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Principles of Medical Biochemistry E-Book

Principles of Medical Biochemistry E-Book

Gerhard Meisenberg | William H. Simmons



For nearly 30 years, Principles of Medical Biochemistry has integrated medical biochemistry with molecular genetics, cell biology, and genetics to provide complete yet concise coverage that links biochemistry with clinical medicine. The 4th Edition of this award-winning text by Drs. Gerhard Meisenberg and William H. Simmons has been fully updated with new clinical examples, expanded coverage of recent changes in the field, and many new case studies online. A highly visual format helps readers retain complex information, and USMLE-style questions (in print and online) assist with exam preparation.

  • Just the right amount of detail on biochemistry, cell biology, and genetics – in one easy-to-digest textbook.
  • Full-color illustrations and tables throughout help students master challenging concepts more easily.
  • Online case studies serve as a self-assessment and review tool before exams.
  • Online access includes nearly 150 USMLE-style questions in addition to the questions that are in the book.
  • Glossary of technical terms.
  • Clinical Boxes and Clinical Content demonstrate the integration of basic sciences and clinical applications, helping readers make connections between the two. New clinical examples have been added throughout the text.

Table of Contents

Section Title Page Action Price
Front Cover Cover
Inside Front Cover ES2
Principles of Medical Biochemistry iii
Copyright iv
Preface v
Faculty resources v
Contents vii
Part One Principles of Molecular Structure and Function 1
Chapter 1 Introduction to Biomolecules 2
Water is the solvent of life 2
Water contains hydronium ions and hydroxyl ions 3
Ionizable groups are characterized by their pk values 4
The blood pH is tightly regulated 4
Acidosis and alkalosis are common in clinical practice 5
Bonds are formed by reactions between functional groups 6
Isomeric forms are common in biomolecules 7
Properties of biomolecules are determined by their noncovalent interactions 8
Triglycerides consist of fatty acids and glycerol 10
Monosaccharides are polyalcohols with a keto group or an aldehyde group 10
Monosaccharides form ring structures 11
Complex carbohydrates are formed by glycosidic bonds 11
Polypeptides are formed from amino acids 14
Nucleic acids are formed from nucleotides 14
Most biomolecules are polymers 15
Summary 16
Questions 16
Chapter 2 Introduction to Protein Structure 18
Amino acids are zwitterions 18
Amino acid side chains form many noncovalent interactions 19
Peptide bonds and disulfide bonds form the primary structure of proteins 20
Proteins can fold themselves into many shapes 22
α-helix and β-pleated sheet are the most common secondary structures in proteins 22
Globular proteins have a hydrophobic core 23
Proteins lose their biological activities when their higher-order structure is destroyed 24
The solubility of proteins depends on pH and salt concentration 25
Proteins absorb ultraviolet radiation 26
Proteins can be separated by their charge or their molecular weight 26
Abnormal protein aggregates can cause disease 27
Neurodegenerative diseases are caused by protein aggregates 29
Protein misfolding can be contagious 30
Summary 31
Further Reading 31
Questions 31
Chapter 3 Oxygen-Binding Proteins: Hemoglobin and Myoglobin 33
The heme group is the oxygen-binding site of hemoglobin and myoglobin 33
Myoglobin is a tightly packed globular protein 34
Red blood cells are specialized for oxygen transport 34
The hemoglobins are tetrameric proteins 34
Oxygenated and deoxygenated hemoglobin have different quaternary structures 36
Oxygen binding to hemoglobin is cooperative 36
2,3-Bisphosphoglycerate is a negative allosteric effector of oxygen binding to hemoglobin 37
Fetal hemoglobin has a higher oxygen-binding affinity than does adult hemoglobin 38
The bohr effect facilitates oxygen delivery 39
Most carbon dioxide is transported as bicarbonate 39
Summary 40
Further Reading 40
Questions 40
Chapter 4 Enzymatic Reactions 41
The equilibrium constant describes the equilibrium of the reaction 41
The free energy change is the driving force for chemical reactions 42
