39f synthesis of, 435 conversion of acetyl CoA to malonyl CoA, 436, 436f, 437f conversion of glucose to cytosolic acetyl CoA, 435–436, 435f desaturation of fatty acids, 438–439, 439f elongation of fatty acids, 438 fatty acid synthase complex, action of, 436–438, 437f, 438f trans, 39 in triacylglycerols, 4, 5f unsaturated, 38–39, 39f, 313, 318–319, 318f for VLDL synthesis, 445, 447 Fatty acid synthase complex action, 436–438, 437f, 438f regulation of, 484f, 485–486 Fatty acylation, 54, 55f, 186 Fatty acylcarnitine, 315, 315f Fatty acyl CoAs, 314 Fatty streak, 474 FCH See Familial combined hyperlipidemia Fed state absorption, digestion, and fate of nutrients in, amino acids, 6f, glucose, 6f, 7–8, 7f, 7t, 9f lipoproteins, 6f, 8–9 blood glucose levels in, 415–416, 416f, 417f fate of glucose in liver, 416, 417f fate of glucose in peripheral tissues, 416, 417f return to fasting levels, 416 changes in hormone levels after meal, 6–7, 6f regulation of carbohydrate and lipid metabolism chylomicrons and VLDLs, 486 glycogen and triacylglycerol synthesis in liver, 483–487, 483f, 484f, 485f, 486f triacylglycerol storage in adipose tissue, 486–487, 486f Feedback regulation, 108f, 109 Feed-forward regulation, 109 FEN1 See Flap endonuclease Ferritin, 190, 203, 203f Ferrochelatase, 537, 537f FH See Familial hypercholesterolemia FH2 See Dihydrofolate FH4 See Tetrahydrofolate Fiber, dietary, 350f, 351 Fibrous cap, 475 Fibrous proteins, 60, 60f, 70–72 Fish oils, 14 Flap endonuclease (FEN1), 154 Flavin adenine dinucleotide (FAD) in glycerol 3P shuttle, 301–302, 301f oxidation of, 88, 250–251, 252f, 316–317 in TCA cycle, 258, 259f, 261, 262f Flavin mononucleotide (FMN), 261, 262f Flavonoids, 292 Flavoproteins, 278–279, 279f Fluid compartments in body, 22, 22f 5-Fluorouracil (5-FU), 134, 141, 141f, 145, 565 FMN See Flavin mononucleotide Foam cells, 473–474 Folate See also Tetrahydrofolate deficiency of, 543, 544, 552–553 RDA, 544 reduction to tetrahydrofolate, 544f relationships with vitamin B12 and SAM, 550–552, 551f as vitamin, 544, 544f Folds, in globular proteins, 64 Food caloric value of, 253 glycemic index of, 351–352 Fragile X syndrome, 196, 205t Frameshift mutation, 181, 181f Free energy, 243, 244t, 246 adding values, 246–248, 247f, 247t, 248f substrate and product concentrations, 248–249 Free radicals, 42–43, 285–286 scavengers of, 291–293 Friedewald formula, 457 Fructokinase action of, 374–375 deficiency of, 375 Fructose, 374 absorption of, 353 dietary, 3, 344 essential fructosuria, 375, 376 malabsorption of, 355–356, 355t metabolism of, 374–375, 374f synthesis in polyol pathway, 375–376, 375f Fructose 1,6-bisphosphate, 299, 300f conversion to fructose 6-phosphate, 410, 411f, 412, 414 from phosphoenolpyruvate, 410, 411f Fructose 1-phosphate, 374–375 Fructose 2,6-bisphosphate regulation of PFK-1 by, 307 switch between catabolic and anabolic pathways and, 489–490 Fructose 6-phosphate (F6P) conversion to glucose-6-phosphate, 411, 411f from fructose 1,6-bisphosphate, 410, 411f, 412, 414 in glycolysis, 299, 300f in pentose phosphate pathway, 380, 380f, 381f 5-FU See 5-Fluorouracil Fuel fatty acids as, 312–320 fuel homeostasis role of fatty acids and ketone bodies, 324–326, 324f, 325f oxidation of ketone bodies as, 322–323, 323f Fuel metabolism, 2–3 body fuel stores, 4, 5t fat, 4–6, 5t glycogen, 4–5 protein, 4–5 daily energy expenditure, 12 healthy body weight, 13–14 9/16/14 9:17 PM INDEX physical activity, 13 resting metabolic rate, 12–13, 13t weight gain and loss, 14 dietary fuels, alcohol, carbohydrates, 3, 4f fats, 4, 5f proteins, 3, 4f dietary requirements and guidelines, 14 carbohydrate, 14 essential fatty acids, 14–15 guidelines, 17 minerals, 16–17 protein, 15–16 vitamins, 16 water, 17 xenobiotics, 17 energy from oxidation, 250–253 fasting state, metabolic changes in brief fast, 9–11, 10f metabolic changes in prolonged fast, 11–12, 11f, 12f fed state, absorption, digestion, and fate of nutrients, 7–9, 7f, 7t changes in hormone levels after meal, 6–7 Fumarate, 509f, 510, 510f Fumarylacetoacetate hydrolase, 529 Functional deficiency, vitamin, 86 Functional groups, 32–33, 33f charge carrying, 33–34, 34f oxidized and reduced, 33, 33f Furanose rings, 37f G G0 phase, 152, 152f G1P See Glucose-1-phosphate G1 phase, 152, 152f G2 phase, 152, 152f G6P See Glucose-6-phosphate GABA See γ-Aminobutyric acid G-actin, 64f GAGs See Glycosaminoglycans Galactitol, 376, 377 Galactocerebroside, 452, 453f Galactokinase action of, 376, 376f deficiency of, 377 Galactose absorption of, 353 accumulation of and cataracts, 376 as epimer of glucose, 36, 36f glucose conversion to, 394, 394f metabolism to glucose-1-phosphate, 376–377, 376f structure of, 345f Galactose 1-phosphate from galactose, 376, 376f inhibition of phosphoglucomutase by, 394–395 Galactose 1-phosphate uridylyltransferase action of, 376–377, 376f deficiency of, 388, 394 Galactosemia, 376f, 377, 388 case study, 373, 376–377, 388–389, 393 Galactosyltransferase, 394, 394f Gallstones, 425, 431 GalNAc See N-acetylgalactosamine γ-Aminobutyric acid (GABA) blood levels in hepatic failure, 511 function of, 536 recycling of, 577f, 578 synthesis of, 536, 536f Gangliosides defects in degradation, 398, 399t Lieberman_Subject_Index.indd 611 structure of, 396, 397f synthesis of, 452, 453f Gangliosidoses, 398, 399t Gastric inhibitory polypeptide (GIP), 336 Gated channels, 117, 117f Gaucher disease, 398 GCC triplet, 196 GC islands, 195 Gel electrophoresis, 210–211, 211f Gene chips, 218 Gene expression eukaryotic regulation of, 193 availability of genes for transcription, 195–196 chromatin remodeling, 195, 195f DNA-binding proteins, structure of, 199–200 DNA methylation, 195 gene amplification, 196 gene deletions, 196 gene rearrangement, 195–196, 196f gene-specific regulatory proteins, 198–199 at multiple levels, 194–195 multiple regulators of promoters, 201–202, 201f posttranscriptional processing of RNA, 202 transcription factor regulation, 200–201 transcription factors, 198–199, 199f at transcription level, 196–202, 197f at translation level, 202–204, 202f, 203f overview, 190 prokaryotic regulation of, 190–191 corepressors, 192–193, 193f operons, 191–193, 191f, 192f, 193f, 194f repressors, 191–193 RNA polymerase binding stimulation, 193, 194f General transcription factors, 165, 196 Genes, 141, 161 alteration in sequence of, 227–228 amplification of, 195–196 through mutation, 228f, 229 deletion of, 195–196 p53, 232–233, 233f promoter regions of, for mRNA, 164–166 rearrangements of, 195–196, 196f through mutation, 228–229, 228f recognition of, by RNA polymerase, 164 regions of, 161, 162f retinoblastoma, 232, 232f sequences of, 162–164, 163f tumor suppressor, 231 cell cycle regulation by, 232–233, 232f, 233f receptors and signal transduction, 233–234 Gene-specific transcription factors, 124, 166, 198 Gene therapy, 220, 513, 540 Genetic code, 178–180, 179t Genetic counseling, 219–220 Genetic disorders of amino acid metabolism, 529t of oxidative phosphorylation, 283 Genetic locus, 141 Genome, 140–141 Genomic imprinting, 195 Genomic library, 213 Geranyl pyrophosphate, 461, 461f Gerstmann-Sträussler-Scheinker disease, 73 GIP See Gastric inhibitory polypeptide Glipizide, 336 Globin fold, 66f, 68 Globosides, 452, 453f 611 Globular proteins, 60, 60f folds in, 64 solubility, 65 GLP See Glucagonlike peptides and Glucagon anorexia nervosa and, 121, 130 cAMP and, 110, 487, 489f following meal, 6–7, 6f gluconeogenesis and, 578–579 metabolic homeostasis and, 330–333 physiological actions, 333t, 334f regulation of liver glycogen metabolism, 365–366, 365f repression of glucokinase by, 483, 483f signal transduction, 339–340, 339f synthesis and secretion, 336–337, 337f Glucagonlike peptides and 2, 336 Glucoamylase, 347–348, 348f, 348t Glucocorticoid, effect on protein metabolism, 569 Glucocorticoid receptor, 198 Glucokinase action of, 299 effect on insulin secretion, 98 glucose binding site in, 80, 80f Km values, 99, 102 regulation of, 483, 483f Gluconeogenesis, 406–407, 407f alanine and, 512 alcohol metabolism effect on, 408 amino acids and, 570, 572 anorexia nervosa and, 121, 130 energy requirements, 414 during fasting, 9–10 glucose-6-phosphate and, 360 inhibition of, 375 intermediates, formation from carbon sources, 408, 408f NADH/NADϩ ratio effect on, 409 pathway, 408 fructose 1,6-bisphosphate to fructose, 410, 411f glucose-6-phosphate to glucose, 411, 411f PEP to fructose 1,6-bisphosphate, 410, 411f pyruvate to phosphoenolpyruvate, 409–410, 409f, 410f precursors for, 407 regulation of, 364, 411–412, 413t conversion of fructose 1,6-bisphosphate to fructose 6-phosphate, 412 conversion of glucose-6-phosphate to glucose, 412 conversion of pyruvate to PEP, 412 enzyme activity or amount, 412, 413f, 413t during fasting, 487, 488f substrate availability, 412 stimulation of, 487 in fasting state, 417 by glucagon, 337, 578–579 Glucosamine 6-phosphate, 395, 395f Glucose See also Glycolysis blood See Blood glucose conversion of glucose-6-phosphate to, 411, 411f, 412, 414 conversion of PEP and glycerol to, 411, 411f conversion to fructose, 375–376, 375f conversion to galactose, 394, 394f dietary, 3, 344 epimers of galactose, 36, 36f mannose, 36, 36f during fasting, 9–10, 12f fate in fed state, 6f, 7–8, 7f, 7t, 9f glucokinase binding site of, 80, 80f 9/16/14 9:17 PM 612 INDEX Glucose (continued) lactose formation from, 394, 394f metabolism in liver, 406 structure of, 35–36, 35f, 36f, 345f transport through blood–brain barrier and into neurons, 354–355, 355f Glucose-1-phosphate (G1P) from