xxii Contents 15.3 The Oxidation of Carbon Fuels Is an Many adults are intolerant of milk because they Important Source of Cellular Energy 435 are deficient in lactase 471 Compounds with high phosphoryl-transfer potential Galactose is highly toxic if the transferase is missing 472 can couple carbon oxidation to ATP synthesis 436 16.2 The Glycolytic Pathway Is Tightly Ion gradients across membranes provide an Controlled 472 important form of cellular energy that can be Glycolysis in muscle is regulated to meet the need coupled to ATP synthesis 437 for ATP 473 Energy from foodstuffs is extracted in three stages 437 The regulation of glycolysis in the liver illustrates 15.4 Metabolic Pathways Contain Many the biochemical versatility of the liver 474 Recurring Motifs 438 A family of transporters enables glucose to enter Activated carriers exemplify the modular design and and leave animal cells 477 economy of metabolism 438 Cancer and exercise training affect glycolysis in a Many activated carriers are derived from vitamins 441 similar fashion 478 Key reactions are reiterated throughout metabolism 443 16.3 Glucose Can Be Synthesized from Metabolic processes are regulated in three Noncarbohydrate Precursors 479 principal ways 445 Gluconeogenesis is not a reversal of glycolysis 481 Aspects of metabolism may have evolved from an The conversion of pyruvate into phosphoenolpyruvate RNA world 447 begins with the formation of oxaloacetate 482 Oxaloacetate is shuttled into the cytoplasm and converted into phosphoenolpyruvate 483 Chapter 16 Glycolysis and Gluconeogenesis 453 The conversion of fructose 1,6-bisphosphate into Glucose is generated from dietary carbohydrates 454 fructose 6-phosphate and orthophosphate is an irreversible step 484 Glucose is an important fuel for most organisms 455 The generation of free glucose is an important 16.1 Glycolysis Is an Energy-Conversion control point 484 Pathway in Many Organisms 455 Six high-transfer-potential phosphoryl groups are Hexokinase traps glucose in the cell and begins spent in synthesizing glucose from pyruvate 485 glycolysis 455 Fructose 1,6-bisphosphate is generated from glucose 16.4 Gluconeogenesis and Glycolysis Are 6-phosphate 486 457 Reciprocally Regulated The six-carbon sugar is cleaved into two Energy charge determines whether glycolysis or 486 three-carbon fragments 458 gluconeogenesis will be most active Mechanism:Triose phosphate isomerase salvages a The balance between glycolysis and gluconeogenesis 459 in the liver is sensitive to blood-glucose concentration 487 three-carbon fragment The oxidation of an aldehyde to an acid powers Substrate cycles amplify metabolic signals and produce heat 489 the formation of a compound with high phosphoryl-transfer potential 460 Lactate and alanine formed by contracting muscle Mechanism:Phosphorylation is coupled to the are used by other organs 489 oxidation of glyceraldehyde 3-phosphate by a Glycolysis and gluconeogenesis are evolutionarily thioester intermediate 462 intertwined 491 ATP is formed by phosphoryl transfer from 1.3-bisphosphoglycerate 463 Chapter 17 The Citric Acid Cycle 497 Additional ATP is generated with the formation of The citric acid cycle harvests high-energy electrons 498 Pyruvate 464 Two ATP molecules are formed in the conversion 17.1 Pyruvate Dehydrogenase Links Glycolysis of glucose into pyruvate 465 to the Citric Acid Cycle 499 NAD+is regenerated from the metabolism Mechanism:The synthesis of acetyl coenzyme a from of pyruvate 466 pyruvate requires three enzymes and five coenzymes 500 Fermentations provide usable energy in the absence Flexible linkages allow lipoamide to move between 468 different active sites 502 of oxygen The binding site for NAD+is similar in many 17.2 The Citric Acid Cycle Oxidizes dehydrogenases 469 Two-Carbon Units 503 Fructose and galactose are converted into glycolytic Citrate synthase forms citrate from oxaloacetate and intermediates 469 acetyl coenzyme A 504
xxii Contents 15.3 The Oxidation of Carbon Fuels Is an Important Source of Cellular Energy 435 Compounds with high phosphoryl-transfer potential can couple carbon oxidation to ATP synthesis 436 Ion gradients across membranes provide an important form of cellular energy that can be coupled to ATP synthesis 437 Energy from foodstuffs is extracted in three stages 437 15.4 Metabolic Pathways Contain Many Recurring Motifs 438 Activated carriers exemplify the modular design and economy of metabolism 438 Many activated carriers are derived from vitamins 441 Key reactions are reiterated throughout metabolism 443 Metabolic processes are regulated in three principal ways 445 Aspects of metabolism may have evolved from an RNA world 447 Chapter 16 Glycolysis and Gluconeogenesis 453 Glucose is generated from dietary carbohydrates 454 Glucose is an important fuel for most organisms 455 16.1 Glycolysis Is