The standard free energy change determines the equilibrium 43
Enzymes are both powerful and selective 43
The substrate must bind to its enzyme before the reaction can proceed 44
Rate constants are useful for describing reaction rates 44
Enzymes decrease the free energy of activation 45
Many enzymatic reactions can be described by michaelis-menten kinetics 46
Km and vmax can be determined graphically 47
Substrate half-life can be determined for first-order but not zero-order reactions 48
Kcat/km predicts the enzyme activity at low substrate concentration 48
Allosteric enzymes do not conform to michaelis-menten kinetics 48
Enzyme activity depends on temperature and pH 49
Different types of reversible enzyme inhibition can be distinguished kinetically 49
Covalent modification can inhibit enzymes irreversibly 51
Enzymes stabilize the transition state 51
Chymotrypsin forms a transient covalent bond during catalysis 52
Summary 53
Further Reading 53
Questions 54
Chapter 5 Coenzymes 55
Enzymes are classified according to their reaction type 55
Oxidoreductases 55
Transferases 56
Hydrolases 56
Lyases 56
Isomerases 56
Ligases 56
Adenosine triphosphate has two energy-rich bonds 56
ATP DONATES phosphate in phosphorylation reactions 58
ATP hydrolysis drives endergonic reactions 59
Cells always try to maintain a high energy charge 59
Dehydrogenase reactions require specialized coenzymes 59
Coenzyme a activates organic acids 60
S -adenosyl methionine donates methyl groups 62
Many enzymes require a metal ion 62
Summary 63
Questions 63
Part Two Genetic Information: DNA, RNA, and Protein SYnthesis 65
Chapter 6 DNA, RNA, and Protein Synthesis 66
All living organisms use dna as their genetic databank 66
DNA contains four bases 68
DNA forms a double helix 68
DNA can be denatured 69
DNA is supercoiled 69
DNA replication is semiconservative 70
DNA is synthesized by DNA polymerases 70
DNA polymerases have exonuclease activities 71
Unwinding proteins present a single-stranded template to the DNA polymerases 72
One of the new DNA strands is synthesized discontinuously 74
RNA plays key roles in gene expression 76
The σ subunit recognizes promoters 76
DNA is faithfully copied into RNA 77
Some RNAs are chemically modified after transcription 79
The genetic code defines the structural relationship between mRNA and polypeptide 80
Transfer RNA is the adapter molecule in protein synthesis 81
Amino acids are activated by an ester bond with the 3′ terminus of the tRNA 82
Many transfer RNAs recognize more than one codon 83
Ribosomes are the workbenches for protein synthesis 83
The initiation complex brings together ribosome, messenger RNA, and initiator tRNA 85
Polypeptides grow stepwise from the amino terminus to the carboxyl terminus 85
Protein synthesis is energetically expensive 88
Gene expression is tightly regulated 88
A repressor protein regulates transcription of the lac operon in E. coli 88
Anabolic operons are repressed by the end product of the pathway 89
Glucose regulates the transcription of many catabolic operons 90
Transcriptional regulation depends on DNA-binding proteins 91
Summary 92
Further Reading 92
Questions 93
Chapter 7 The Human Genome 94
Chromatin consists of DNA and histones 94
The nucleosome is the structural unit of chromatin 95
Covalent histone modifications regulate DNA replication and transcription 95
DNA methylation silences genes 95
All eukaryotic chromosomes have a centromere, telomeres, and replication origins 97
Telomerase is required (but not sufficient) for immortality 97
Eukaryotic DNA replication requires three DNA polymerases 99
Most human DNA does not code for proteins 100
Gene families originate by gene duplication 100
The genome contains many tandem repeats 101
Some DNA sequences are copies of functional RNAs 101
Many repetitive DNA sequences are (or were) mobile 102
L1 elements encode a reverse transcriptase 103
ALU sequences spread with the help of L1 reverse transcriptase 105
Mobile elements are dangerous 105
Humans have approximately 20,000 genes 105
Transcriptional initiation requires general transcription factors 106
Genes are surrounded by regulatory sites 107
Gene expression is regulated by DNA-binding proteins 107
Long noncoding RNAs play roles in gene expression 108
