Medical Biochemistry

Front Matter......Page 1
Resident Drawing......Page 2
Copyright Page......Page 3
List of Contributors......Page 4
Acknowledgments......Page 7
Dedication......Page 8
Preface......Page 9
Abbreviations......Page 10
A textbook is a snapshot of rapidly changing knowledge......Page 18
Keywords......Page 19
One studies biochemistry to understand the interplay of nutrition, metabolism, and genetics in health and disease: let’s start here with the shortest possible overview of the field......Page 20
Proteins, carbohydrates, and lipids are the major structural components of the body......Page 21
The genome underpins it all......Page 22
Further reading......Page 23
Abbreviations......Page 24
Classification of amino acids based on chemical structure of their side chains......Page 25
Keywords......Page 26
Phenylalanine, tyrosine, and tryptophan have aromatic side chains......Page 27
Basic amino acids......Page 28
Amino acids are amphoteric molecules - they have both basic and acidic groups......Page 29
The H-H equation describes the titration of an amino acid and can be used to predict the net charge and isoelectric point of a protein......Page 30
The primary structure of a protein is the linear sequence of its amino acids......Page 31
The β-pleated sheet......Page 32
The quaternary structure of multisubunit proteins is determined by covalent and noncovalent interactions between the subunit surfaces......Page 33
Protein purification is a multistep process, based on protein size, charge, solubility, and ligand binding......Page 34
Small molecules, such as salts, can be removed from protein solutions by dialysis or ultrafiltration......Page 35
Gel filtration chromatography separates proteins on the basis of size......Page 36
Polyacrylamide gel electrophoresis in sodium dodecylsulfate can be used to separate proteins based on charge......Page 37
Historically, analysis of protein sequence was carried out by chemical methods; today, both sequence analysis and protein identification are performed by mass spectrometry......Page 38
X-ray crystallography and nuclear magnetic resonance (NMR) spectroscopy are usually used for determination of the three-dimensional structure of proteins......Page 40
Further reading......Page 41
Abbreviations......Page 42
Cyclization of sugars......Page 43
Keywords......Page 44
Lipids are found primarily in three compartments in the body: plasma, adipose tissue, and biological membranes......Page 46
Fatty acids exist in free form and as components of more complex lipids......Page 47
Triglycerides are the storage form of lipids in adipose tissue......Page 49
Eukaryotic cells have a plasma membrane and intracellular membranes that define compartments with specialized functions......Page 50
Membranes maintain the structural integrity, cellular recognition processes, and transport functions of the cell......Page 51
Abbreviations......Page 53
Membrane proteins are required for transport of larger molecules across biomembranes......Page 54
Keywords......Page 55
Saturability and specificity are important characteristics of membrane transport systems......Page 57
Membrane channels or pores are open, less selective conduits for transport of ions, metabolites, and even proteins across biomembranes......Page 58
Primary active transport systems use ATP to drive ion pumps (ion-transporting ATPases, or pump ATPases)......Page 59
Uniport, symport, and antiport are examples of secondary active transport......Page 60
Membrane depolarization opens up voltage-dependent ion channels at the neuromuscular junction......Page 61
A Na+/K+-ATPase drives uptake of glucose into intestinal and renal epithelial cells......Page 62
P-ATPase in gastric parietal cells maintains the low pH of the stomach......Page 63
Summary......Page 64
Abbreviations......Page 65
Globins constitute an ancient family of soluble metalloproteins......Page 66
Keywords......Page 67
Mb binds O2 that has been released from Hb in tissue capillaries and subsequently diffused into tissues......Page 69
Hb is the principal O2-transporting protein in human blood; it is localized exclusively in erythrocytes......Page 70
Hemoglobin subunits may assume two different conformations that differ in O2 affinity......Page 71
Acidic pH (protons) decreases the O2 affinity of Hb......Page 73
2-3-Bisphoglycerate (2,3-BPG), an intermediate in carbohydrate metabolism, is an important allosteric effector of Hb......Page 74
Nitric oxide, a potent vasodilator, is stored on Hb as S-nitrosoHb (SNO-Hb)......Page 75
Hemoglobin variants......Page 76
More than 1000 mutations in the genes encoding the α- and β-globin polypeptides have been documented......Page 78
Summary......Page 79
Abbreviations......Page 80
One international unit (IU) of enzyme catalyzes conversion of 1 µmol of substrate to product per minute......Page 81
Keywords......Page 82
Helper molecules, referred to as coenzymes, play an essential part in many enzyme-catalyzed reactions......Page 83
Enzyme reactions are multistep in nature and comprise several partial reactions......Page 84
Alternative graphical analyses permit more accurate determination of the Km and Vmax of an enzyme......Page 86
Enzymatic reactions involve functional groups on amino acid side chains, coenzymes, substrates, and products......Page 87
Competitive inhibitors cause an apparent increase in Km without changing Vmax......Page 88
Uncompetitive inhibitors cause an apparent decrease in Vmax......Page 89
Many drugs and poisons irreversibly inhibit enzymes......Page 90
Positive and negative cooperativity......Page 91
Kinetic assays are more rapid than endpoint assays......Page 93
Relevant websites......Page 94
Abbreviations......Page 95