glucose-6-phosphate, 245, 245f in glycogen synthesis, 359–362, 360f Glucose-6-phosphate (G6P) as branch point in carbohydrate metabolism, 299f conversion to glucose, 411, 411f, 412, 414 deficiency, 366 from fructose 6-phosphate, 411, 411f glucose-1-phosphate from, 245, 245f in glycogen synthesis, 359–360 in glycolysis, 299, 299f, 300f hexose monophosphate shunt, 379 in pentose phosphate pathway, 377, 378f, 379, 381f Glucose-6-phosphate dehydrogenase deficiency of, 389 inhibition of, 381 in pentose phosphate pathway, 377, 378f regulation of, 484–485, 484f synthesis of, 381 Glucose–alanine cycle, 508, 508f, 575–576, 575f Glucose intolerance, 417 Glucose transporters (GLUT), 334, 352–353, 353t, 354f, 488–489 Glucosidase, 362 Glucuronate, formation of, 393–394, 393f Glucuronides, 393–394, 393f GLUT See Glucose transporters Glutamate biosynthesis of, 520f, 522–523, 522f deamination of, 505–506, 506f from α-ketoglutarate, 505, 505f, 507, 507f role of in amino acid synthesis, 507, 507f in metabolism of amino acid nitrogen, 507, 507f as neurotransmitter, 535 in urea production, 507, 507f structure of, 48f, 50 synthesis of, 535–536, 536f in brain, 577–578, 577f Glutamate dehydrogenase, 505–507, 506f Glutaminase, 507, 536, 578 Glutamine amino acid nitrogen transport to liver, role in, 508, 508f BCAA conversion to, 574–575, 574f, 575f biosynthesis, 520f, 522f deamidation of, 506f, 507 functions of, 571, 571t metabolism of in brain, 577–578, 577f in hypercatabolic state, 579 release from muscle, 569, 570f structure of, 48f, 49–50 synthesis in skeletal muscle, 573, 574f tissue metabolism and, 570f, 571 in urea synthesis, 577 use as fuel by kidney, 572, 572f utilization in gut, 576–577, 576f Glutamine phosphoribosyl amidotransferase, 557, 557f, 559 Glutamine synthetase, 507–508 Glutathione peroxidase, 290–291, 291f Glutathione reductase, 290–291, 291f Glycation diabetes mellitus and, 492 of LDL receptors, 473 Glycemic index, 351–352 Glyceraldehyde, 35–36, 35f Lieberman_Subject_Index.indd 612 Glyceraldehyde 3P, 299, 300f, 380, 380f, 381f, 410, 411f dehydrogenase, 299, 300f Glycerol gluconeogenic intermediate, 408, 408f, 411f from glucose, release of from chylomicrons, 430–431 in fasting state, 417, 418f by LPL, 486, 486f synthesis of phospholipids, 449, 450f, 451 in triacylglycerol, 4, 5f, Glycerol 3-phosphate, in triacylglycerol synthesis, 445, 446f Glycerol 3P shuttle, 301–302, 301f Glycerolipids, 449, 449f Glycerophospholipids degradation of, 451, 451f ether, 448–449, 449f, 451 synthesis of, 449, 450f, 451 Glycine biosynthesis of, 520, 520f degradation of, 524, 526f genetic disorders of amino acid metabolism, 529t heme synthesis from, 537, 537f, 538f structure of, 48f, 49 Glycocalyx, 115, 115f Glycocholic acid, 464, 464f Glycogen, 359 activated intermediates in synthesis, 247–248, 247f, 247t, 248f as body fuel store, 4–5, 5t degradation of, 360–362, 360f, 362f, 395 energetics of synthesis of, 247, 247f function in skeletal muscle and liver, 359–360, 360f glucose conversion to, 6f, 7–8 in liver, 7–8, 10f, 11f neonatal stores of, 358, 364, 367, 370, 370t nomenclature of enzymes metabolizing, 364–365 regulation of, 363–364, 364t in liver, 364–368, 364t, 365f in skeletal muscle, 368–369, 369f structure of, 4f, 38, 38f, 359, 359f synthesis of, 360–362, 360f, 361f glucokinase, 483f glycogen synthase, 483, 484f prevention of futile cycling, 360 pyruvate carboxylase, 484 pyruvate dehydrogenase, 484 pyruvate kinase, 483f regulation of, 483, 483f Glycogenin, 361 Glycogenolysis during fasting, 10 glucose-6-phosphate and, 360 process of, 359–360, 360f rate of, 364 stimulation of by epinephrine, 364, 369, 369f by exercise, 368–369, 369f in fasting state, 417 Glycogen phosphorylase glycogen degradation by, 361–362, 362f, 367 inhibition of by fructose 1-phosphate, 375 by glucose-1-phosphate levels, 375 insulin effect on, 416 in muscle, 367, 369, 369f nomenclature of, 364–365 phosphorylation of, 365, 365f Glycogen storage diseases, 362, 363t, 367–368, 370t Glycogen synthase action of, 362 inhibition by glucagon-directed phosphorylation, 366 insulin effect on, 416 in muscle, 367, 369, 369f nomenclature of, 365 regulation of, 365, 365f, 483, 484f Glycolipids degradation of, 398, 399t formation of sugars for synthesis of, 394–395, 395f function and structure of, 396, 397f plasma membrane, 115 red blood cell antigenic determinants, 392, 396 synthesis of, 398 Glycolysis, 298 anaerobic, 8, 253, 298, 301f, 302, 302f, 368 acid production, 303 energy yield, 303 lactate fate, 304 tissues dependent on, 303 biosynthetic functions, 298, 304–305, 304f bisphosphoglycerate shunt, 305 gluconeogenesis compared, 406–407, 407f glucose oxidation, glycerol 3P shuttle, 301–302, 301f lactic acidemia, 307–308, 308f malate–aspartate shuttle, 302, 302f net overall reaction, 301 oxidative fates of pyruvate and NADH in, 301–302, 301f, 302f phases of, 298, 298f reactions of, 298–301, 298f, 299f, 300f regulation by need for ATP, 305–306, 305f ATP, ADP, and AMP concentrations, 306 hexokinase regulation, 305f, 306 phosphofructokinase regulation, 306–307, 306f pyruvate dehydrogenase, 307 pyruvate kinase, 307 regulation during fasting, 487, 488f regulatory enzymes of, 413t Glycophorin, 116f Glycoproteins branched, 395, 395f formation of sugars for synthesis of, 394–395, 395f plasma membrane, 115 red blood cell antigenic determinants, 392, 396, 403 structure and function of, 395–396, 395f synthesis of, 396, 397f Glycosaminoglycans (GAGs), 36, 398–399, 400f Glycosidases, 119, 344, 346–349, 348t Glycosides, 37–38, 38f Glycosidic bonds, 392 Glycosylation, 54, 186 cellular location of, 399 of hemoglobin, 72, 72f, 75, 406 of lens protein, 376 N-glycosylation, 54, 55f, 120 nonenzymatic, 72, 72f O-glycosylation, 54, 55f Glycosyltransferases, 392, 392f, 396, 399, 401 GMP See Guanosine monophosphate Golgi complex, 120, 186, 396, 397f, 398 Gouty arthritis, case study, 32, 42, 44, 78, 91, 94, 94t, 121, 556, 565, 565t G-protein–coupled receptors (GPCR), 126–128, 126f G-proteins activity, 104–105, 105f glucagon signal transduction and, 339 glycogen regulation and, 365f, 367 GPCR See G-protein–coupled receptors Growth factors and receptors, 230 Growth hormone, production of, 219 9/16/14 9:17 PM INDEX GTP See Guanosine triphosphate Guanine base pairing of, 137, 137f nucleoside, 135t structure of, 41, 42f, 135, 135f, 136f Guanosine monophosphate (GMP) degradation of, 564, 564f feedback inhibition in purine synthesis, 559 phosphorylation of, 558 synthesis of, 558, 558f Guanosine triphosphate (GTP), generation in TCA cycle, 260, 260f H Haploid, 140, 172 Hartnup disease, 498, 501t, 502 HAT See Histone acetyltransferases HCl See Hydrochloric acid HCO3Ϫ See Bicarbonate HDL See High-density lipoprotein Heavy metals, as enzyme inhibitors, 92 Helicases, 149 Helix-loop-helix transcription factors, 200, 200f Helix-turn-helix motif, 200, 200f Hematopoietic growth factors, 219 Heme chlorophyll compared, 537 in cytochromes, 280, 280f degradation of, 538, 539f oxygen binding, 68–69, 69f porphyrias and, 537 structure of, 68, 68f, 280f synthesis of, 9, 537–538, 537f, 538f Hemoglobin A-1-c, 60, 72, 75, 331 bicarbonate buffer system and, 27, 28f developmental variation in structure of, 53 gene location for, 194 glycosylation of, 72, 72f, 75, 406 oxygen binding, 67–70, 69f, 70f oxygen saturation curves for, 67f sickle cell, 46, 50–52, 56–57, 69 structure–function relationship, 67–70, 69f, 70f structure of, 66f thalassemia syndromes, 161, 165, 169, 174, 178, 181–182, 187, 187t Hemolysis, caused by reactive oxygen species, 382f Hemolytic anemia, 425 Henderson-Hasselbalch equation, 25, 27 Heparin, 399, 400f, 431, 448 Hepatic encephalopathy, 511, 514–515, 515t Hepatitis A, case study, 505–506, 509, 511, 513–515, 515t Hepatitis B infections, 238 Hepatocytes, Heptahelical receptors, 126–128, 126f HER2 See Human epidermal growth factor receptor Hereditary breast cancer, 157 Hereditary fructose intolerance (HFI), 373, 375, 376, 387–388 Hereditary nonpolyposis colorectal cancer, 157 Hereditary orotic aciduria, 561, 565t Hers disease, 367 Heterochromatin, 195 Heterogenous nuclear RNA (hnRNA), 163f, 167f, 194 Heterotrimeric G-proteins, 127–128, 127f Hexokinase fructose metabolism by, 375 isoforms of, 99, 299, 375 Km values of, 99, 99f regulation of, 305f, 306 Hexose monophosphate shunt, 379 HFI See Hereditary fructose intolerance Lieberman_Subject_Index.indd 613 HGPRT See Hypoxanthine–guanine phosphoribosyl transferase HHV-8 See Human herpesvirus High-density lipoprotein (HDL), 429 atherosclerosis, protection from, 469 characteristics of, 467t deficiency of, 469 fate of, 469–470 increase with exercise, estrogen, and ethanol, 475 interactions with other particles, 470–471, 471f maturation of, 469 reverse cholesterol transport, 469, 470f serum levels of, 457 synthesis of, 468–469 transfer of proteins to chylomicrons, 429–430, 430f High-energy bonds activated intermediates with, 249 ATP, 242–243, 243f Highly variable regions, of DNA, 216–217 High-protein meal, amino acid metabolism and, 578–579, 578f Histamine effects of, 534 metabolism of, 533–534, 535f Histidine deamination of, 506–507, 506f as essential amino acid, 15 structure of, 48f, 50–51, 51f titration curve of, 51f Histidine decarboxylase, 533 Histone acetyltransferases (HAT), 195, 195f Histones, 119, 140, 140f, 141f HIV See Human immunodeficiency virus HMG-CoA See β-Hydroxy-β-methylglutarylCoA HMG-CoA reductase See Hydroxymethylglutaryl coenzyme A reductase hnRNA See Heterogenous nuclear RNA Holoprotein, 68 Homeostasis, metabolic, 