mRNA processing starts during transcription 109
Translational initiation requires many initiation factors 111
mRNA processing and translation are often regulated 113
Regulation of Messenger RNA Stability 113
Tissue-Specific Initiation and Termination of Transcription 113
Alternative Splicing 113
Translational Repressors 113
mRNA Editing 113
Small RNA molecules inhibit gene expression 115
Mitochondria have their own DNA 116
Human genomes are very diverse 117
Human genomes have many low-frequency copy number variations 117
Summary 118
Further Reading 118
Questions 119
Chapter 8 Protein Targeting and Proteostasis 120
A signal sequence directs polypeptides to the endoplasmic reticulum 120
Glycoproteins are processed in the secretory pathway 121
The endocytic pathway brings proteins into the cell 124
Lysosomes are organelles of intracellular digestion 126
Autophagy recycles cellular proteins and organelles 127
Poorly folded proteins are either repaired or destroyed 127
Ubiquitin marks proteins for destruction 127
The proteostatic system protects cells from abnormal proteins 129
Summary 131
Further Reading 131
Questions 131
Chapter 9 Introduction to Genetic Diseases 132
Four types of genetic disease 132
Mutations occur in the germline and in somatic cells 133
Mutations are an important cause of poor health 134
Small mutations lead to abnormal proteins 134
Most mutations are caused by replication errors 135
Mutations can be induced by radiation and chemicals 135
Mismatch repair corrects replication errors 136
Missing bases and abnormal bases need to be replaced 138
Nucleotide excision repair removes bulky lesions 139
Repair of dna double-strand breaks is difficult 139
Hemoglobin genes form two gene clusters 141
Many point mutations in hemoglobin genes are known 142
Sickle cell disease is caused by a point mutation in the β-chain gene 143
SA heterozygotes are protected from tropical malaria 144
α-thalassemia is most often caused by large deletions 145
Many different mutations can cause β-thalassemia 146
Fetal hemoglobin protects from the effects of β-thalassemia and sickle cell disease 147
Polygenic diseases have multiple genetic risk factors 147
Genetic risk factors are discovered in genome-wide association studies 148
Summary 149
Further Reading 149
Questions 150
Chapter 10 Viruses 152
Viruses can replicate only in a host cell 152
Bacteriophage T4 destroys its host cell 153
DNA viruses substitute their own DNA for the host cell DNA 153
λ phage can integrate its DNA into the host cell chromosome 154
RNA viruses require an RNA-dependent RNA polymerase 157
Retroviruses replicate through a DNA intermediate 157
Plasmids are small “accessory chromosomes” or “symbiotic viruses” of bacteria 160
Bacteria can exchange genes by transformation and transduction 160
Jumping genes can change their position in the genome 162
Summary 164
Further Reading 164
Questions 164
Chapter 11 DNA Technology 165
Restriction endonucleases cut large DNA molecules into smaller fragments 165
Large probes are used to detect copy number variations 165
Small probes are used to detect point mutations 166
Southern blotting determines the size of restriction fragments 167
DNA can be amplified with the polymerase chain reaction 168
PCR is used for preimplantation genetic diagnosis 169
Allelic heterogeneity is the greatest challenge for molecular genetic diagnosis 170
Normal polymorphisms are used as genetic markers 170
Tandem repeats are used for DNA fingerprinting 171
DNA microarrays can be used for genetic screening 172
DNA microarrays are used for the study of gene expression 174
DNA is sequenced by controlled chain termination 174
Massively parallel sequencing permits cost-efficient whole-genome genetic diagnosis 175
Gene therapy targets somatic cells 177
Viruses are used as vectors for gene therapy 177
Retroviruses can splice a transgene into the cell’s genome 178
Genome editing is based on the making and healing of DNA double strand breaks 179
Designer nucleases are used for genome editing 180
Antisense oligonucleotides can block the expression of rogue genes 181
Genes can be altered in animals 181
Tissue-specific gene expression can be engineered into animals 183
Human germline genome editing is technically possible 184