Vitamin A is stored in the liver and needs to be transported to its sites of action......Page 96
Keywords......Page 97
Vitamin A is toxic in excess......Page 98
Inhibitors of vitamin K action are valuable antithrombotic drugs......Page 99
Beriberi was the first-discovered deficiency disease......Page 100
Severe niacin deficiency results in dermatitis, diarrhea, and dementia......Page 101
Folate deficiency is one of the commonest vitamin deficiencies......Page 102
The function of vitamin B12 needs to be considered together with folate......Page 103
Dietary supplementation of vitamins......Page 105
The benefits of vitamin supplementation in cancer and cardiovascular disease are uncertain......Page 106
Major minerals present in the human body are sodium, potassium, chloride, calcium, phosphate, and magnesium......Page 107
Erythrocyte content of iron affects its absorption from the intestine......Page 108
Zinc is a trace element contained in approximately 100 enzymes associated with carbohydrate and energy metabolism, protein synthesis and degradation, and nucleic acid synthesis......Page 109
Rare copper deficiency leads to anemia; skin and hair may also be affected......Page 110
Other metals......Page 111
Abbreviations......Page 112
The BMR is a measure of the total daily energy expenditure by the body at rest......Page 114
Keywords......Page 115
The free energy of metabolic reactions is related to their equilibrium constants by the Gibbs’ equation......Page 116
ATP is a product of catabolic reactions and a driver of biosynthetic reactions......Page 117
NAD+, FAD, and FMN are the major redox coenzymes......Page 118
The mitochondrial electron transport chain transfers electrons in a defined multistep sequence from reduced nucleotides to oxygen......Page 119
Electrons are funneled into the electron transport chain by several flavoproteins......Page 120
Electron shuttles are required for mitochondrial oxidation of NADH produced in the cytoplasmic compartment......Page 121
Cytochrome c is a peripheral membrane protein, shuttling electrons from complex III to complex IV......Page 123
Synthesis of adenosine triphosphate: the chemiosmotic hypothesis......Page 124
P : O ratios......Page 125
“Respiratory control” is the dependence of oxygen uptake by mitochondria on the availability of ADP......Page 126
Uncoupling proteins (UCP)......Page 127
Antimycin A inhibits complex III (QH2–cytochrome c reductase)......Page 128
Inhibitors of the ADP–ATP translocase......Page 129
Regulation by covalent modification and allosteric effectors (ATP–ADP)......Page 130
Further reading......Page 131
Abbreviations......Page 132
The erythrocyte, or red blood cell, relies exclusively on blood glucose as a metabolic fuel......Page 133
Keywords......Page 134
Fructose-6-phosphate......Page 135
Fructose-1,6-BP is cleaved in the middle by a reverse aldol reaction......Page 136
Substrate-level phosphorylation produces ATP from another high-energy phosphate compound......Page 137
Phosphoglycerate kinase and pyruvate kinase catalyze substrate-level phosphorylation reactions......Page 138
LDH regenerates NAD+ consumed in the GAPDH reaction, producing lactate, the end product of anaerobic glycolysis......Page 139
PFK-1 is the primary site of regulation of glycolysis......Page 140
Regulatory enzymes are rate-limiting steps in metabolic pathways......Page 141
NADPH is synthesized by two dehydrogenases in the first and third reactions of the pentose phosphate pathway......Page 142
Excess pentose phosphates are converted to Fru-6-P and glyceraldehyde-3-P in the interconversion stage of the pentose phosphate pathway......Page 143
The pentose phosphate pathway protects against oxidative damage in the red cell......Page 144
Summary......Page 145
Abbreviations......Page 146
Acetyl-CoA is a common product of many catabolic pathways......Page 147
Keywords......Page 148
Pyruvate may be directly converted to four different metabolites......Page 150
The TCA cycle is a sequence of reactions for oxidation of acetyl-CoA to CO2 and reduced nucleotides......Page 151
Aconitase......Page 152
Isocitrate dehydrogenase and α-ketoglutarate dehydrogenase......Page 154
Succinyl-CoA synthetase......Page 155
Energy yield from the tricarboxylic acid cycle......Page 156
Pyruvate dehydrogenase and isocitrate dehydrogenase regulate TCA cycle activity......Page 157
Abbreviations......Page 159
The length of the fatty acid dictates where it is activated to CoA......Page 160
Keywords......Page 161
The carnitine shuttle bypasses the impermeability of the mitochondrial membrane to coenzyme A......Page 162
Oxidation of the β-carbon (C-3) facilitates sequential cleavage of acetyl units from the carboxyl end of fatty acids......Page 163
Odd-chain fatty acids produce succinyl-CoA from propionyl-CoA......Page 164
Ketogenesis is a pathway for regenerating CoA from excess acetyl-CoA......Page 165
What does the liver do with the excess acetyl-CoA that accumulates in fasting or starvation?......Page 166
Ketogenesis is activated in concert with gluconeogenesis during fasting and starvation......Page 167
Further reading......Page 169
Abbreviations......Page 170
Glycogen, a highly branched glucan, is the storage form of glucose in tissues......Page 171
Keywords......Page 172
Glycogenesis is activated in the liver and muscle after a meal......Page 173
Three hormones (insulin, glucagon, and cortisol) counterregulate glycogenolysis and glycogenesis......Page 174
Glucagon activates glycogenolysis during the postabsorptive state......Page 175
Epinephrine activates glycogenolysis during stress, increasing blood glucose concentration......Page 178
Muscle lacks a glucagon receptor and glucose-6-phosphatase; it is not a source of blood sugar during hypoglycemia......Page 179