330–331, 330f, 331f hormones, 331–333, 332f, 333f, 334f signals that regulate, 331f Homocysteine, 522–525, 522f, 540–541, 551–552, 551f, 552f Homocystine, 522, 522f, 540–541 Homocystinuria, 524, 540–541 Homogentisate oxidase, 528, 528f Homologous chromosomes, 140 Hormone response elements, 198, 199f Hormones See also specific hormones mechanisms of action, 337–338 intracellular receptors, 340 plasma membrane receptors, 338–340 of metabolic homeostasis, 331–333, 332f, 333f, 334f signal transduction by by cortisol, 340 by epinephrine and norepinephrine, 340–341, 340f by glucagon, 339–340, 339f by insulin, 338, 339f Hormone-sensitive lipase (HSL), 487, 489f HSL See Hormone-sensitive lipase H substance, 396, 398f HTLV-1 See Human T-lymphotrophic virus type Humalog (lispro), 46, 53, 57, 219 Human epidermal growth factor receptor (HER2), 230 Human herpesvirus (HHV-8), 238 Human immunodeficiency virus (HIV), 134, 143–145, 238 Human T-lymphotrophic virus type (HTLV-1), 238 Humulin, 46, 53, 57 613 Hyaluronate, 399, 400f Hybridization, 139, 139f, 210 Hydrochloric acid (HCl), 28, 496 Hydrogen bonds in amino acids, 49f, 50 in water, 23, 23f Hydrogen breath test, 349 Hydrogen ions, urinary pH and, 28 Hydrogen peroxide, 119, 286 Hydrolysis, 81–82, 83f, 84 Hydropathic index, 47, 49 Hydrophilic, 34 Hydrophobic, 34, 49, 49f Hydroxylation, 55f, 56, 186 Hydroxyl radical, 42–43, 286 Hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase action of, 459, 459f inhibition of, 80, 435, 454, 474 regulation of, 462 Hydroxyphenylpyruvate dioxygenase, 528–529 Hydroxyproline, 70–71 Hyperammonemia, 578, 580t Hypercatabolic states, amino acid metabolism in, 579 Hypercholesterolemia, 18, 18t, 458, 458t, 473, 479–480, 480t Hypergalactosemia, cataracts from, 376, 377 Hyperglycemia, 331, 341t Hyperhomocysteinemia, 551–552, 551f Hyperlipidemia, 18, 18t case study, 434, 447, 453–455 Hyperphenylalaninemia, 529, 538–540 Hypertriglyceridemia, 434 Hyperuricemia, 387, 565 Hypervariable, protein region, 52 Hypoglycemia, 420t from exogenous insulin administration, 371 from insulinoma, 330, 332, 334, 338 NADH/NADϩ ratio and, 387 as stress signal, 334f, 338 Hypolactasia, 350 Hypoxanthine, 179, 564–565 Hypoxanthine–guanine phosphoribosyl transferase (HGPRT), 559f, 560–561, 560f I Ibuprofen, 444, 444f I-cell disease (mucolipidosis II), 186 ICF See Intracellular fluid IDL See Intermediate-density lipoprotein IFs See Initiation factors IGT See Impaired fasting glucose tolerance IMP See Inosine monophosphate Impaired fasting glucose tolerance (IGT), 406 Inborn errors of metabolism, 367, 518 Induced-fit model for substrate binding, 79f, 80–81 Inducers, 192, 192f, 198 Inducible operon, 192, 192f Induction, 192, 192f Inhibitors, enzyme, 90 covalent, 90, 91f heavy metals, 92 reversible inhibition, 100 competitive inhibition, 100, 101f noncompetitive inhibition, 100–101, 101f simple product inhibition, 101 transition state analogues, 90–91, 92f, 93f Initiation complex, 182–183, 182f Initiation factors (IFs), 182, 182f Inosine monophosphate (IMP) from deamination of AMP, 575, 575f dehydrogenase, 559 structure, 557f synthesis of, 556–557, 556f, 557f Inositol, 450f, 451 9/16/14 9:17 PM 614 INDEX Insertions, 181, 215 Insulin blood levels of, 336 effect on lipolysis, 487 lipoprotein lipase, 447, 447f protein metabolism, 569 exogenous administration, 370t, 371 following meal, 6–7, 6f glucose-6-phosphate induction by, 484–485, 484f glycogen storage and, 416 Humalog, 46, 53, 57, 219 Humulin, 46, 53, 57 induction of glucokinase by, 483 LPL elevation from, 486–487 metabolic homeostasis and, 330–333 physiological actions, 333t, 334f production of, 219 proinsulin, 334, 335f regulation of liver glycogen metabolism, 365–367, 365f release after meal, 415, 416f signal transduction, 338, 339f species variations in, 53, 54f stimulation and inhibition of release of, 336 synthesis and secretion, 334–335, 335f Insulin counterregulatory hormones, 330f, 333, 333t, 334f Insulin-dependent diabetes mellitus See Type diabetes mellitus Insulin/glucagon ratio, during fasting, 487 Insulinoma, 330, 336, 341t Insulin receptor, 125–126, 126f Insulin resistance, 341, 452–453, 487, 492 Integral proteins, 115–116, 115f Interferons, 201 Intermediate-density lipoprotein (IDL) characteristics of, 467t formation of, 467–468 from VLDL, 445 Intermediate filaments, 121 Internal elastic lamina, 473–474, 474f Interphase, 152, 152f Intestinal absorption of cholesterol, 458 Intestinal brush border membrane, disaccharidases of, 347–349, 348f, 349f Intestine amino acid utilization in, 576–577, 576f bile salt metabolism, 465, 465f enzymes and protein digestion, 498 Intima, 473 Intracellular domains, membrane protein, 124 Intracellular fluid (ICF), 22, 22f intracellular pH, 27–28 Intracellular receptors, 124, 124f Intraluminal shear forces, 475 Intrinsic factor, 548 Introns, 167–169, 168f, 169f, 172 Ion channel receptors, 125 Ionizing radiation, 287 Ion product of water, 24 Ions, 23, 23t Iproniazid, 533 IRE-BP See Iron response element-binding protein Iron chelation therapy, 75 deficiency anemia, 190, 205, 205t, 258, 271–272, 280 role of, 16 Iron response element-binding protein (IRE-BP), 203, 203f Islets of Langerhans, 334 Isocitrate, 259, 260f, 262f Isocitrate dehydrogenase, 266–267, 266t Isoelectric point, 50 Lieberman_Subject_Index.indd 614 Isoforms, 53 Isoleucine degradation of, 525, 527, 527f as essential amino acid, 15 structure of, 48f, 49 Isomaltase, 348 Isomerase, in pentose phosphate pathway, 379–380, 379f, 381f Isopentenyl pyrophosphate from mevalonate, 460, 460f squalene from, 461, 461f Isoprene group, 32f Isoprenes mevalonate conversion to, 460, 460f squalene synthesis from, 461, 461f Isozymes, 53, 109 J JAK See Janus kinase JAK– receptor complex, 201 Janus kinase (JAK), 452 Jaundice, 374, 393, 395, 432 Joules, Juvenile diabetes mellitus See Type diabetes mellitus K Kϩ See Potassium Ka See Association constant Karyotype analysis, 225 kcal See Kilocalories Kd See Dissociation constant Keratan sulfate, 399, 400f Ketoacidosis alcohol-induced, 386–387 type diabetes mellitus and, 22, 27, 29, 32–33, 43–44, 312, 325, 327, 406–407, 420t, 483, 492 Ketogenic diets, 323 Ketone bodies acetyl CoA conversion to, 313 in alcohol-induced ketoacidosis, 386–387 during fasting, 9–12, 10f, 12f fatty acid conversion to, 11 fuel homeostasis role, 324–326, 324f, 325f levels in starvation, 418 metabolic acidosis with, 32–33 oxidation of, 322–323, 323f production in liver during fasting, 487–488 regulation of synthesis, 325–326, 325f synthesis of, 33–34, 322, 323f tissue use of, 325 Ketosis, 315, 325 Kidney, amino acid utilization and, 572, 572f, 573f Kidney stones (renal calculi), 42 calcium oxalate, 524 case study, 496, 499, 502 Kilocalories (kcal), Kinase, 125–126, 125t, 126f Km, enzyme, 98–102, 98f, 99f, 101f Krebs bicycle, 510f Krebs cycle See Tricarboxylic acid cycle Kussmaul breathing, 27, 29, 312, 325, 373, 407 Kwashiorkor, 14, 18t, 496, 501t L Label, 210 Lac operon, 192, 192f, 194 Lactase, 349–350, 351f Lactase-glucosylceramidase, 349, 349f Lactate in anaerobic glycolysis, 6f, 10, 303 conversion to pyruvate, 304, 408, 408f fate of, 304 gluconeogenic intermediate, 408, 408f lactate/pyruvate ratio, 283 from pyruvate, 303 uric acid excretion and, 387 Lactate dehydrogenase, 302, 302f, 304, 408 Lactic acid, 303 Lactic acidemia, 307–308, 308f, 309t Lactic acidosis, NADH/NADϩ ratio and, 387 Lactose, 37, 38f dietary, 3, 344 intolerance of, 349–351, 351f, 355t structure of, 345f synthesis from UDP-galactose and glucose, 394, 394f Lactose synthase, 394 Lagging strand, 151, 153–154, 153f Lanosterol, 461, 461f LCAT See Lecithin cholesterol acyltransferase LDL See Low-density lipoprotein LDL direct test, 457 LDL receptor, 472–473 LDL receptor–related protein (LRP), 473 Leading strand, 151, 153–154, 153f Lecithin, 469, 470f Lecithin cholesterol acyltransferase (LCAT), 469, 470f Leptin, 452 Lesch-Nyhan syndrome, 561, 565t Leucine degradation of, 525, 527, 527f as essential amino acid, 15 stimulation of insulin release by, 415 structure of, 48f, 49 Leucine zipper, 200, 200f Leukemia, 226 Leukotrienes, 15, 440, 441f Li-Fraumeni syndrome, 232 Ligand binding, quantitation of, 67 Ligands, 63 Lignin, 344 Limit dextrins, 347 Lineweaver-Burk plots, 101f Lineweaver-Burk transformation, 98–99, 98f, 99f Linoleic acid in cholesterol esters, 459 conversion to arachidonic acid, 439, 439f, 441f in diet, 17, 439 oxidation of, 318–319, 318f roles of, 439 Linolenic acid, 438–439 Lipase adipose triacylglycerol, 448, 448f gastric, 424 hormone-sensitive, 448, 448f lingual, 424 pancreatic, 425–427, 426f inhibition of, 430 Lipid-anchored proteins, 116 Lipid-based anchors, 120 Lipid bilayer, 114, 115f Lipid-free radicals, 288 Lipid-lowering agents, 480, 481t Lipid peroxides, 288 Lipids See also Fatty acids dietary absorption of, 426–427, 427f chylomicron fate, 430–431 chylomicron synthesis, 427–429, 427f, 428f, 429f transport in blood, 429–430, 430f digestion of triacylglycerols, 424 bile salts, 425, 425f pancreatic lipase, 425–427, 426f, 427 fatty acylation, 54, 55f in plasma membrane, 115–116 regulation of metabolism in fasting fatty acids use in muscle, 488–489 9/16/14 9:17 PM INDEX ketone body production by liver, 487–488 lipolysis in adipose tissue, 487, 489f regulation of metabolism in fed state triacylglycerol storage in adipose tissue, 486–487, 486f triacylglycerol synthesis in liver, 483–487, 484f structure of acylglycerols, 40, 40f fatty acids, 38–39, 39f phosphoacylglycerols, 40, 40f sphingolipids, 