Summary 184
Further Reading 184
Questions 185
Part Three Cell and Tissue Structure 187
Chapter 12 Biological Membranes 188
Membranes consist of lipid and protein 188
Phosphoglycerides are the most abundant membrane lipids 188
Most sphingolipids are glycolipids 190
Cholesterol is the most hydrophobic membrane lipid 191
Membrane lipids form a bilayer 192
The lipid bilayer is a two-dimensional fluid 192
The lipid bilayer is a diffusion barrier 193
Membranes contain integral and peripheral membrane proteins 194
Membranes are asymmetrical 194
Membranes are fragile 196
Membrane proteins carry solutes across the lipid bilayer 196
Transport against an electrochemical gradient requires metabolic energy 198
Active transport consumes ATP 199
Sodium cotransport brings molecules into the cell 199
Summary 201
Further Reading 201
Questions 201
Chapter 13 The Cytoskeleton 203
The erythrocyte membrane is reinforced by a spectrin network 203
Keratins give strength to epithelia 204
Actin filaments are formed from globular subunits 206
Striated muscle contains thick and thin filaments 207
Myosin is a two-headed molecule with atpase activity 207
Muscle contraction requires calcium and ATP 210
The cytoskeleton of skeletal muscle is linked to the extracellular matrix 211
Microtubules consist of tubulin 213
Eukaryotic cilia and flagella contain a 9+2 array of microtubules 214
Cells form specialized junctions with other cells and with the extracellular matrix 214
Summary 216
Further Reading 216
Questions 217
Chapter 14 The Extracellular Matrix 218
Collagen is the most abundant protein in the human body 218
The Tropocollagen molecule forms a long triple helix 220
Collagen fibrils are staggered arrays of tropocollagen molecules 220
Collagen is subject to extensive posttranslational processing 220
Collagen metabolism is altered in aging and disease 222
Many genetic defects of collagen structure and biosynthesis are known 223
Elastic fibers contain elastin and fibrillin 224
The amorphous ground substance contains hyaluronic acid 225
Sulfated glycosaminoglycans are covalently bound to core proteins 226
Cartilage contains large proteoglycan aggregates 227
Proteoglycans are synthesized in the er and degraded in lysosomes 228
Mucopolysaccharidoses are caused by deficiency of glycosaminoglycan-degrading enzymes 229
Bone consists of calcium phosphates in a collagenous matrix 230
Basement membranes contain type iv collagen, laminin, and heparan sulfate proteoglycans 230
Fibronectin glues cells and collagen fibers together 231
Summary 232
Further Reading 233
Questions 234
Part Four Molecular Physiology 235
Chapter 15 Extracellular Messengers 236
Steroid hormones are made from cholesterol 236
Progestins are the biosynthetic precursors of all other steroid hormones 238
Thyroid hormones are synthesized from protein-bound tyrosine 242
T4 becomes activated to T3 in the target tissues 243
Both hypothyroidism and hyperthyroidism are common disorders 244
Insulin is released together with the C-peptide 245
Proopiomelanocortin forms several active products 245
Angiotensin is formed from circulating angiotensinogen 246
Immunoassays are used for determination of hormone levels 247
Catecholamines are synthesized from tyrosine 249
Indoleamines are synthesized from tryptophan 249
Histamine is produced by mast cells and basophils 251
Neurotransmitters are released at synapses 251
Acetylcholine is the neurotransmitter of the neuromuscular junction 252
There are many neurotransmitters 252
Summary 254
Further Reading 254
Questions 255
Chapter 16 Intracellular Messengers 256
Receptor-hormone interactions are noncovalent, reversible, and saturable 256
Many neurotransmitter receptors are ion channels 257
Steroid and thyroid hormones bind to transcription factors 258
Seven-transmembrane receptors are coupled to G proteins 258
Adenylate cyclase is regulated by G proteins 260
Hormones can both activate and inhibit the camp cascade 261
Cytoplasmic calcium is an important intracellular signal 263
Phospholipase C generates two second messengers 263
Both camp and calcium regulate gene transcription 264
Muscle contraction and exocytosis are triggered by calcium 265
Atrial natriuretic factor acts through a membrane-bound guanylate cyclase 265