Insulin opposes the action of glucagon and stimulates gluconeogenesis......Page 181
Gluconeogenesis is required to maintain blood glucose during fasting and starvation......Page 182
Glucose cannot be synthesized from fatty acids!......Page 183
Fructose-2,6-bisphosphate allosterically counterregulates glycolysis and gluconeogenesis......Page 185
Summary......Page 186
Abbreviations......Page 187
Carboxylation of acetyl-CoA to malonyl-CoA is the committed step of fatty acid synthesis......Page 188
Keywords......Page 189
Synthesizing a fatty acid chain: Fatty acid synthase......Page 190
Malate shuttle allows recruitment of two-carbon units from the mitochondrion to the cytoplasm......Page 191
The ω-3 and ω-6 fatty acids (or their precursors) must be supplied with diet......Page 194
Triacylglycerols produced in the liver on the smooth endoplasmic reticulum can only be transiently stored......Page 195
Adipose tissue is an active endocrine organ......Page 196
Abbreviations......Page 197
Humans cannot metabolize the sterol structure......Page 199
Keywords......Page 200
Cholesterol is absorbed in the intestine by specific transporters......Page 201
Squalene is a linear molecule capable of a ring formation......Page 202
Final stages of cholesterol biosynthesis occur on a carrier protein......Page 203
Plant sterols and cholesterol precursors are markers of cholesterol absorption and metabolism......Page 204
Sterol regulatory element-binding proteins (SREBP) are transcriptional regulators of cholesterol synthesis......Page 205
Liver removes cholesterol either in a free form or as bile acids......Page 207
Secondary bile acids are synthesized in the intestine......Page 208
Cholesterol is the precursor of all steroid hormones......Page 209
Steroidogenesis is controlled by cytochrome P450 monooxygenases......Page 210
Conversion of androgens into estrogens involves removal of the methyl group at C-19......Page 211
Summary......Page 212
Abbreviations......Page 213
Muscle protein and adipose lipids are consumed to support gluconeogenesis during fasting and starvation......Page 214
Keywords......Page 215
Turnover of endogenous proteins......Page 216
Amino acids destined for energy metabolism must be deaminated to yield the carbon skeleton......Page 217
Ammonia is detoxified by incorporation into glutamine, then eventually into urea......Page 218
The urea cycle is a hepatic pathway for disposal of excess nitrogen......Page 219
The urea cycle is split between the mitochondrial matrix and the cytosol......Page 220
N-acetylglutamate (and indirectly, arginine) is an essential allosteric regulator of the urea cycle......Page 222
Amino acids may be either glucogenic or ketogenic......Page 223
The 20 amino acids are metabolized by complex pathways to various intermediates in carbohydrate and lipid metabolism......Page 224
Evolution has left our species without the ability to synthesize almost half the amino acids required for the synthesis of proteins and other biomolecules......Page 225
Inherited diseases of amino acid metabolism......Page 226
Phenylketonuria (PKU)......Page 227
Maple syrup urine disease (MSUD)......Page 228
Relevant websites......Page 229
Abbreviations......Page 230
Purines and pyrimidines are synthesized by both de novo and salvage pathways......Page 231
Keywords......Page 232
Salvage pathways for purine nucleotide biosynthesis......Page 233
Uric acid is the end product of purine catabolism in humans......Page 235
Most persons with hyperuricemia remain asymptomatic throughout life, but there is no gout without hyperuricemia......Page 236
De novo pathway......Page 237
Pyrimidine salvage pathways......Page 238
Ribonucleotide reductase catalyzes reduction of ribose to deoxyribose in nucleotides for the synthesis of DNA......Page 239
Thymine is synthesized by a complex reaction pathway, providing many opportunities for chemotherapy......Page 240
Summary......Page 241
Abbreviations......Page 243
Sugars are attached to specific amino acids in proteins......Page 244
Keywords......Page 245
N-glycans have either “high-mannose” or “complex” structures built on a common core......Page 247
Structure–function relationships in mucin glycoproteins......Page 248
Metabolism of galactose......Page 249
Fructose accounts for about half the sugar in both sucrose (table sugar) and high-fructose corn syrup......Page 250
GDP-Man and GDP-Fuc......Page 251
Fru-6-P is the precursor of amino sugars......Page 252
N-glycan assembly begins in the endoplasmic reticulum......Page 253
O-glycans are synthesized in the Golgi apparatus......Page 255
N-glycans have an important role in protein folding......Page 256
Sugars are involved in chemical recognition interactions with lectins......Page 257
Summary......Page 259
Abbreviations......Page 260
Phospholipids are in a constant state of synthesis, turnover, and remodeling......Page 261
Keywords......Page 262
Remodeling pathway......Page 264
Structure and biosynthesis of sphingosine......Page 265
Sphingomyelin is the only sphingolipid that contains phosphate and is the major phospholipid in the myelin sheath of nerves......Page 266
Gangliosides are glycosphingolipids containing sialic (N-acetylneuraminic) acid......Page 267
Lysosomal storage diseases resulting from defects in glycolipid degradation......Page 268
ABO blood group antigens......Page 269
Further reading......Page 271
Abbreviations......Page 272
The left-handed triple-helical structure of collagen is unique among proteins......Page 273
Keywords......Page 274
Fibrillar collagens provide tensile strength to tendons, ligaments, and skin......Page 275
Nonfibrillar, lattice-forming collagens are major structural components of basement membranes......Page 276