40, 41f steroids, 40–41, 41f Lipolysis in adipose cells, 9, 10f, 448, 448f stimulation in fasting state, 417, 418f Lipophilic hormones, 124 Lipoprotein lipase (LPL) ApoC-II activation of, 430, 470, 471f cleavage of triacylglycerols in VLDL and chylomicrons by, 445, 470, 471f deficiency of, 447–448 fatty acid release, 486, 486f insulin effect on, 447, 447f, 486–487 Lipoproteins apolipoproteins See Apolipoproteins characteristics of, 467t cholesterol transport in blood, 465–466 chylomicrons See Chylomicrons components of, 428–429, 428f in fed state, 6f, 8–9 high-density See High-density lipoprotein intermediate-density See Intermediatedensity lipoprotein low-density See Low-density lipoprotein receptor-mediated endocytosis, 471–472, 472f receptors, 472 very low density See Very low density lipoprotein Lipoxygenase pathway, 440, 441f Lipstatin, 430 Lispro See Humalog Liver alcohol dehydrogenase, 89, 94, 97, 100 amino acid metabolism, 570–571, 570f, 577 bile salt metabolism, 426–427, 427f, 465, 465f bilirubin metabolism, 538 cholesterol synthesis, 462–463 disease, alcohol-induced, 385–387, 386f enzyme, regulation of, 492t during fasting, 9–10, 12, 12f fate of dietary glucose in, 416 flow chart of changes in metabolism, 491t folate metabolism, 544 glucose–alanine cycle, 575–576, 575f glucose metabolism in, 6f, 7–8, 406 glycogen and triacylglycerol synthesis in, 483–487, 483f, 484f, 485f, 486f, 491f glycogen function in, 359–360, 360f ketone body production in, 487–488 regulation of carbohydrate and lipid metabolism during fasting, 487–489, 488f, 489f, 491f glycogen metabolism, 364–368, 364t, 365f role of alanine and glutamine in transporting amino acid nitrogen to liver, 508, 508f triacylglycerol production in, 445, 446f Liver transaminases, 312 Lock-and-key model for substrate binding, 80, 80f Long-chain fatty acids, 312 activation of, 313–315, 314f Lieberman_Subject_Index.indd 615 β-oxidation of, 316–319, 317f, 318f, 319f branched, 321 cellular uptake of, 313 transport into mitochondria, 315–316, 315f Low-density lipoprotein (LDL) atherosclerosis and, 18 characteristics of, 467t cholesterol transport, 467–468 in fed state, 8–9 glycation of, 492 receptor, 472–473 receptor-mediated endocytosis of, 471–472, 472f serum levels, 457–458, 473 therapy for lowering, 457–458, 458t, 480, 481t from VLDL, 8–9, 445 LPL See Lipoprotein lipase LRP See LDL receptor–related protein Lung cancer, case study, 148, 155, 158t, 159, 226, 237, 239, 239t Lung surfactant, 451, 455 Lymphatic system, lipid transport in, 429 Lysine, 15 structure of, 48f, 50–51, 50f Lysosomal digestive enzymes, 119 Lysosomal protein turnover, 500 Lysosomal storage diseases, 119, 186 Lysosomes, 119 glycogen degradation in, 362 glycolipid degradation in, 398 glycoproteins in, 396 proteoglycan degradation, 402 M Macrophages, 287 Macrophage scavenger receptors, 473 Mad cow disease, 73 Magnesium, role of, 16 Malate, oxaloacetate from, 410, 410f, 412 Malate–aspartate shuttle, 302, 302f Malate dehydrogenase, 435f, 436 Malathion, case study, 78, 90, 91f, 93–94, 94t Malic enzyme, regulation of, 484–485, 484f Malnutrition, 14, 18t Malondialdehyde, 288 Malonyl CoA conversion of acetyl CoA, 436, 436f, 437f, 485, 485f fatty acid synthase and, 437f inhibition of fatty acid oxidation by, 437–438, 438f Maltase, 348, 348f, 348t Mannose, as epimer of glucose, 36, 36f, 395 MAO See Monoamine oxidase Maple syrup urine disease, 527 Marasmus, 13–14, 18t Matrix, mitochondria, 118, 118f Maturity onset diabetes of young (MODY), 98, 110t, 336, 341t MCAD deficiency See Medium-chain acyl CoA dehydrogenase deficiency McArdle disease, 368 Mechanical work, 245–246 Medium-chain acyl CoA dehydrogenase (MCAD) deficiency, case study, 312–313, 318, 322, 326–327 Medium-chain fatty acids, 313, 319 Megaloblastic anemia, 543, 547, 553, 553t Melanomas, case study, 148, 156, 158t, 159, 226, 231, 239–240, 239t Melatonin, 292–293, 533, 534f Membranes, 114 Membrane-spanning domains, membrane protein, 124 MEOS See Microsomal ethanol oxidizing system 615 MERRF See Myoclonic epileptic ragged red fiber disease Messenger RNA (mRNA) in bacterial transcription, 166, 166f capping of, 168 codon, 178 intron removal, 168–169, 168f, 169f microRNAs, 203–204, 203f poly(A) tail addition, 168 polycistronic, 191, 191f protein product and, 180, 180f structure of, 142, 142f synthesis of eukaryotic, 167–168, 167f translation of, 202–203, 202f, 203f transport and stability of, 204, 204f Metabolic acidosis, 32 Metabolic homeostasis, 330–331, 330f, 331f hormones, 331–333, 332f, 333f, 334f signals that regulate, 331f Metabolic pathways allosteric enzymes in, 103 regulation of, 108, 108f counterregulation of opposing pathways, 109 feedback regulation, 108f, 109 feed-forward regulation, 109 rate-limiting step, 108, 108f substrate channeling through compartmentation, 109 tissue isozymes, 109 Metabolism of ethanol, 381–385, 383f, 384f toxic effects of, 385–387, 386f of glucose in liver, 406 of sugar fructose, 374–376, 374f, 375f galactose, 376–377, 376f pentose phosphate pathway, 377–381, 378f, 379f, 380f, 381f, 382f Metal ions in catalysis, 89 Methionine in cysteine synthesis, 521–522, 521f degradation, 524–525, 526f elevated blood levels, 540–541 as essential amino acid, 15 genetic disorders of amino acid metabolism, 529t from homocysteine, 550, 550f, 551–552, 552f in SAM synthesis, 550, 550f structure of, 48f, 50 Methionine synthase, 548–549 Methotrexate, 547–548 Methylation, 186, 195 Methylmalonic acid, 543 Methylmalonyl CoA, 526f, 548–549, 549f Methyl trap hypothesis, 550–551 Methylxanthine, 339–340 Mevalonate conversion to isoprenes, 460, 460f synthesis from acetyl CoA, 459, 459f Micelles bile salt, 427 formation of, 426 Michaelis-Menten equation, 97–98, 98f Microarrays, 217–218 MicroRNAs (miRNAs), 144, 203–204, 203f apoptosis and, 236–237 Microsomal ethanol oxidizing system (MEOS), 97, 100, 107, 109–110, 383–384, 383f, 384f Microsomal triglyceride transfer protein (MTP), 429, 429f, 445 Microtubules, 121 Milk, digestion of, 424 Minerals, 16–17 miRNAs See MicroRNAs Mismatch repair, 157, 157f 9/16/14 9:17 PM 616 INDEX Mitochondria red blood cells lack of, replication by, 118–119 structure of, 118, 118f transport of long-chain fatty acids into, 315–316, 315f transport through inner and outer membranes of, 293–294, 293f Mitochondrial disorders, 119 Mitochondrial DNA (mtDNA), OXPHOS diseases and, 282–283, 282t Mitochondrial integrity pathway, 235, 235f Mitochondrial myopathy, 284 Mitosis, 152, 152f Moclobemide, 533 Modulator proteins, 104 calcium-calmodulin family of, 104, 105f MODY See Maturity onset diabetes of young Molecular oxygen, 119 Molybdenum, 16 Monoacylglycerols, 40 Monoamine oxidase (MAO), 532–533, 533f Monomeric G proteins, 104–105, 105f Monosaccharides, 35 D- and L-sugars, 35–36, 35f oxidized and reduced sugars, 37, 37f ring structures, 36, 37f stereoisomers and epimers, 36, 36f substituted sugars, 36–37 transport into tissues, 354, 354f Monounsaturated fatty acids, 5f, 38–39, 39f mRNA See Messenger RNA mtDNA See Mitochondrial DNA MTP See Microsomal triglyceride transfer protein Mucolipidosis II See I-cell disease Mucopolysaccharides, 399 Mucopolysaccharidoses, 402, 402t Multimer, 67 Muscle See also Skeletal muscle glucose metabolism in, 416, 417f regulation of use of glucose and fatty acids by, 488–489 release of amino acids, 569, 570f Muscular dystrophy, 116 Mutagens, 155, 155f Mutarotases, 36 Mutarotation, 36 Mutations deletions, 181, 215 detection of, 216–218, 217f DNA damage leading to chemical and physical alterations, 227–228 gain-of-function mutations, 228–229, 228f repair enzyme mutations, 229 frameshift, 181, 181f insertions, 181, 215 mitochondrial DNA, 282–283, 282t point, 180–181, 215 polymorphisms, 215–218, 217f types of, 180t Myasthenia gravis, case study, 113, 121, 128–129 Myocardial infarction aspirin therapy, 435, 442, 455 case study, 46, 56t, 57, 60, 66, 68, 74t, 75, 242, 255, 255t, 275–276, 281, 287, 294, 307, 435, 442, 445, 453–455, 458 cause of, 53 creatine kinase in, 46, 53, 57, 57f, 60, 66, 75, 275 myoglobin release, 68 troponin T in, 53, 57, 60, 75, 275 Myoclonic epileptic ragged red fiber disease (MERRF), 283 Myoclonus, 283 Lieberman_Subject_Index.indd 616 Myoglobin oxygen saturation curves for, 67f release from muscle, 68 structure–function relationship, 67–70, 69f structure of, 66f Myopathy, case study, 275–276, 284, 294 MyPlate web site, 19 Myristoylation, 54, 55f N Naϩ See Sodium N-acetylgalactosamine (GalNAc), 396, 398f N-acetylglucosamine 6-phosphate, 395f N-acetylglutamate (NAG), 511, 511f N-acetylmannosamine, 395 N-acetylneuraminic acid (NANA), 395, 395f NADϩ See Nicotinamide adenine dinucleotide NADH See Nicotinamide adenine dinucleotide NADH:CoQ oxidoreductase See NADH dehydrogenase NADH dehydrogenase, 277–278, 279f NADH/NADϩ ratio effect on gluconeogenesis, 409 effect on ketone body production, 487–488 ethanol ingestion and, 385–387 NADPH See Nicotinamide-adenine dinucleotide phosphate NADPH/NADPϩ ratio, 377 NAG See N-acetylglutamate NANA See N-acetylneuraminic acid Naproxen, cyclooxygenase inhibition, 444, 444f Negative control, 193 Neonatal jaundice, 393 NER See Nucleotide excision repair Neural tube defects, 544, 552, 553t Neurofibromatosis, 233 Neuromuscular junction, 122f Neurotransmitters action of, 122, 122f, 530f inactivation and degradation of, 532, 533f acetylcholine, 535 synthesis of acetylcholine, 534–535, 535f amino acid pool and, 577 catecholamines, 530–532, 531f GABA, 536, 536f general features, 529–530, 530f from glucose, glutamate, 