Nitric oxide stimulates a soluble guanylate cyclase 267
cGMP is a second messenger in retinal rod cells 268
Receptors for insulin and growth factors are tyrosine-specific protein kinases 269
Growth factors and insulin trigger multiple signaling cascades 271
Cytokine receptors use the JAK-STAT pathway 271
Many receptors become desensitized after overstimulation 273
Summary 273
Further Reading 273
Questions 274
Chapter 17 Plasma Proteins 275
Plasma proteins are both synthesized and destroyed in the liver 275
Albumin prevents edema 275
Albumin binds many small molecules 277
Some plasma proteins are specialized carriers of small molecules 277
Deficiency of α1 -antitrypsin causes lung emphysema 278
Levels of plasma proteins are affected by many diseases 279
Blood components are used for transfusions 280
Blood clotting must be tightly controlled 281
Platelets adhere to exposed subendothelial tissue 281
Insoluble fibrin is formed from soluble fibrinogen 283
Thrombin is derived from prothrombin 284
Factor X can be activated by the extrinsic and intrinsic pathways 284
Negative controls are necessary to prevent thrombosis 286
Plasmin degrades the fibrin clot 287
Heparin and vitamin K antagonists are used as anticoagulants 288
Clotting factor deficiencies cause abnormal bleeding 289
Tissue damage causes release of cellular enzymes into blood 289
Serum Enzymes are Used for the Diagnosis of Many Diseases 290
Plasma Cholinesterase 290
Transaminases 290
Alkaline Phosphatase 291
γ -Glutamyl Transferase 291
Acid Phosphatase and Prostate-Specific Antigen 291
Lactate Dehydrogenase (LDH) 291
Creatine Kinase 292
Pancreatic enzymes 292
Summary 292
Further Reading 293
Questions 293
Chapter 18 Defense Mechanisms 294
Lipophilic xenobiotics are metabolized to water-soluble products 294
Cytochrome P-450 is involved in phase I metabolism 294
Phase II metabolism makes xenobiotics water-soluble for excretion 296
Phase III metabolism excretes xenobiotic metabolites 297
Drug-metabolizing enzymes are inducible 298
The innate immune system uses pattern recognition receptors 298
Infection triggers inflammation 299
Lymphocytes possess antigen receptors 300
B Lymphocytes produce immunoglobulins 301
Antibodies consist of two light chains and two heavy chains 301
Different immunoglobulin classes have different properties 303
Adaptive immune responses are based on clonal selection 305
Immunoglobulin genes are rearranged during B-cell development 306
The T-cell receptor recruits cytosolic tyrosine protein kinases 309
Mediators of inflammation are produced from arachidonic acid 310
Prostaglandins are synthesized in all tissues 311
Prostanoids participate in many physiological processes 312
Leukotrienes are produced by the lipoxygenase pathway 312
Antiinflammatory drugs inhibit the synthesis of eicosanoids 312
Summary 314
Further Reading 314
Questions 315
Chapter 19 Cellular Growth Control and Cancer 316
The cell cycle is controlled at checkpoints 316
Cells can be grown in culture 317
Cyclins play key roles in cell cycle control 317
Retinoblastoma protein guards the G1 checkpoint 317
Cell proliferation is triggered by mitogens 318
Mitogens regulate gene expression 319
Cells can commit suicide 320
Cancers are monoclonal in origin 322
Cancer is caused by activation of growth-promoting genes and inactivation of growth-inhibiting genes 323
Some retroviruses contain an oncogene 324
Retroviruses can cause cancer by inserting themselves next to a cellular proto-oncogene 325
Many oncogenes code for components of mitogenic signaling cascades 326
Growth Factors 326
Receptor Tyrosine Kinases 326
Nonreceptor Tyrosine Protein Kinases 327
Cytoplasmic Serine/Threonine Kinases 327
G Proteins 327
Nuclear Transcription Factors 328
Cancer susceptibility syndromes are caused by inherited mutations in tumor suppressor genes 329
Many tumor suppressor genes are known 330
Components of the cell cycle machinery are abnormal in most cancers 331
DNA Damage causes either growth arrest or apoptosis 332
Most spontaneous cancers are defective in p53 action 333
The PI3K/protein kinase B pathway is activated in many cancers 334
The products of some viral oncogenes neutralize the products of cellular tumor suppressor genes 334
Tumors become more malignant through darwinian selection 336