Procollagen is finally modified to collagen in the Golgi apparatus......Page 277
Fibronectin and laminin have multiple binding sites for ECM proteins and proteoglycans......Page 279
Glycosaminoglycans are the polysaccharide components of proteoglycans......Page 281
Defects of proteoglycan degradation lead to mucopolysaccharidoses......Page 282
Integrins are plasma membrane proteins that bind to and transmit mechanical signals between the ECM and intracellular proteins......Page 283
Summary......Page 284
Abbreviations......Page 286
Watson and Crick model of DNA......Page 287
Keywords......Page 288
Three-dimensional DNA......Page 289
The human genome......Page 290
Nucleosomes are the building blocks of chromatin......Page 291
The cell cycle in eukaryotes......Page 292
DNA synthesis proceeds in opposite directions along the leading and lagging strands of the template DNA......Page 293
Multiple enzymatic pathways repair a wide range of chemical modifications of DNA......Page 294
Deamination: Excision repair......Page 295
8-Oxo-2′-deoxyguanosine......Page 296
DNA sequencing, hybridization, and cloning are fundamental techniques of genetic engineering......Page 297
The stability of a nucleic acid duplex can be assessed by determining its melting temperature (Tm)......Page 298
Restriction enzymes cleave DNA at specific nucleotide sequences......Page 299
Analysis of restriction fragment length may be used to detect a mutation or polymorphism in a gene......Page 300
Bacterial plasmids are bioengineered to optimize their use as vectors......Page 301
Summary......Page 303
Abbreviations......Page 305
rRNAs: the ribosomal RNAs......Page 306
Keywords......Page 307
mRNA: prokaryotic and eukaryotic mRNAs differ significantly in structure and processing......Page 308
Transcription is a dynamic process involving interaction of enzymes with DNA to produce RNA molecules......Page 310
Elongation is the process by which single nucleotides are added to the growing RNA chain......Page 311
Posttranscriptional processing of ribonucleic acids......Page 312
rRNAs and tRNAs are synthesized as larger precursors (pre-RNAs) that are processed to yield mature transcripts (Fig. 21.6)......Page 313
Pre-mRNA processing......Page 314
Alternative splicing produces multiple mRNAs from a single pre-mRNA transcript......Page 315
Micro-RNAs, siRNA, RNAi, and RISC......Page 316
miRNAs......Page 317
Summary......Page 318
Abbreviations......Page 319
The genetic code is degenerate and not quite universal......Page 320
Keywords......Page 321
The ribosome is a multistep assembly line for protein synthesis......Page 322
Some flexibility in base pairing occurs at the 3′ base of the mRNA codon......Page 323
How does the ribosome know where to begin protein synthesis?......Page 324
Synthesis of a protein is initiated at the first AUG (methionine) codon in the mRNA......Page 325
Factors involved in the elongation stage of protein synthesis are targets of some antibiotics......Page 326
ER stress, the result of errors in protein folding, develops in many chronic conditions, including obesity, diabetes, and cancer......Page 327
Cellular fate of proteins is determined by their signal peptide sequences......Page 329
Most proteins require posttranslational modification before they become biologically active......Page 330
Ubiquitin targets proteins to the proteasome for degradation......Page 331
Further reading......Page 332
Abbreviations......Page 333
Gene transcription depends on key cis-acting DNA sequences in the region of the gene......Page 334
Keywords......Page 335
Promoters are usually upstream of the transcription start point of a gene......Page 336
Enhancers modulate the strength of gene expression in a cell......Page 337
Transcription factors can affect transcription directly by controlling the function of RNA polymerase or indirectly by affecting the chromatin structure......Page 338
Transcription factors have highly conserved DNA-binding sites......Page 339
Steroid receptors possess many characteristics of transcription factors and provide a model for the role of zinc finger proteins in DNA binding......Page 340
Steroid receptors are products of a highly conserved gene family......Page 341
Chromatin structure affects access of transcription factors to genes and thereby affects gene expression......Page 342
Methylation is one of several epigenetic modifications of DNA; patterns of DNA methylation at birth affect risk for a number of age-related diseases......Page 343
The editosome modifies the internal nucleotide sequence of mature mRNAs......Page 345
Human genes are biallelic, but sometimes only one allele of the gene is expressed......Page 346
Further reading......Page 348
Abbreviations......Page 349
Studies of the genome, transcriptome, proteome, and metabolome pose different challenges......Page 350
Keywords......Page 351
Karyotyping assesses the general chromosomal architecture......Page 352
Comparative genome hybridization compares two genomes of interest......Page 353
Gene mutations can be studied by sequencing......Page 354
Four principles of DNA sequencing......Page 355
Gene expression and transcriptomics......Page 356
Studying gene transcription by gene (micro)arrays and RNA sequencing......Page 358
Mapping of the occupancy of transcription-factor-binding sites can reveal which genes are likely to be regulated by these factors......Page 359
Proteomics is the study of the protein complement of a cell, the protein equivalent of the transcriptome or genome......Page 360
There is no protein equivalent of PCR that would allow for the amplification of protein sequences, so we are limited to the amount of protein that can be isolated from the sample......Page 361