535–536, 536f histamine, 533–534, 535f serotonin, 532–533, 534f NF-1, 233 N-glycosylation, 54, 55f, 120 NH3 See Ammonia Niacin See Nicotinic acid Nicotinamide adenine dinucleotide (NADϩ, NADH) electron transfer from, to O2, 276–277 fatty acid desaturation and, 438, 439f glycolysis and, 301–304, 302f levels in alcoholism, 446 oxidation of, 250–251, 251f oxidation–reduction reactions, 88, 89f pyruvate inhibition, 283 in TCA cycle, 258, 259f, 261, 262f Nicotinamide-adenine dinucleotide phosphate (NADPH) in fatty acid synthesis, 435f, 436, 437–438, 438f in folate metabolism, 546, 547f generation in pentose phosphate pathway, 377, 378f, 381 inhibition of glucose-6-phosphate dehydrogenase, 381 Nicotinic acetylcholine receptor, 122, 122f, 129 Nicotinic acid (niacin), 454, 502 structure of, 41, 42f Nitric oxide (NO), 288–289, 289f Nitrogen fate of amino acid, 505–508, 505f, 506f, 507f, 508f urea cycle, 508–512, 509f, 510f, 511f, 514f Nitrogen balance, 15–16, 571, 579 Nitrogen dioxide, 43 Nitrogenous bases, 41–42, 42f Nitroprusside, 281 NO See Nitric oxide Nomenclature, of biological compounds, 35, 35f Nonclassical galactosemia, 376f, 377 Noncompetitive inhibitor, 100–101, 101f Nonenzymatic glycosylation, 72, 72f Nonhistone chromosomal proteins, 140 Non-Hodgkin lymphoma, 547 Nonpolar bonds, 34 Nonreducing ends, 359 Nonsteroidal anti-inflammatory drugs (NSAIDs) action of, 444 inhibition of cyclooxygenase, 442–444 Norepinephrine inactivation of, 532, 533f signal transduction, 340–341 structure of, 340f synthesis of, 530–532, 531f Northern blots, 211, 212f NRTI See Nucleotide reverse transcriptase inhibitor NSAIDs See Nonsteroidal anti-inflammatory drugs Nuclear pores, 119 Nuclear receptors, 198 Nucleases, 119 Nucleic acids, structure of chromosomes, 139–141, 140f DNA, 134–139 RNA, 141–144 Nucleolus, 119, 120f Nucleophilic catalysis, 84 Nucleosides, 41–42, 135, 135t, 136f Nucleosome, 140, 140f Nucleotide excision repair (NER), 156, 156f Nucleotide reverse transcriptase inhibitor (NRTI), 150 Nucleotides, 41–42, 135, 136f Nucleotide sugars, interconversions involving, 392–395 Nucleus, 114, 119, 120f Nutrients, absorption, digestion, and fate of, 7–9, 7f, 7t O O2 See Oxygen Obesity, case study, 2, 4–5, 7–8, 13–14, 17–18, 18t Odd-chain fatty acids, 313, 319, 319f O-glycosylation, 54, 55f Okazaki fragments, 151, 153–154 Oleate, 5f Oleic acid, 438 Oligonucleotides, 144, 209, 216 Oligosaccharides, 395–396 structure of, 37–38, 38f Oncogenes, 226–227, 227f, 229 cell cycle and, 231, 231f signal transduction cascades and, 229, 230f growth factors and receptors, 230 signal transduction proteins, 230–231, 230f transcription factors, 230f, 231 One-carbon metabolism, 552, 552f Operon, 165, 191–193, 191f, 192f, 193f, 194f Organelles, 114 Origin of replication, 148, 149f, 153, 153f, 154f Orlistat, 430 9/16/14 9:17 PM INDEX Ornithine biosynthesis, 522–523, 522f origin of, 510–511, 510f in urea cycle, 498 Ornithine transcarbamoylase (OTC), 509f, 510, 513, 515t, 563 Orotate, 510 Orotate phosphoribosyltransferase, 561, 562f Orotic acid, 561, 562f Osmolality, 24 Osmotic diuresis, 24, 407 Osmotic pressure, 24 Osteopenia, 518 Osteoporosis, 16, 18t, 518, 540 OTC See Ornithine transcarbamoylase Oxalate, 524 Oxaloacetate, 260–261, 260f from aspartate, 505, 505f in fatty acid synthesis, 435–436, 435f gluconeogenesis and, 409–410, 409f, 410f, 412 in TCA cycle, 258 Oxidases, 253–254, 253f, 287 Oxidation, 33, 33f of branched-chain amino acids in skeletal muscle, 573–574, 574f fatty acids, 320–322, 321f, 322f of ketone bodies as fuels, 322–323, 323f medium-chain fatty acids, 319 protein denaturation, 72 reactions, 119, 253 of tetrahydrofolate, 545–546, 545f Oxidation–reduction, 250 coenzymes, 88, 89f components of electron transport chain, 278–280, 279f, 280f FAD in, 250–251, 252f NADH in, 250–251, 251f Oxidative phosphorylation, 3, 3f, 298 components of electron transport chain, 278, 279f coenzyme Q, 279, 279f copper and reduction of oxygen, 279f, 280 cytochromes, 280, 280f NADH dehydrogenase, 278, 279f succinate dehydrogenase, 278–279, 279f coupling electron transport and ATP synthesis, 283 regulation through coupling, 283–284 uncoupling, 284–285, 284f energy transformation, 250–253, 251f, 252f, 252t energy yield from electron transport chain, 281 overview of, 276, 276f ATP synthase, 277–278, 277f, 278f electrochemical potential gradient, 277 electron transfer from NADH to O2, 276–277 OXPHOS disease, 282–283, 282t proton pumping, 280–281 respiratory chain inhibition, 281, 281t Oxime, 93 OXPHOS diseases, 282–283, 282t Oxygen (O2) See also Reactive O2 species ADP control of consumption of, 283–284, 284f copper and reduction of, 279f, 280 electron transfer from NADH to, 276–277 radical reactions with cell components, 287–288, 287f toxicity, cell defenses against, 289–290, 290f nonenzymatic, 291–293 scavenging enzymes, 290–291, 290f, 291f Oxygenases, 253f, 254, 287 Lieberman_Subject_Index.indd 617 Oxygen binding and heme, 68–69 Oxygen saturation curves, for myoglobin and hemoglobin, 67f Oxypurinol, 565 P p53 gene, 232–233, 233f P450 enzymes See Cytochrome P450 enzymes PAF See Platelet-activating factor PAH See Phenylalanine hydroxylase Palindrome, 209, 209f Palmitate, 5f, 435–437 Palmitic acid, 317–318, 438 Palmitoleic acid, 438 Palmitoylation, 54, 55f Palmityl CoA, 436, 452, 452f Pancreas enzymes and protein digestion, 496f, 497–498 following meal, 6–7, 6f Pancreatic amylase, 347, 347f, 426 Pancreatic lipase action of, 425–427, 426f inhibition of, 430 Pancreatitis, 347, 426, 432, 498 PAPS See 3Ј-Phosphoadenosine 5Ј-phosphosulfate Paraaminobenzoic acid, 543 Paracrine actions, 123, 123f Parkinson disease, 533 Partial charges, 34, 35f Patched, 233–234, 238 P-ATPases See Plasma membrane ATPases PCNA See Proliferating cell nuclear antigen PCR See Polymerase chain reaction PDC See Pyruvate dehydrogenase complex Pellagra, 502, 529 Penicillin, as enzyme inhibitor, 91, 92f Pentose phosphate pathway, 377 direction of, 382t nonoxidative phase, 377, 379–380, 379f, 380f, 381f oxidative phase, 377, 378f, 379 reaction sequence, 379–380, 380f red blood cell integrity and, 381, 382f role in NADPH generation, 381, 382f PEP See Phosphoenolpyruvate PEPCK See Phosphoenolpyruvate carboxykinase Pepsin, 84, 496–498, 497f Pepsinogen, 496, 497f Peptide bonds, 47, 47f, 61–62, 61f, 184 Peripheral neuropathy in diabetes mellitus, 376 sorbitol accumulation and, 376 Peripheral proteins, 115–116, 115f Pernicious anemia, 548–549, 553t Peroxidases, 287 Peroxidation of lipid molecules, 288 Peroxisomal oxidation of fatty acids, 320–321, 321f Peroxisome proliferator–activated receptor α (PPARα), 452–453 Peroxisomes, 119 PEST sequences, 500 PGI2 See Prostacyclin PGM See Phosphoglucomutase pH enzyme optimum, 90 intracellular, 27–28 urinary, 28 of water, 24 Phenobarbital, 384 Phenylacetate, 513, 514f Phenylalanine conversion to tyrosine, 520, 520f, 523, 524f degradation of, 528–529, 528f as essential amino acid, 15 617 excess in phenylketonuria, 518, 538–540 genetic disorders of amino acid metabolism, 529t plasma levels, 538–540 structure of, 48f, 49 Phenylalanine hydroxylase (PAH), 523, 524f, 528f, 529, 538–540 Phenylbutyrate, 513, 514f Phenyl group, 32, 32f Phenylketonuria (PKU), 518, 528, 528f, 538–540 Philadelphia chromosome, 190, 196, 205, 225, 229 Phosphatases, 119 Phosphate ions, urinary pH and, 28 Phosphatidic acid, 40, 40f, 445, 446f, 449, 450f Phosphatidylcholine, 40, 40f, 115, 449, 450f, 452, 455, 469 Phosphatidylethanolamine, 115, 449, 450f Phosphatidylinositol, 450f, 451 Phosphatidylserine, 115, 449, 450f Phosphoacylglycerols, 40, 40f 3Ј-Phosphoadenosine 5Ј-phosphosulfate (PAPS), 401, 401f Phosphodiesterase, 339–340 Phosphoenolpyruvate (PEP) conversion to fructose 1,6-bisphosphate, 410, 411f conversion to glucose, 411, 411f from oxaloacetate, 409, 410f from phosphoglycerate, 299, 300f from pyruvate, 406–407, 407f, 409–410, 409f, 410f, 412 Phosphoenolpyruvate carboxykinase (PEPCK), 202, 409, 410f, 412, 414 Phosphofructokinase action in glycolysis, 299, 300f activation by insulin, 447 regulation of, 306–307, 306f, 483f, 484 Phosphoglucomutase (PGM), 243, 245f, 249, 360, 360f, 394–395 Phosphoglucose isomerase, 411, 411f Phospholipase A1, 451, 451f Phospholipase A2, 426, 426f, 440, 451, 451f Phospholipase C, 440, 451, 451f Phospholipase D, 451, 451f Phospholipids in membranes, 115, 115f synthesis of, 449, 450f, 451 in VLDLs, 7–8 5Ј-Phosphoribosyl 1Ј-amine, 557, 557f 5Ј-Phosphoribosyl-1Ј-pyrophosphate (PRPP), 556–558, 556f, 557f, 560, 560f Phosphoribosyl transferase, 560, 560f Phosphorus, 16 Phosphorylation See also Oxidative phosphorylation of AMP and GMP, 558 fructose, 375 glycogen regulation and, 366–368 of glycogen synthase, 366 as posttranslational modification, 55f, 56, 103–104, 103f, 186 substrate-level, 260, 260f, 298–299, 300f Phosphoryl transfer reactions, 246–247, 247f, 247t Phototherapy, 393 Phytanic acid, oxidation of, 321, 321f PKU See Phenylketonuria Plant oils, dietary, 14 Plasmalogens, 119, 451 Plasma membrane ATPases (P-ATPases), 246 Plasma membrane receptors adenyl cyclase and cAMP phosphodiesterase, 128 changes in response to signals, 128 G-protein–coupled, 126–128, 126f 9/16/14 9:17 PM 618 INDEX Plasma membrane receptors (continued) heterotrimeric G-proteins, 127–128, 127f intracellular receptors compared, 124, 124f ion channel receptors, 125 kinase, 125–126, 125t, 126f signal transduction, 124–128 Plasmids, 135, 213 Platelet-activating factor (PAF), 451 Platelets in leukemia, 226 TXA2 in, 442 PLP See Pyridoxal phosphate