Intestinal polyps are benign lesions 336
Intestinal polyps can evolve into colon cancer 337
Summary 338
Further Reading 338
Questions 339
Part Five Metabolism 341
Chapter 20 Digestive Enzymes 342
Saliva contains α-amylase and lysozyme 342
Protein and fat digestion start in the stomach 343
The pancreas is a factory for digestive enzymes 344
Fat digestion requires bile salts 344
Some digestive enzymes are anchored to the surface of the microvilli 346
Poorly digestible nutrients cause flatulence 347
Many digestive enzymes are released as inactive precursors 348
Summary 349
Further Reading 349
Questions 350
Chapter 21 Introduction to Metabolic Pathways 351
Alternative substrates can be oxidized in the body 351
Metabolic processes are compartmentalized 352
Free energy changes in metabolic pathways are additive 352
Most metabolic pathways are regulated 353
Feedback inhibition and feedforward stimulation are the most important regulatory principles 353
Metabolism is regulated to ensure homeostasis 354
Inherited enzyme deficiencies cause metabolic diseases 354
Vitamin deficiencies, toxins, and endocrine disorders can disrupt metabolic pathways 355
Summary 356
Questions 356
Chapter 22 Glycolysis, Tricarboxylic Acid Cycle, and Oxidative Phosphorylation 357
Glucose uptake into the cells is regulated 357
Glucose degradation begins in the cytoplasm and ends in the mitochondria 358
Glycolysis begins with ATP-dependent phosphorylations 359
Most glycolytic intermediates have three carbons 360
Phosphofructokinase is the most important regulated enzyme of glycolysis 361
Lactate is produced under anaerobic conditions 362
Pyruvate is decarboxylated to acetyl-CoA in the mitochondria 363
The TCA cycle produces two molecules of carbon dioxide for each acetyl residue 363
Reduced coenzymes are the most important products of the TCA cycle 366
Oxidative pathways are regulated by energy charge and [NADH]/[NAD+] ratio 366
The TCA cycle provides a pool of metabolic intermediates 367
Antiporters transport metabolites across the inner mitochondrial membrane 369
The respiratory chain channels electrons from NADH and FADH2 to molecular oxygen 370
The standard reduction potential is the tendency to donate electrons 371
The respiratory chain contains flavoproteins, iron-sulfur proteins, cytochromes, ubiquinone, and protein-bound copper 372
The respiratory chain contains large multiprotein complexes 372
The respiratory chain creates a proton gradient 373
The proton gradient drives ATP synthesis 374
The efficiency of glucose oxidation is close to 40% 375
Oxidative phosphorylation is limited by the supply of ADP 376
Brown adipose tissue contains an uncoupling protein 376
Mutations in mitochondrial DNA can cause disease 377
Summary 378
Further Reading 378
Questions 378
Chapter 23 Oxygen Deficiency and Oxygen Toxicity 380
Ischemia leads to infarction 380
Oxidative phosphorylation is inhibited by many poisons 381
Hypoxia inducible factor adjusts cell metabolism to hypoxia 383
Reactive oxygen derivatives are formed during oxidative metabolism 384
The respiratory chain is a major source of superoxide 384
Cells have specialized enzymes to destroy reactive oxygen species 385
Free radical formation is affected by energy supply and energy consumption 386
Some vitamins and phytochemicals can scavenge free radicals 387
The NRF2 transcription factor coordinates defenses against reactive oxygen species 388
Phagocytic cells use reactive oxygen species for intracellular killing 389
Summary 390
Further Reading 390
Questions 390
Chapter 24 Carbohydrate Metabolism 392
An adequate blood glucose level must be maintained at all times 392
Gluconeogenesis bypasses the three irreversible reactions of glycolysis 392
Fatty acids cannot be converted into glucose 393
Glycolysis and gluconeogenesis are regulated by hormones 394
Glycolysis and gluconeogenesis are fine tuned by allosteric effectors and hormone-induced enzyme phosphorylations 394
Fructose-2,6-bisphosphate switches the liver from gluconeogenesis to glycolysis 396
Glucokinase is regulated by two regulatory proteins 396
Carbohydrate is stored as glycogen 398
Glycogen is synthesized from glucose 398
Glycogen is degraded by phosphorolytic cleavage 399
Glycogen metabolisSm is regulated by hormones and metabolites 400