A classic protein-separation method is two-dimensional (2D) polyacrylamide gel electrophoresis (2DE, 2D-PAGE)......Page 362
Mass spectrometry is a technique used to determine the molecular masses of molecules in a sample......Page 363
Quantitative mass spectrometry......Page 364
Non-MS-based technologies......Page 366
Metabolomics......Page 367
The most common methods for biomarker discovery have developed from those used in transcriptomics, proteomics, and metabolomics (i.e., gene arrays; mass spectrometry, often coupled with chromatography; and NMR spectroscopy)......Page 368
Further reading......Page 369
Abbreviations......Page 370
Intracellular receptors for steroid and thyroid hormones and retinoids are transcription factors......Page 371
Keywords......Page 372
Some receptors possess intrinsic protein kinase activity......Page 374
Some membrane receptors are coupled to G-proteins......Page 375
G-proteins act as molecular switches......Page 376
Glucagon and β-adrenergic receptors are coupled to cAMP......Page 377
Adenylyl cyclase is regulated by G-protein α-subunits......Page 378
cAMP can stimulate cellular signaling independent of PKA......Page 379
IP3 stimulates intracellular calcium mobilization......Page 380
Calmodulin has a wide range of target effectors......Page 381
Other phospholipases hydrolyze phosphatidylcholine or phosphatidylethanolamine, generating a range of lipid second messengers......Page 383
Arachidonic acid is the precursor of eicosanoids......Page 384
Abbreviations......Page 385
Action potentials are caused by changes in ion flows across cell membranes......Page 387
Keywords......Page 388
A change in voltage that tends to drive the resting potential toward zero from the normal negative voltage is known as a depolarization, whereas a process that increases the negative potential is called hyperpolarization......Page 389
Neurotransmitters act by binding to specific receptors and opening or closing ion channels......Page 390
The action of transmitters must be halted by their removal from the synaptic cleft......Page 391
Glutamate and excitotoxicity......Page 392
GABA is synthesized from glutamate by the enzyme glutamate decarboxylase......Page 393
Norepinephrine (also known as noradrenaline) is a major transmitter in the sympathetic nervous system......Page 394
Dopamine is both an intermediate in the synthesis of norepinephrine and a neurotransmitter......Page 395
Serotonin, also called 5-hydroxytryptamine (5-HT), is derived from tryptophan......Page 396
Acetylcholine (ACh) is the transmitter of the parasympathetic autonomic nervous system and of the sympathetic ganglia (Fig. 26.1)......Page 397
Many peptides act as neurotransmitters......Page 399
Summary......Page 400
Abbreviations......Page 401
Structurally, hormones may be modified amino acids, peptides, glycoproteins, or steroids......Page 402
Keywords......Page 403
The inactivation of hormones is key to their function as controllers of homeostasis......Page 404
Isolated measurements of hormones that exhibit circadian rhythm, such as cortisol and growth hormone are of limited value......Page 405
Structure......Page 406
The hypothalamus secretes hormones that may stimulate or inhibit the release of hormones from the anterior pituitary......Page 407
Thyroxine (T4) and triiodothyronine (T3)......Page 408
Hyperthyroidism, also described as an “overactive thyroid,” is the excessive production and secretion of thyroid hormones and is caused by a number of conditions (Table 27.4)......Page 410
Hypothyroidism, also described as an “underactive thyroid,” is thyroid hormone deficiency......Page 411
Serum TSH is typically used as a first-line screen for thyroid disease; an fT4 may also be requested if there is a strong clinical suspicion of thyroid disease or if there is an indication to consider pituitary disease......Page 412
Anatomy and biochemistry of the adrenal gland......Page 413
There are four broad areas of cortisol action: negative feedback to the hypothalamus and anterior pituitary, metabolic homeostasis, fluid/electrolyte homeostasis, and antiinflammatory/immunosuppressive effects......Page 414
Primary adrenal insufficiency......Page 415
Adrenal insufficiency may result from genetic conditions caused by defects in steroid biosynthesis......Page 416
Hypercortisolism......Page 417
Measurement of plasma ACTH in the presence of hypercortisolemia is used to determine whether cortisol production is ACTH-driven rather than autonomous......Page 418
Action of gonadotropins on the testes......Page 419
Endocrine failure of the testes may be primary, due to trauma or inflammation of the testes, for example, or secondary, due to a failure of the hypothalamus or pituitary......Page 420
In the mature female, there are cyclic changes in the hypothalamic–pituitary–gonadal axis orchestrated by the GnRH pulse generator......Page 421
Aside from their role in the menstrual cycle, the female sex steroids have additional roles......Page 423
The overall action of GH is to promote growth of bone, cartilage, and soft tissue......Page 424
Measurement of IGF-1 has clinical utility as an indicator of integrated GH activity......Page 425
Excess GH secretion is most commonly due to a pituitary tumor......Page 426
Endocrine systems not considered in this chapter......Page 427
Further reading......Page 429
Abbreviations......Page 430
In recent years, extensive research of the cell cycle has defined a number of key control points......Page 431
Keywords......Page 432
Growth factors selectively initiate signaling cascades......Page 433
Signaling cascade involving Ras GTPase is important in regulating cell division......Page 434
Janus kinases (JAK) link the hematopoietic receptors with the downstream signaling and gene transcription......Page 436