Podagra See Gouty arthritis Point mutations, 180–181, 215 Polar bonds, 34 Polyadenylation signal, 168 Polyadenylation sites, 202 Poly(A) tail, 167f, 168 Polycistronic mRNA, 191, 191f Polycistronic transcript, 166 Polymerase chain reaction (PCR), 214–216, 215f Polymorphism in protein structure, 52 Polymorphisms, 215–218, 217f Polynucleosome, 140f Polyol pathway, 375–376, 375f Polypeptide chains, 47 Polysaccharides, structure of, 38, 38f Polysomes, 185 Polyunsaturated fatty acids, 5f, 38–39, 39f, 440 Polyuria, 24 Pompe disease, 119 Porphyrias, 537 Positive control, 193 Posttranslational modifications, 54, 55f, 120, 185–186 Potassium (Kϩ), 19, 23, 23t PPARα See Peroxisome proliferator–activated receptor α Prader-Willi syndrome, 195, 205t Prenylation, 54, 55f, 186 Preparative phase of glycolysis, 298, 298f Presynaptic membrane, 122 Pribnow box, 164–165, 164f, 165f Primaquine, 389 Primary structure, protein, 47, 60–61, 61f Primase, 151, 153–154, 153f, 154t Primer, 151 Prions, 73–74, 73f, 74t Probes, DNA or RNA, 210, 210f Procarboxypeptidases, 497–498, 497f Processivity, 150 Procollagen, 71 Proelastase, 497f Progesterone, synthesis of, 477f, 478–479 Progestins, synthesis of, 478–479 Proglucagon, 336 Proinsulin, 334, 335f Prokaryotic cells, 114 DNA synthesis in, 148, 148f base-pairing errors, 150–151 bidirectional replication, 148, 149f DNA ligase, 151, 151f DNA polymerase action, 149–150, 150f, 150t DNA unwinding, 149 replication forks, 148, 149f, 151, 151f RNA primer requirement, 151, 151f semiconservative replication, 148–149, 148f, 149f gene expression in, 190–191 corepressors, 192–193, 193f operons, 191–193, 191f, 192f, 193f, 194f repressors, 191–193 RNA polymerase binding stimulation, 193, 194f promoters, 164–166, 164f Lieberman_Subject_Index.indd 618 regulation of gene expression in, 190–191 transcription in, 166, 166f Proliferating cell nuclear antigen (PCNA), 154 Proline biosynthesis, 520f, 522, 522f structure of, 48f, 49 Promoters, 161–162, 162f consensus sequences, 164–165 eukaryotic, 164–166, 164f multiple regulators of, 201–202, 201f operons and, 191, 191f prokaryotic, 164–166, 164f Propionate, as gluconeogenic intermediate, 408 Propionyl CoA, 408, 525, 526f, 527f Prostacyclin (PGI2), 442, 443f Prostaglandins, 15 biosynthesis of, 442–444, 443f functions of, 443t inactivation of, 445 nomenclature of, 442 structure of, 440, 441f, 442, 442f Prosthetic groups, 68, 86 Proteases, 82, 119 Proteasomes, 108, 500, 501f Protein disulfide isomerase, 70 Protein-energy malnutrition, 13–14 Protein kinase A actions of, 104 active and inactive, 104f glycogen regulation and, 365f, 366–367, 487 Protein phosphatases, regulation of, 366 Proteins See also Enzymes attachment of glycosaminoglycans to, 399, 401f deficiency in diet, 496 degradation in starvation, 418–419, 419f dietary high-protein meal and changes in amino acid metabolism, 578–579, 578f insulin release and, 415, 416f requirement, 500–501 as dietary fuel, dietary requirements, 15 essential amino acids, 15 nitrogen balance, 15–16 digestion of, 496, 496f, 497f by enzymes from intestinal cells, 498 by pancreatic enzymes, 496f, 497–498 in stomach, 496–497, 496f DNA replication involvement of, 154t excess consumption of, 499 folding of, 70 denaturation, 72–73 fibrous proteins, 70–72 misfolding and prions, 73–74, 73f, 74t primary structure and, 70 glycosylation of, 420 high-quality, 15 oxygen radical reactions with, 288 in plasma membrane, 115–116, 115f posttranslational modifications, 185–186 processing of, 185 quantitation of ligand binding, 67 structural variations in, 51–52 polymorphism, 52 by species, 53, 54f tissue and developmental variations, 53 structure of, 4f descriptions of, 60–61, 60f, 61f myoglobin and hemoglobin structure– function relationships, 67–70, 69f, 70f peptide backbone, 61–62, 61f primary, 47, 60–61, 61f, 70 quaternary, 61, 61f, 66–70 secondary, 61–63, 61f, 62f tertiary, 61, 61f, 63–66, 64f, 65f three-dimensional structures, 61–62, 61f targeting of, to subcellular and extracellular locations, 186, 187f turnover of, 9, 11 intracellular amino acid pool, 499–500 lysosomal protein turnover, 500 ubiquitin-proteasome pathway, 500, 501f Protein synthesis See Translation Proteoglycans, 398–399 in cartilage, 398 degradation, 402 formation of sugars for synthesis of, 394–395 structure and function, 36–37, 399, 400f synthesis of, 399–402, 400f, 401f, 402f Proteolysis, 82 Proteolytic cleavage, 105–107 Proteolytic regulation of HMG-CoA reductase, 462 Proteomics, 220–221, 221f Protomer, 67 Proton ionophores, 284, 284f Proton leak, 285 Proton motive force, 277 Proton pumping, 280–281 Protooncogene, 226 gain-of-function mutations in, 228–229, 228f PRPP See 5Ј-Phosphoribosyl-1Ј-pyrophosphate PRPP synthetase, 556–557, 556f, 558, 558f Pseudomonas aeruginosa, 496 P (peptidyl) site, 182–185, 182f, 183f, 184f Purine biosynthesis of, 556, 556f from amino acids, degradation, 564, 564f de novo synthesis of of adenosine monophosphate, 557, 557f of guanosine monophosphate, 558, 558f of inosine monophosphate, 556–557, 556f, 557f phosphorylation of AMP and GMP, 558 regulation of, 558–559, 558f dietary uptake, 556 in DNA, 135, 135f folate metabolism and, 546–547 in RNA, 141 salvage pathways, 559–561, 559f, 560f, 561f structure of, 41, 42f Purine nucleoside phosphorylase, 560, 560f, 565t Purine nucleotide cycle, 506f, 507, 575, 575f Pyranose rings, 37f Pyridines, structure of, 41, 42f Pyridoxal phosphate (PLP) in amino acid synthesis, 520–521, 521f as cofactor in amino acid metabolism, 519 as cofactor of cystathionine β-synthase, 541 in heme synthesis, 537, 538f in neurotransmitter synthesis, 531f, 532 reactive sites of, 87f synthesis of, 88 in transamination reactions, 505, 505f Pyridoxamine deficiency, 515t Pyridoxine See Vitamin B6 Pyrimidine biosynthesis of, from amino acids, degradation, 565 de novo synthesis, 561–562, 561f, 562f regulation of, 562 dietary uptake, 556 in DNA, 135, 135f in RNA, 141 salvage pathways, 562, 562f, 562t structure of, 41, 42f Pyrimidine dimers, 157 Pyrimidine nucleoside phosphorylase, 562, 562f 9/16/14 9:17 PM INDEX Pyruvate in cytosolic acetyl CoA generation, 435–436 gluconeogenesis and, 406–407 conversion to phosphoenolpyruvate, 406–407, 407f, 409–410, 409f, 410f, 412 gluconeogenic intermediate conversion to, 408, 408f in glycolysis, 301, 301f inhibition by NADH/NADϩ ratio, 283 Pyruvate carboxylase, 270, 270f, 409–410, 410f, 412, 435–436, 484 Pyruvate dehydrogenase action of, 435–436 deficiency of, 323 inactivation in gluconeogenesis, 412 regulation of, 307, 484 Pyruvate dehydrogenase complex (PDC), 263, 263f deficiencies of, 268 regulation of, 269, 269f structure of, 268, 268f Pyruvate kinase, 307, 409, 414, 483f, 484 Q Quantitation, of ligand binding, 67 Quaternary structure, of protein, 61, 61f, 66–67, 66f quantitation of ligand binding, 67 in sickle cell disease, 69 R Radiation, 228, 228f Radicals, 42, 285 Ras, 127, 227, 230, 230f regulation of, 233 Rate-limiting step, 108, 108f R-binders, 547 RDA See Recommended Dietary Allowance RDS See Respiratory distress syndrome Reactive nitrogen–oxygen species, 288–289, 289f Reactive O2 species (ROS) cell defenses against, 289–290, 290f nonenzymatic, 291–293 scavenging enzymes, 290–291, 290f, 291f characteristics of, 286 hemolysis caused by, 382f nature of, 285–286, 285f sources of, 286–287, 287f Reactivity, 34, 35f Reading frame, 180, 180f Receptor-mediated endocytosis, 117, 471–472, 472f Receptors changes in response to signals, 128 intracellular, 124, 124f, 340 kinase, 125–126, 125t, 126f nuclear, 198 signal transduction, 124–128 steroid hormone/thyroid hormone superfamily of, 124 tumor suppressor genes and, 233–234 Recognition sites, substrate, 79, 79f Recombinant DNA techniques, 209 for disease diagnosis DNA chip, 217–218 DNA polymorphisms, 215–216 oligonucleotide probes, 216 PCR, 216 repetitive DNA, 216–217, 217f RFLPs, 216 for disease prevention and treatment gene therapy, 220 genetic counseling, 219–220 Lieberman_Subject_Index.indd 619 therapeutic protein production, 219 vaccines, 218–219 for DNA fragments and copies of genes chemical synthesis of DNA, 209–210 DNA produced by reverse transcriptase, 209 restriction fragments, 209–210, 209f, 210f for DNA sequence amplification cloning of DNA, 213–214, 214f polymerase chain reaction, 214–215, 215f for DNA sequence identification DNA sequencing, 211–213, 212f gel electrophoresis, 210–211, 211f probes, 210, 210f specific sequence detection, 211, 211f, 212f proteomics, 220–221, 221f Recommended Dietary Allowance (RDA), 14, 544 Red blood cells bicarbonate and hemoglobin in, 27, 28f glucose use by, Reducing sugar, 377, 388 Reduction, 33, 33f, 253, 545–546 See also Oxidation–reduction Reduction potential, 252, 252t REE See Resting energy expenditure Refsum disease, 321 Repair enzyme, mutations in, 229 Repetitive DNA detection of polymorphisms due to, 216–217, 217f sequences in eukaryotes, 172–173, 173f Replication forks, 148, 149f, 151, 151f Repressible operon, 193f Repression, 192 Repressors, 165, 191–193, 198 RER See Rough endoplasmic reticulum Reserpine, 530 Resonance structures, 61f, 62 Respiration, 3, 3f Respiratory distress syndrome (RDS), case study, 434–435, 451, 455 Resting energy expenditure (REE), 13 Resting metabolic rate (RMR), 12–13, 13t, 254, 285 Restriction endonucleases, 209 Restriction fragment length polymorphisms (RFLPs), 216 Restriction fragments, 209–210, 209f, 210f Retinoblastoma gene, 232, 232f Retinoid X receptor (RXR), 199, 200f Retroviruses, 143, 143f, 220 Reverse transcriptase, 