Glycogen accumulates in several enzyme deficiencies 403
Fructose is channeled into glycolysis/gluconeogenesis 404
Excess fructose is problematic 404
Excess galactose is channeled into the pathways of glucose metabolism 406
The pentose phosphate pathway supplies NADPH and ribose-5-phosphate 407
Fructose is the principal sugar in seminal fluid 409
Amino sugars and sugar acids are made from glucose 409
Summary 410
Further Reading 411
Questions 411
Chapter 25 The Metabolism of Fatty Acids and Triglycerides 412
Fatty acids differ in chain length and number of double bonds 412
Chylomicrons transport triglycerides from the intestine to other tissues 414
Adipose tissue is specialized for the storage of triglycerides 415
Fat metabolism in adipose tissue is under hormonal control 416
Fatty acids are transported into the mitochondrion 417
β -Oxidation produces acetyl-CoA, NADH, and FADH2 418
Special fatty acids require special reactions 419
The liver converts excess fatty acids to ketone bodies 420
Fatty acids are synthesized from acetyl-CoA 423
Acetyl-CoA is shuttled into the cytoplasm as citrate 424
Fatty acid synthesis is regulated by hormones and metabolites 424
AMP-Activated protein kinase adapts metabolic pathways to cellular energy status 426
Most fatty acids can be synthesized from palmitate 427
Fatty acids regulate gene expression 428
Polyunsaturated fatty acids can be oxidized nonenzymatically 429
Summary 429
Further Reading 430
Questions 430
Chapter 26 The Metabolism of Membrane Lipids 432
Phosphatidic acid is an intermediate in phosphoglyceride synthesis 432
Phosphoglycerides are remodeled continuously 432
Sphingolipids are synthesized from ceramide 433
Deficiencies of sphingolipid-degrading enzymes cause lipid storage diseases 434
Cholesterol is the least soluble membrane lipid 438
Cholesterol is derived from both endogenous synthesis and the diet 438
Cholesterol biosynthesis is regulated at the level of HMG-CoA reductase 439
Bile acids are synthesized from cholesterol 440
Bile acids are subject to extensive enterohepatic circulation 441
Most gallstones consist of cholesterol 443
Summary 443
Further Reading 444
Questions 444
Chapter 27 Lipid Transport 445
Most plasma lipids are components of lipoproteins 445
Lipoproteins have characteristic lipid and protein compositions 446
Dietary lipids are transported by chylomicrons 447
VLDL is a precursor of LDL 447
LDL is removed by receptor-mediated endocytosis 449
Cholesterol regulates its own metabolism 450
HDL is needed for reverse cholesterol transport 451
Lipoproteins can initiate atherosclerosis 452
Lipoproteins respond to diet and lifestyle 454
Hyperlipoproteinemias are grouped into five phenotypes 456
Type I hyperlipoproteinemia 457
Type II hyperlipoproteinemia 458
Type III hyperlipoproteinemia 458
Type IV hyperlipoproteinemia 458
Type V hyperlipoproteinemia 459
Hyperlipidemias are treated with diet and drugs 459
Summary 461
Further Reading 461
Questions 462
Chapter 28 Amino Acid Metabolism 463
Amino acids can be used for gluconeogenesis and ketogenesis 463
The nitrogen balance indicates the net rate of protein synthesis 463
The amino group of amino acids is released as ammonia 464
Ammonia is detoxified to urea 465
Urea is synthesized in the urea cycle 465
Hyperammonemia can be treated with diet and drugs 467
Some amino acids are closely related to common metabolic intermediates 470
Glycine, serine, and threonine are glucogenic 470
Proline, arginine, ornithine, and histidine are degraded to glutamate 472
Methionine and cysteine are metabolically related 473
Valine, leucine, and isoleucine are degraded by transamination and oxidative decarboxylation 475
Phenylalanine and tyrosine are both glucogenic and ketogenic 477
Melanin is synthesized from tyrosine 477
Lysine and tryptophan have lengthy catabolic pathways 480
The liver is the most important organ of amino acid metabolism 481
Glutamine participates in renal Ł acid-base regulation 483
Summary 484
Further Reading 484
Questions 485
Chapter 29 Metabolism of Iron and Heme 486
Iron is conserved very efficiently in the body 486
Iron uptake by cells is regulated 487
Dietary iron is absorbed in the duodenum 487
Iron deficiency is the most common micronutrient deficiency worldwide 490