Mitogenic signals activated by growth factors exert their effects between the onset of the G1 phase and a point late in the G1 phase, called the restriction point......Page 437
Cell death is a fundamentally important part of a cell’s life cycle, and appropriate regulation of this process is critical to maintaining the homeostatic regulation of a multicellular organism......Page 439
IAP gene family: its main function is to inhibit apoptosis......Page 440
There are alternative routes to apoptosis......Page 441
Autophagy is induced by a variety of stress stimuli, including nutrient and energy stress as well as hypoxia, oxidative stress, infections, ER stress, and mitochondrial damage......Page 442
Cells that develop mutations affecting normal regulation of the cell cycle are able to undergo unchecked proliferation, resulting in a loss of homeostatic regulation and the development of a tumor or neoplasm......Page 444
Mutations that lead to the expression of established oncogenes do not necessarily lead to the development of cancer if they occur in nonsusceptible cells......Page 445
Whole-exome/genome sequencing of individual patients, utilized to determine the specific mutational landscape within cancer subtypes, has enabled links to be established between seemingly diverse cancers that result from similar genetic mutations......Page 446
The tumor suppressor PTEN is one of the most commonly inactivated proteins in sporadic cancer......Page 447
Abbreviations......Page 449
The replicative capacity of cells decreases with age......Page 451
Keywords......Page 452
In poikilotherms, the rate of aging is correlated with temperature, physical activity, and metabolic rate......Page 453
Theories of aging can be divided into two general categories: Biological and chemical......Page 454
The free-radical theory of aging is the most widely accepted theory of aging......Page 455
Mitochondrial DNA is particularly susceptible to oxidative damage......Page 457
The effect of genetics on longevity is readily apparent in animal models......Page 458
Caloric restriction delays the onset of age-related diseases, including cancer......Page 460
Summary......Page 461
Aging resources and links:......Page 462
Abbreviations......Page 463
A large volume of fluid is secreted and reabsorbed by the GI tract......Page 464
Keywords......Page 465
Sodium cotransporters are a common mode of intestinal transport......Page 466
Other modes of sodium transport include electroneutral and electrogenic transport......Page 467
Components of digestion......Page 468
There is considerable functional reserve in all aspects of digestion and absorption......Page 469
Disaccharides and polysaccharides require hydrolytic cleavage into monosaccharides before absorption......Page 470
Active and passive transport systems transfer monosaccharides across the brush-border membrane......Page 471
There are at least two carrier-mediated transport mechanisms for monosaccharides......Page 472
Bile salts and pancreatic enzymes act on the lipid emulsion in the duodenum......Page 473
Bile salts are essential for solubilizing lipids during the digestive process......Page 474
The fate of fatty acids depends on their chain length......Page 475
Final digestion of peptides depends on peptidases present in small intestine......Page 476
Abbreviations......Page 478
Organs and tissues differ in their handling of fuels......Page 479
Keywords......Page 480
Insulin......Page 481
Insulin acts through a membrane receptor that triggers multiple intracellular signaling pathways; intracellular insulin signaling occurs through complex cascades of phosphorylation reactions......Page 482
The GRB2-SOS-Ras-MAPK signaling pathway has mitogenic effects......Page 483
Metabolic effects of insulin......Page 484
Glucagon and other antiinsulin (counterregulatory) hormones increase plasma glucose concentration by stimulating glycogenolysis and gluconeogenesis......Page 485
Incretin hormones are secreted by the gut and potentiate insulin secretion......Page 486
Human metabolism oscillates between the fed state and the fasting state; the molar ratio of insulin to glucagon in plasma depends on which pattern of metabolism is present......Page 487
Prolonged fasting (starvation)......Page 488
The metabolic response to stress mobilizes energy substrates from all available sources; during stress, metabolism is driven by the antiinsulin hormones......Page 489
The stress response includes insulin resistance......Page 491
Susceptibility to type 1 diabetes is inherited......Page 493
In type 2 diabetes, ketoacidosis is rare......Page 494
Key features of diabetic ketoacidosis are hyperglycemia, ketonuria, dehydration, and metabolic acidosis......Page 495
Oxidative stress, advanced glycation (glycoxidation) end products, and activity of the polyol pathway contribute to the development of complications......Page 496
Hypoglycemia......Page 498
The key diagnostic tests for diabetes are measurements of plasma glucose and glycated hemoglobin concentration......Page 499
Oral glucose tolerance test (OGTT) assesses blood glucose response to a carbohydrate load......Page 500
HbA1c is used to diagnose diabetes and to monitor glycemic control......Page 501
Lifestyle modification is the mainstay of diabetes prevention and treatment......Page 502
Biguanides and thiazolidinediones sensitize the peripheral tissues to insulin......Page 503
Summary......Page 504
Abbreviations......Page 505
The glycemic index and glycemic load provide quantitative and qualitative insight into the handling of carbohydrate-containing foods......Page 507
Keywords......Page 508
Proteins......Page 509
Current dietary recommendations for general population focus on a balanced diet......Page 510