143, 143f, 145, 152, 157–158, 158f, 209 Reversible inhibitor, 100 competitive inhibition, 100, 101f noncompetitive inhibition, 100–101, 101f RFLPs See Restriction fragment length polymorphisms Riboflavin, 272 Ribonucleic acid See RNA Ribonucleotide reductase, 563–564, 563t Ribose purine synthesis from, 556, 556f reduction to deoxyribose, 563 structure of, 135f Ribose 5-phosphate, in pentose phosphate pathway, 377, 379–380, 379f, 380f, 381f Ribosomal RNA (rRNA) structure of, 142–143, 144f synthesis of eukaryotic, 119, 169–170, 170f Ribosomes See also Translation A, P, and E sites, 182–185, 182f, 183f, 184f assembly, 119 619 polyribosomes, 185 structure of, 142–143, 144f synthesis of, 170 translation process, 182–185, 182f, 183f, 184f translocation of, 185 Ribozyme, 142 Ribulose 5-phosphate, in pentose phosphate pathway, 377, 378f, 379, 379f, 381f Rickets, 479, 480t Rifampin, 162, 168, 174 Ring structures, of monosaccharides, 36, 37f RMR See Resting metabolic rate RNA editing, 202 general features of, 141–142 messenger See Messenger RNA oligonucleotides, 144 processing of, 119 ribosomal See Ribosomal RNA snRNPs, 144 transfer See Transfer RNA RNA polymerase, 151, 157 action of, 161–162, 162f promoter, 164–166, 164f recognition of genes by, 164 regulation of binding by repressors, 191–193 stimulation of binding, 193 types of, 162–166 RNase H, 152, 154 RNA synthesis, 161–162, 162f See also Transcription Rofecoxib (Vioxx), 444 ROS See Reactive O2 species Rough endoplasmic reticulum (RER), 119–120, 120f, 186 RXR See Retinoid X receptor S S-adenosylhomocysteine (SAH), 524, 526f S-adenosylmethionine (SAM), 524, 526f, 550, 550f, 551 SAH See S-adenosylhomocysteine Salicylate See Aspirin Salivary mucin, 395 Salivary α-amylase, 346–347, 347f SAM See S-adenosylmethionine Sanger method of DNA sequencing, 211–213, 212f Saturated fatty acids, 5f, 38, 39f Saturation kinetics, 98 Scavenger receptors, 473, 474 Schiff base, 72f Schilling test, 543 Scissile bond, 82 Scoliosis, 518 Secondary bile salts, 465, 465f, 466f Secondary structure, 61–62, 61f, 62f α-helix, 62, 62f, 63f β-sheet, 62–63, 63f nonrepetitive, 63, 64f Second messenger, 339 Sedimentation coefficient, 143 Sedoheptulose 7-phosphate, in pentose phosphate pathway, 380, 380f, 381f Seizure, hypoglycemia and, 358, 371 Selenocysteine, 56 Semiconservative replication, 148–149, 148f, 149f Sepsis, 568, 571, 579 SER See Smooth endoplasmic reticulum Serine biosynthesis of, 520, 520f deamination of, 506f, 507 sphingolipids from, 452, 452f structure of, 48f, 49–50 Serine dehydratase, 507 9/16/14 9:17 PM 620 INDEX Serine proteases, 497 Serotonin inactivation of, 532 metabolism of, 532–533, 534f Serum amyloid A protein, in acute-phase response, 580 Serum total bilirubin, 506 Shivering, 283–284 Sickle cell disease, case study, 46, 50–52, 56–57, 56t, 60, 69, 74–75, 74t, 180, 209, 216, 222t, 424–425, 427–428, 431–432, 431t Sickle cell trait, case study, 208, 216, 219, 222, 222t Signaling chemical messengers, general features of, 121–124, 121f endocrine, paracrine, and autocrine actions, 123, 123f intracellular transcription factor receptors, 124, 124f plasma membrane receptors adenyl cyclase and cAMP phosphodiesterase, 128 changes in response to signals, 128 G-protein–coupled, 126–128, 126f heterotrimeric G-proteins, 127–128, 127f intracellular receptors compared, 124, 124f ion channel receptors, 125 kinase, 125–126, 125t, 126f signal transduction, 124–128 termination of, 128–129, 128f Signal recognition particle (SRP), 186 Signal termination, 127–129, 128f Signal transducer and activator of transcription (STAT) factors, 452 Signal transduction, 338 by cortisol, 340 by epinephrine and norepinephrine, 340–341, 340f by glucagon, 339–340, 339f by insulin, 338, 339f oncogenes and, 229, 230f growth factors and receptors, 230 signal transduction proteins, 230–231, 230f transcription factors, 230f, 231 pathway, 124–125 proteins, 230–231, 230f tumor suppressor genes and, 233–234 Simple diffusion, 117, 117f Simple product inhibition, 101 Skeletal muscle amino acids, utilization, 572–576, 574f, 575f glycogen function in, 359–360, 360f regulation of glycogen synthesis and degradation in, 368–369, 369f SLE See Systemic lupus erythematosus Small intestinal disaccharidases, 347–349, 348f, 349f Small nuclear ribonucleoproteins (snRNPs), 144, 168, 169 Smooth endoplasmic reticulum (SER), 119–120, 120f Smoothened, 233–234, 238 snRNPs See Small nuclear ribonucleoproteins Snurps, 144 SOCS-3 See Suppressor of cytokine signaling-3 SOD See Superoxide dismutase Sodium (Naϩ) cotransport of, and amino acids, 498, 499f as electrolyte, 19, 23, 23t Sodium chloride, 25 Sodium-dependent glucose transporters, 352–353 Solenoid structures, 140 Solubility, 34, 65 Lieberman_Subject_Index.indd 620 Sorbitol, 375–376 Sorbitol dehydrogenase, 375f Southern blots, 211, 212f Spectrin, 116, 116f S phase, 152, 152f Sphingolipidoses, 398, 399t Sphingolipids, 40, 41f, 396, 448–449, 449f, 451–452, 452f, 453f Sphingomyelin, 40, 41f, 115, 452, 453f Sphingosine, 40, 41f, 449 Spina bifida, 544 Spin restriction, 286 Spliceosome, 168 Splicing, 169, 169f Squalene conversion to steroid nucleus, 461, 461f formation, 461, 461f SRP See Signal recognition particle Starch dietary, 3, 344, 345f digestion of, 346–347, 347f structure of, 4f Start codon, 180, 180f Starvation blood glucose levels during, 417–419, 419f death from, 12 STAT factors See Signal transducer and activator of transcription factors Statins, 458, 458t, 474, 480 STAT proteins, 201 Stearate, 5f Stearic acid, 438 Steatorrhea, 427, 432 Stem cells, 205 Stereoisomers, 36, 36f Steroid hormones, 475–476 structure of, 40–41, 41f synthesis of, 476, 477f of adrenal androgens, 477f, 478 of aldosterone, 477f, 478 of cortisol, 476, 477f, 478 of estrogens, 477f, 478–479 of progestins, 477f, 478–479 of testosterone, 477f, 478 of vitamin D, 479, 479f Steroid hormone/thyroid hormone receptors, 124, 198–199, 199f, 200f Stomach, protein digestion in, 496–497, 496f Stop/nonsense codons, 179, 185 Streptomycin, 183 Structural components, Structural domains, 64, 64f Structural genes, 191 Subintimal extracellular matrix, 473, 474f Substituted sugars, 36–37 Substrate binding cooperativity in allosteric enzymes, 102 induced-fit model, 79f, 80–81 lock-and-key model, 80, 80f sites for, 79 Substrate channeling through compartmentation, 109 Substrate cycling, 360 Substrate-level phosphorylation, 260, 260f, 298–299, 300f Succinate, 260–261, 260f Succinate dehydrogenase, 278–279, 279f Succinyl CoA amino acid conversion to, 525, 526f, 527 heme synthesis from, 537, 537f, 538f from methylmalonyl CoA, 549 propionyl CoA conversion to, 319, 319f in TCA cycle, 259, 260f, 261–263, 263f Sucrase—isomaltase complex, 348, 348f, 348t Sucrose dietary, 3, 344 intolerance, 348 structure of, 345f Sugars See also Carbohydrates; specific sugars absorption of, 351–354, 352f, 353t amino, 394–395, 395f D- and L-, 35–36, 35f interconversions involving nucleotide sugars, 392–395 metabolism of fructose, 374–376, 374f, 375f galactose, 376–377, 376f polyol pathway, 375–376, 375f oxidized and reduced, 37, 37f in pentose phosphate pathway, 377 direction of, 382t nonoxidative phase, 377, 379–380, 379f oxidative phase, 377, 378f, 379 reaction sequence, 379–380, 380f red blood cell integrity and, 381, 382f role in NADPH generation, 381, 382f substituted, 36–37 Sugar transferases, 392 Sulfa drugs, mechanism of action, 543 Sulfatides, 452, 453f Sulfation, 400f, 401 Sulfonamide, 389 Sulfonylurea, 336 Sulfur, role of, 17 Sulfuric acid, 28 Supercoils, DNA, 139 Superoxide, 43, 286, 287f Superoxide dismutase (SOD), 290, 290f Suppressor of cytokine signaling-3 (SOCS-3), 452 Systemic lupus erythematosus (SLE), case study, 161, 169, 175, 392, 399, 403–404, 404f T Tangier disease, 469 TAT See Tyrosine aminotransferase TATA-binding protein (TBP), 165, 165f TATA box, 164–165, 164f, 165f Taurocholic acid, 464, 464f Tautomers, 42 Tay-Sachs disease case study, 178, 187–188, 187t, 392, 398, 403 as lysosomal storage disease, 119 TBP See TATA-binding protein TCA cycle See Tricarboxylic acid cycle Telomerase, 154–155, 155f Telomeres, 154–155, 154f, 155 Temperature, enzyme optimum, 90 Template strand, 162–163, 163f Termination signal, 166 Tertiary structure, 61, 61f, 63–64 domains in, 64, 64f folds in globular proteins, 64 solubility of globular proteins, 65 of transmembrane proteins, 65–66, 65f Testosterone, synthesis of, 477f, 478 Tetrahydrobiopterin (BH4) as cofactor in amino acid metabolism, 520, 523 defect in synthesis, 529 Tetrahydrofolate (FH4) carbon recipients, 546–547, 546t, 547f carbon sources, 546, 546f, 546t as cofactor in amino acid metabolism, 520, 524 folate, 544, 544f oxidation and reduction, 545–546, 545f relationships with vitamin B12 and SAM, 550–552, 551f structure and forms of, 543, 544f Thalassemia, case study, 161, 165, 169, 174, 178, 181–182, 187, 187t Therapeutic proteins, production of, 219 Thermodynamics, 244t Thermogenesis, 250, 285 9/16/14 9:17 PM INDEX Thiamine, 272–273 deficiency of, 86, 94, 94t, 263, 272, 379, 527 Thiamine pyrophosphate (TPP), 86, 87f, 263 Thin filaments, 121 Thioredoxin, 563 Threonine deamination of, 506f, 507 as essential amino acid, 15 glycine from, 520, 520f structure of, 48f, 49–50 Thrombolysis, 294 Thromboxanes, 15 biosynthesis of, 440, 441f, 442–444, 443f function of, 443t inactivation of, 445 structure of, 441f, 442 Thymidine triphosphate (TTP), 562 Thymidylate synthase, 565 Thymine base pairing of, 137, 137f degradation of, 565 folate metabolism and, 546–547 nucleoside, 