Bone marrow and liver are the most important sites of heme synthesis 491
Heme is synthesized from succinyl-CoA and glycine 492
Porphyrias are caused by deficiencies of heme-synthesizing enzymes 493
Heme is degraded to bilirubin 494
Bilirubin is conjugated and excreted by the liver 495
Elevations of serum bilirubin cause jaundice 496
Many diseases can cause jaundice 497
Summary 499
Further Reading 499
Questions 500
Chapter 30 The Metabolism of Purines and Pyrimidines 501
Purine synthesis starts with ribose-5-phosphate 501
Purines are degraded to uric acid 502
Free purine bases can be salvaged 503
Pyrimidines are synthesized from carbamoyl phosphate and aspartate 503
DNA synthesis requires deoxyribonucleotides 504
Many antineoplastic drugs inhibit nucleotide metabolism 504
Uric acid has limited water solubility 506
Hyperuricemia causes gout 508
Abnormalities of purine-metabolizing enzymes can cause gout 509
Gout can be treated with drugs 509
Summary 510
Further Reading 510
Questions 510
Chapter 31 Micronutrients 511
Riboflavin is a precursor of flavin mononucleotide and flavin adenine dinucleotide 511
Niacin is a precursor of NAD and NADP 512
Thiamine deficiency causes weakness and amnesia 514
Vitamin B6 plays a key role in amino acid metabolism 515
Pantothenic acid is a building block of coenzyme a 516
Biotin is a coenzyme in carboxylation reactions 516
Folic acid deficiency causes megaloblastic anemia 517
Vitamin B12 requires intrinsic factor for its absorption 519
Vitamin c is a water-soluble antioxidant 521
Retinol, retinal, and retinoic acid are the active forms of vitamin a 523
Vitamin d is a prohormone 525
Vitamin e prevents lipid oxidation 526
Many vitamins and phytochemicals are antioxidants 527
Vitamin k is required for blood clotting 528
Zinc is a constituent of many enzymes 528
Copper participates in reactions of molecular oxygen 529
Some trace elements serve very specific functions 530
Summary 531
Further Reading 531
Questions 532
Chapter 32 Integration of Metabolism 533
Insulin is released in response to elevated glucose 533
Insulin stimulates the utilization of nutrients 534
Protein synthesis is coordinated by the mTOR complex 535
Glucagon maintains the blood glucose level 536
Catecholamines mediate the flight-or-fight response 536
Glucocorticoids are released in chronic stress 537
Energy is expended continuously 538
Stored fat and glycogen are degraded between meals 539
Adipose tissue is the most important energy depot 540
The liver converts dietary carbohydrates to glycogen and fat after a meal 541
The liver maintains the blood glucose level during fasting 541
Ketone bodies provide lipid-based energy during fasting 544
Obesity is common in all affluent countries 544
Appetite control is the most important determinant of obesity 546
Obesity is related to insulin resistance 547
Diabetes is caused by insulin deficiency or insulin resistance 549
In diabetes, metabolism is regulated as in starvation 550
Diabetes is diagnosed with laboratory tests 551
Diabetes leads to late complications 552
Many drugs are available for diabetes treatment 553
Contracting muscle has three energy sources 553
Creatine Phosphate 553
Anaerobic Glycolysis 553
Oxidative Metabolism 554
Catecholamines coordinate metabolism during exercise 555
Physical exercise leads to adaptive changes 557
Ethanol is metabolized to acetyl-CoA in the liver 558
Liver metabolism is deranged by alcohol 560
Alcohol abuse leads to fatty liver and liver cirrhosis 561
Most “diseases of civilization” are caused by aberrant lifestyles 561
Aging is the greatest challenge for medical research 564
Antiaging treatments are being investigated 565
Summary 566
Further Reading 566
Questions 567
Answers to questions 569
Chapter 1 569
Chapter 2 569
Chapter 3 569
Chapter 4 569
Chapter 5 569
Chapter 6 569
Chapter 7 569
Chapter 8 569
Chapter 9 569
Chapter 10 569
Chapter 11 569
Chapter 12 569
Chapter 13 569
Chapter 14 569
Chapter 15 569
Chapter 16 569
Chapter 17 569
Chapter 18 569
Chapter 19 569
Chapter 20 569
Chapter 21 569
Chapter 22 569
Chapter 23 569
Chapter 24 569
Chapter 25 569
Chapter 26 569
Chapter 27 569
Chapter 28 570
Chapter 29 570
Chapter 30 570
Chapter 31 570
Chapter 32 570
Glossary 571
Credits 590
Index 591
Inside Back cover ES3