The hypothalamus and brainstem translate the information about energy balance into eating behavior......Page 511
Adipose tissue also secretes proinflammatory cytokines......Page 512
Basal metabolic rate is the energy expenditure required to maintain body function at complete rest......Page 514
In health, physical activity is the most important changeable component of energy expenditure......Page 515
Nutrient intake changes during the life cycle......Page 516
Simplified assessment of nutritional status......Page 517
Full assessment involves measurements of vitamins and trace metals......Page 518
Malnutrition is a gradual decline in nutritional status, which leads to a decrease in functional capacity and to other complications......Page 520
There are two types of protein–calorie malnutrition: marasmus and kwashiorkor......Page 521
Cachexia is weight loss predominantly related to disease......Page 522
Summary......Page 523
Abbreviations......Page 524
Lipoproteins differ in size and density......Page 525
Keywords......Page 526
Apolipoproteins are proteins present in lipoprotein particles; they fulfill structural and metabolic functions......Page 527
Enzymes and lipid transfer proteins......Page 529
Plasma lipoprotein cholesterol forms an extracellular pool available to cells......Page 530
HDL particles remove cholesterol from cells......Page 531
Cardiovascular risk means the probability of an ASCVD event......Page 532
Atherosclerosis......Page 534
Normal endothelium has anticoagulant and antiadhesion properties......Page 535
Oxidized lipoproteins are taken up by macrophages......Page 536
Platelets stimulate thrombotic phenomena in the plaques......Page 537
Dyslipidemias......Page 538
Conditions associated with high plasma HDL concentration......Page 540
Statins inhibit HMG-CoA reductase......Page 541
Summary......Page 542
Abbreviations......Page 543
Structure of the liver facilitates exchange of metabolites between hepatocytes and plasma......Page 544
Keywords......Page 545
Response to an acute insult is associated with wide-ranging changes in liver protein synthesis......Page 546
Impaired clearance of ammonia causes brain damage......Page 547
Bile acids are key elements in fat metabolism......Page 548
Three of the 18 cytochrome P-450 gene families share the responsibility for drug metabolism......Page 549
Cytochrome P-450 gene polymorphisms determine the response to many drugs......Page 550
Alcohol excess is a major cause of liver disease......Page 551
Symptoms of alcohol intolerance are exploited to reinforce abstinence......Page 552
Transaminases......Page 553
Cholestatic disease......Page 554
Prehepatic hyperbilirubinemia results from excess production of bilirubin caused by hemolysis or a genetic abnormality in the hepatic uptake of unconjugated bilirubin......Page 555
Posthepatic jaundice is caused by obstruction of the biliary tree......Page 556
Liver cancer is associated with particularly high plasma concentrations of α-fetoprotein......Page 557
Abbreviations......Page 558
The capillary vessel wall separates plasma and the interstitial fluid......Page 560
Keywords......Page 561
The Na+/K+-ATPase is subject to regulation by a number of hormones, including aldosterone......Page 562
The electrochemical gradient drives the passive movement of electrolytes through ion channels......Page 563
Balance between the oncotic and hydrostatic pressures is fundamental for the circulation of substrates and nutrients......Page 564
Sodium transport systems in the renal tubules......Page 565
Aldosterone regulates sodium and potassium homeostasis......Page 569
Vasopressin regulates water reabsorption by the kidneys......Page 571
Clinical abnormalities that develop after excessive fluid loss depend on the ionic composition of the lost fluid......Page 572
Assessment of water and electrolyte status in clinical practice......Page 574
Abbreviations......Page 575
Bicarbonate buffer remains at equilibrium with atmospheric air......Page 576
Keywords......Page 577
Respiratory and metabolic components of the acid–base balance are interlinked......Page 579
Inside cells, hydrogen ion is buffered by proteins and phosphates......Page 580
Ventilation and lung perfusion together determine gas exchange......Page 581
Erythrocytes transport CO2 to the lungs in a “fixed” form - as bicarbonate......Page 582
Ammonia generated by glutaminase reaction participates in the excretion of hydrogen ion......Page 583
Metabolic acidosis results from excessive production or inefficient metabolism or excretion, of nonvolatile acids......Page 584
Alkalosis is rarer than acidosis......Page 585
Summary......Page 586
Abbreviations......Page 587
The sarcomere: The functional contractile unit of muscle......Page 588
Keywords......Page 589
Interaction between actin and myosin during muscle contraction is dependent on cytoplasmic Ca++ concentration......Page 590
Troponins modulate the interaction between actin and myosin......Page 591
Titin modulates the passive tension of muscle......Page 592
T tubules transmit electrochemical signals for efficient muscle contraction......Page 593
Energy resources in the muscle cell......Page 595
Creatine phosphate is a high-energy phosphate buffer used for rapid regeneration of ATP in muscle......Page 596
Muscle consists of two types of striated muscle cells: Fast-glycolytic and slow-oxidative fibers......Page 597
Tissue engineering and replacement of muscle......Page 598
Strength or resistance training increases muscle mass......Page 599
Summary......Page 600
Abbreviations......Page 601
Bone is a specialized connective tissue that, along with cartilage, forms the skeletal system......Page 602
Keywords......Page 603