135t structure of, 41, 42f, 135, 135f, 136f, 141, 142f uracil compared with, 141, 142f Thymine dimer, 155, 155f Thyroid hormone receptor, 199, 200f Tissue plasminogen activator (TPA), 219, 275–276, 294 Tissue-specific isoforms or isozymes, 53 TNM system, 239 Tolerable Upper Intake Level (UL), 16 Topoisomerases, 139, 149 Total body water, 22 TPA See Tissue plasminogen activator TPP See Thiamine pyrophosphate Trace minerals, 16 Transactivators, 198 Transaldolase, in pentose phosphate pathway, 379, 380, 380f, 381f Transaminases, 505 Transamination reactions, 505, 505f Transcellular water, 22 Trans configuration, 61 Transcription, 161 of bacterial genes, 166, 166f of eukaryotic genes, 167 mRNA synthesis, 167–169, 167f, 168f, 169f rRNA synthesis, 169–170, 170f tRNA synthesis, 170–172, 171f, 172f regulation at level of, 196–202, 197f, 199f, 200f, 201f regulation of availability of genes for, 195–196 RNA polymerase action, 161–162, 162f types, 162–166 site of, 119 Transcription-coupled repair, 157 Transcription factors, 165–166, 196–202, 197f intracellular receptors of, 124, 124f as proto-oncoproteins, 230f, 231 regulation of, 200–201 Transcription regulation of HMG-CoA reductase, 462 Transduced cells, 213 Trans fatty acids, 39 Transfected cells, 213 Transferrin receptor, 204, 204f Transfer RNA (tRNA) anticodon, 178–179, 178f, 179f formation of aminoacyl-tRNA, 181–182, 181f structure of, 143–144, 144f, 171f synthesis of eukaryotic, 170–172, 171f, 172f Transformed cells, 213 Transition state analogues, 90–91, 92f, 93f Lieberman_Subject_Index.indd 621 Transition state complex, 79, 81, 81f, 84 Transketolase activity of red blood cells, 379 in pentose phosphate pathway, 379, 380, 380f, 381f Translation aminoacyl-tRNA formation, 181–182, 181f elongation, 183–184, 183f energy required for, 185 genetic code, 178–180, 179t initiation, 182–183, 182f, 202–203, 202f, 203f mutations, effect of, 180–181, 180t, 181f polysomes, 185 posttranslation modifications of proteins, 185–186 regulation at level of, 202–203, 202f, 203f targeting of proteins to subcellular and extracellular locations, 186, 187f termination of, 185 Translocation, 185 Transmembrane proteins, 60, 60f, 65–66, 65f Transport of amino acids into cells, 499 cotransport of Naϩ and amino acids, 498, 499f of membrane systems, 117, 117f Transport work, 246 Trehalase, 348–349, 348t, 349f Triacylglycerols as body fuel store, 313 in chylomicrons, 428 composition of VLDL, 445 as dietary fuel, digestion of, 424 bile salts, 425, 425f pancreatic lipase, 425–426, 426f fate of VLDL, 445 fatty acid release from, 448, 448f as fuel store, 5–6, 5t glucose conversion to, 6f, 7–8 lowering-agents, 454 regulation of synthesis in liver, 483–487, 484f resynthesis in intestinal epithelial cells, 427–428, 427f serum levels, 457, 487 storage in adipose tissue, 447, 447f, 486–487, 486f structure of, 5f, 40f synthesis of, 445, 446f Tricarboxylic acid (TCA) cycle, 3, 3f amino acid degradation and, 525, 526f, 527 anaplerotic reactions, 269–270, 270f, 271f coenzymes of, 261–263, 262f, 263f energetics, 263–265, 264f intermediates of, 269 precursors of acetyl CoA, 267, 268f pyruvate dehydrogenase complex, 267–269, 268f, 269f sources of acetyl CoA, 267 reactions of, 258–261, 259f, 260f regulation of, 265–267, 265f, 266t Triglycerides See Triacylglycerols Triose kinase, 375 Triose phosphates, 299, 300f Troponin T, 53, 57, 60, 75, 275 Trp operon, 193 Trypsin, 497–498, 497f Trypsinogen, 497–498, 497f Tryptophan degradation of, 529 as essential amino acid, 15 serotonin from, 532–533, 534f structure of, 48f, 49 TTP See Thymidine triphosphate Tuberculosis, case study, 168, 175 Tubulin, 121 621 Tumor, 226–227 Tumor suppressor genes, 231 cell cycle regulation by p53, 232–233, 233f retinoblastoma gene, 232, 232f receptors and signal transduction patched and smoothened, 233–234 Ras regulation, 233 Tunica media, 473–474, 474f Turnover, of proteins, 9, 11 TXA2, 442–445, 443f, 443t TXA3, 443 TXB2, 445 Type diabetes mellitus, 22, 29t case studies, 22, 24, 27, 29, 29t, 46, 53, 56t, 57, 60, 72, 74t, 75, 219, 312, 325, 327, 337, 341, 341t, 367, 406, 415, 417, 420, 483, 486–487, 492 coma due to, 22, 24, 312, 327 insulin deficiency, 486–487, 492 ketoacidosis and, 22, 27, 29, 32–33, 43–44, 312, 325, 327, 407, 483, 492 Kussmaul breathing in, 27, 29, 312, 325 LPL deficiency, 486, 487 osmotic diuresis in, 24, 29, 327 peripheral neuropathy from, 376 treatment of Humalog, 46, 53, 57, 219 Humulin, 46, 53, 57 insulin use, 22, 29, 46, 406 rehydration, 24, 29 vascular complications, 420, 492 Type diabetes mellitus, 18t, 330–331 adipose mass and, 18 case studies, 344, 352, 355, 355t, 367 glucose intolerance, 417 insulin levels in, 337, 355 insulin resistance in, 341, 487, 492 peripheral neuropathy from, 376 sulfonylurea therapy, 336 vascular complications with, 420, 492 Tyramine, 532–533 Tyrosine biosynthesis of, 520, 520f, 523, 524f degradation of, 528–529, 528f, 532 genetic disorders of amino acid metabolism, 529t structure of, 48f, 49, 51 Tyrosine aminotransferase (TAT), 528f, 529 Tyrosine hydroxylase, 531f, 532 Tyrosinemia, 528, 528f U Ubiquinone, 279 Ubiquitin, 108, 500 Ubiquitin-proteasome pathway, 500, 501f UCPs See Uncoupling proteins UDP-galactose See Uridine diphosphate-galactose UDP-glucose See Uridine diphosphate glucose UDP-glucose epimerase, 376 UDP-glucuronate, 393, 393f UDP sugars, 396 UL See Tolerable Upper Intake Level Ultratrace minerals, 16 UMP See Uridine monophosphate Uncompetitive inhibitor, 100–101, 101f Uncoupling oxidative phosphorylation, 284–285, 284f Uncoupling proteins (UCPs), 285 Unsaturated fatty acids, 38–39, 39f, 313, 318–319, 318f Upstream events, 125 Upstream sequences, 164 Uracil, 141, 142f Urea arginine production of, 509f, 510 as protein degradation measure, 418–419, 419f synthesis in hypercatabolic state, 579 9/16/14 9:17 PM 622 INDEX Urea cycle, 508–509 disorders of, 512–513, 514f function during fasting, 512 reactions of, 509, 509f arginine cleavage, 509f, 510 arginine production, 509f, 510, 510f, 512 ornithine synthesis, 510–511 synthesis of carbamoyl phosphate, 509–510, 509f regulation of, 511–512, 511f Uric acid, 42 Uridine, for orotic aciduria, 561 Uridine diphosphate-galactose (UDP-galactose) cerebroside synthesis from, 398 formation of, 376 lactose formation from, 394, 394f Uridine diphosphate glucose (UDP-glucose) cerebroside synthesis from, 398 formation of, 361, 361f phosphoglucomutase and, 395 reactions of, 392, 392f UDP-glucuronate formation from, 393, 393f Uridine monophosphate (UMP), synthesis of, 561, 562f Uridine phosphorylase, 562 Urinary pH, 28 Urine tests, 19 Urobilinogen, 538, 539f V Vaccines, 218–219 Valine degradation of, 525, 527, 527f as essential amino acid, 15 structure of, 48f, 49 Variable loop, tRNA, 171, 171f Variable number of tandem repeats (VNTR), 216–217, 217f V-ATPases See Vesicular ATPases VDACs See Voltage-dependent anion channels Vector, 213 Very long chain fatty acids, 321, 321f Lieberman_Subject_Index.indd 622 Very low density lipoprotein (VLDL), 467 apoB and, 428–429, 428f characteristics of, 467t cholesterol transport, 467, 468f composition of, 445, 447f fate of, 445, 468f, 486–487 in fed state, 6f, 7–9 LDL from, 8–9, 445 levels in alcoholism, 446 FCH, 445 remnants, 467 serum levels, 487 structure of, 428f synthesis of, 445, 446f, 462 Vesicular ATPases (V-ATPases), 119, 246 Vioxx See Rofecoxib Viruses, 135, 143, 220, 229 cancer and, 238 Vitamin B6, deficiency of, 507, 521, 529 Vitamin B12 absorption and transport, 547–548 deficiency of, 543, 547, 549, 553 functions of, 548–549, 549f, 550f relationships with folate and SAM, 550–552, 551f structure and forms of, 547, 548f supplements, 553 Vitamin C, 292 Vitamin D3, 479f Vitamin D synthesis, 479, 479f Vitamin E, 291–292 Vitamins, 16 deficiency of, 86 dietary requirements and guidelines for, 16 fat-soluble, 16, 428 water-soluble, 16 VLDL See Very low density lipoprotein Vmax, enzyme, 98–102, 98f, 99f, 101f, 103f VNTR See Variable number of tandem repeats Voltage-dependent anion channels (VDACs), 293f, 294 W Water dissociation of, 24 fluid compartments in body, 22, 22f hydrogen bonds in, 23, 23f ion product of, 24 movement of, 24 pH, 24 properties of, 23 required intake, 17 structure of, 23, 23f Weight gain and loss, 14, 218, 420t, 452 Western blots, 211, 212f Work biochemical, 246–249 energy available to do, 242–245, 242f, 243f, 244t, 245f mechanical, 245–246 transport, 246 X Xanthelasma, 479 Xanthine, 564–565 Xanthine oxidase, 91, 93f, 564–565 Xanthomas, 453 Xanthosine monophosphate (XMP), 558, 558f Xanthurenic acid, 507 Xenobiotics, 17 XMP See Xanthosine monophosphate Xylulose 5-phosphate, in pentose phosphate pathway, 379–380, 379f, 380f, 381f Z ZDV See Zidovudine Zellweger syndrome, 119, 321, 451 Zidovudine (ZDV), 145 Zinc insulin binding, 57 role of, 16 Zinc finger motifs, 199–200, 200f Zwitterion, 47 Zymogens, 105–106, 496–498, 497f 9/16/14 9:17 PM ... incorporate breakfast cereals composed of wheat bran, barley, and oats into her morning routine Lieberman_Ch 22. indd 3 52 9/16/14 2: 07 AM CHAPTER 22 ■ DIGESTION, ABSORPTION, AND TRANSPORT OF CARBOHYDRATES... Transport of Carbohydrates CHAPTER OUTLINE I DIETARY CARBOHYDRATES III DIETARY FIBER II DIGESTION OF DIETARY CARBOHYDRATES A Salivary and pancreatic α-amylase B Disaccharidases of the intestinal brush... with no abnormal findings on physical examination A stool sample was taken I DIETARY CARBOHYDRATES Carbohydrates are the largest source of calories in the average American diet and usually constitute