Osteoblasts are bone-forming cells......Page 604
Bone markers......Page 605
Vitamin D is synthesized in the skin by ultraviolet (UV) radiation......Page 606
Calcium is absorbed in the small intestine and is excreted in urine and feces......Page 608
Hypercalcemia is most commonly caused by primary hyperparathyroidism or by malignancy......Page 609
Hypocalcemia is common in clinical practice......Page 610
Rickets can also develop as a result of phosphate deficiency......Page 611
Summary......Page 612
Abbreviations......Page 613
There are six sources of the CSF......Page 615
Keywords......Page 616
Cells of the nervous system......Page 617
Because of their great length, neurons depend on an efficient system of axonal transport......Page 618
Neurotransmission is an energy-demanding process......Page 619
Types of synapse......Page 620
The best-studied neurotransmitter is acetylcholine......Page 621
Catecholamine transmission......Page 622
Even at rest, the neuron is working to pump ions along ionic gradients......Page 623
The mechanism by which the human eye can detect a single photon of light provides a fascinating example of the chemical processes underlying neuronal function......Page 624
Summary......Page 625
Abbreviations......Page 626
Hematopoiesis......Page 627
Keywords......Page 628
Leukocytes protect the body from infection......Page 629
Proteins that transport metal ions......Page 630
Immunoglobulins are proteins produced in response to foreign substances (antigens)......Page 631
Immunoglobulins share a common Y-shaped structure of two heavy and two light chains......Page 632
The acute-phase response is a nonspecific response to tissue injury or infection......Page 633
C-reactive protein (CRP) is a major component of the acute-phase response and a marker of bacterial infection......Page 634
High-sensitivity CRP assay is used in the assessment of cardiovascular risk......Page 635
Summary......Page 636
Abbreviations......Page 637
Hemostasis requires the coordinated function of blood vessels, platelets, coagulation factors, and the fibrinolytic system......Page 638
Keywords......Page 639
The lysis of fibrin is as important to health as its formation......Page 640
Endothelial damage exposes blood to tissue factor and to collagen......Page 641
Congenital defects in platelet adhesion/aggregation can cause lifelong excessive bleeding......Page 642
The coagulation cascade......Page 643
Congenital deficiencies of coagulation factors (I–XIII) result in excessive bleeding......Page 645
Activated partial thromboplastin time (APTT) assesses the intrinsic pathway......Page 646
The term “final common pathway” refers to the conversion of prothrombin to thrombin via Xa, with Va acting as a cofactor......Page 647
Coagulation inhibitors are essential to prevent excessive thrombin formation and thrombosis......Page 648
The fibrinolytic system acts to limit excessive formation of fibrin through plasmin-mediated fibrinolysis......Page 650
Plasmin inhibitors prevent excessive fibrinolytic activity......Page 651
Abbreviations......Page 652
Oxygen is activated by transition metal ions, such as iron or copper, in the active site of metalloenzymes......Page 654
Keywords......Page 655
ROS are reactive, strongly oxidizing forms of oxygen......Page 656
Peroxynitrite is a strongly oxidizing reactive nitrogen species......Page 657
There are several levels of protection against oxidative damage......Page 658
Our first line of defense against oxidative damage is sequestration or chelation of redox-active metal ions......Page 659
Vitamin C is the outstanding antioxidant in biological systems......Page 661
Glutathionylation of proteins - protection against ROS under stress......Page 662
ROS are essential for many metabolic and signaling pathways......Page 663
Abbreviations......Page 665
The third level of defense is the adaptive immune response......Page 666
Keywords......Page 667
Neutrophils and macrophages use their receptors to recognize attacking microbes......Page 668
NOD-like receptors are located in the cytoplasm......Page 669
Cytokines are soluble mediators of inflammatory and immune responses......Page 670
Adhesion molecules mediate adhesion between cells......Page 671
T and B lymphocytes have distinct cell-surface markers that can assist in assigning their identification......Page 672
Antigen is recognized by specific receptors on T and B cells......Page 673
The MHC complex of genes is grouped into three regions, termed class I, II, and III......Page 674
There is an almost infinite range of possibilities for antibody specificities......Page 675
T-lymphocyte progenitors travel to the thymus, where they develop into T lymphocytes......Page 676
Immunologic memory distinguishes the adaptive immune response from the innate response......Page 677
T helper cell subsets: TH1/TH2, TH17, TFH, and T regulatory (Treg)......Page 678
Humoral immune responses are characterized by the release of antibodies from fully matured plasma cells......Page 679
Activation of the complement system is one of the most important antibody functions......Page 681
Autoimmunity is normally prevented by thymic education; a breakdown in the processes may lead to autoimmune disease......Page 682
Harnessing the power of antibodies for immunotherapy......Page 683
Abbreviations......Page 684
Final notes and cautions when using reference intervals......Page 686
Relevant websites......Page 694
A 72-year-old woman with hypersecretion of androgens: Leydig cell tumor......Page 695
A 32-year-woman with an elevated prolactin: Macroprolactin......Page 696
Recurrent pancreatitis and severe mixed hyperlipidemia: Lipoprotein lipase deficiency......Page 697
Rhabdomyolysis as a consequence of muscle ischemia......Page 698