an Energy-Conversion Pathway in Many Organisms 455 Hexokinase traps glucose in the cell and begins glycolysis 455 Fructose 1,6-bisphosphate is generated from glucose 6-phosphate 457 The six-carbon sugar is cleaved into two three-carbon fragments 458 Mechanism: Triose phosphate isomerase salvages a three-carbon fragment 459 The oxidation of an aldehyde to an acid powers the formation of a compound with high phosphoryl-transfer potential 460 Mechanism: Phosphorylation is coupled to the oxidation of glyceraldehyde 3-phosphate by a thioester intermediate 462 ATP is formed by phosphoryl transfer from 1,3-bisphosphoglycerate 463 Additional ATP is generated with the formation of pyruvate 464 Two ATP molecules are formed in the conversion of glucose into pyruvate 465 NAD1 is regenerated from the metabolism of pyruvate 466 Fermentations provide usable energy in the absence of oxygen 468 The binding site for NAD1 is similar in many dehydrogenases 469 Fructose and galactose are converted into glycolytic intermediates 469 Many adults are intolerant of milk because they are deficient in lactase 471 Galactose is highly toxic if the transferase is missing 472 16.2 The Glycolytic Pathway Is Tightly Controlled 472 Glycolysis in muscle is regulated to meet the need for ATP 473 The regulation of glycolysis in the liver illustrates the biochemical versatility of the liver 474 A family of transporters enables glucose to enter and leave animal cells 477 Cancer and exercise training affect glycolysis in a similar fashion 478 16.3 Glucose Can Be Synthesized from Noncarbohydrate Precursors 479 Gluconeogenesis is not a reversal of glycolysis 481 The conversion of pyruvate into phosphoenolpyruvate begins with the formation of oxaloacetate 482 Oxaloacetate is shuttled into the cytoplasm and converted into phosphoenolpyruvate 483 The conversion of fructose 1,6-bisphosphate into fructose 6-phosphate and orthophosphate is an irreversible step 484 The generation of free glucose is an important control point 484 Six high-transfer-potential phosphoryl groups are spent in synthesizing glucose from pyruvate 485 16.4 Gluconeogenesis and Glycolysis Are Reciprocally Regulated 486 Energy charge determines whether glycolysis or gluconeogenesis will be most active 486 The balance between glycolysis and gluconeogenesis in the liver is sensitive to blood-glucose concentration 487 Substrate cycles amplify metabolic signals and produce heat 489 Lactate and alanine formed by contracting muscle are used by other organs 489 Glycolysis and gluconeogenesis are evolutionarily intertwined 491 Chapter 17 The Citric Acid Cycle 497 The citric acid cycle harvests high-energy electrons 498 17.1 Pyruvate Dehydrogenase Links Glycolysis to the Citric Acid Cycle 499 Mechanism: The synthesis of acetyl coenzyme a from pyruvate requires three enzymes and five coenzymes 500 Flexible linkages allow lipoamide to move between different active sites 502 17.2 The Citric Acid Cycle Oxidizes Two-Carbon Units 503 Citrate synthase forms citrate from oxaloacetate and acetyl coenzyme A 504
Contents xxiii Mechanism:The mechanism of citrate synthase Ubiquinol is the entry point for electrons from FADH2 prevents undesirable reactions 504 of flavoproteins 535 Citrate is isomerized into isocitrate 506 Electrons flow from ubiquinol to cytochrome c Isocitrate is oxidized and decarboxylated to through Q-cytochrome c oxidoreductase 535 alpha-ketoglutarate 506 The Qcycle funnels electrons from a two-electron Succinyl coenzyme A is formed by the oxidative carrier to a one-electron carrier and pumps protons 536 decarboxylation of alpha-ketoglutarate 507 Cytochrome c oxidase catalyzes the reduction of A compound with high phosphoryl-transfer potential molecular oxygen to water 53 is generated from succinyl coenzyme A 507 Toxic derivatives of molecular oxygen such as Mechanism:Succinyl coenzyme A synthetase superoxide radical are scavenged by protective enzymes 540 transforms types of biochemical energy 508 Electrons can be transferred between groups that are Oxaloacetate is regenerated by the oxidation not in contact 542 of succinate 509 The conformation of cytochrome c has remained The citric acid cycle produces high-transfer-potential essentially constant for more than a billion years 543 electrons,ATP,and CO2 510 18.4 A Proton Gradient Powers the 17.3 Entry to the Citric Acid Cycle and Synthesis of ATP 543 Metabolism Through It Are Controlled 512 ATP synthase is composed of a proton-conducting The pyruvate dehydrogenase complex is regulated unit and a catalytic unit 545 allosterically and by reversible phosphorylation 513 Proton flow through ATP synthase leads to the release The citric acid cycle is controlled at several points 514 of tightly bound ATP:The binding-change mechanism 546 Defects in the citric acid cycle contribute to the Rotational catalysis is the world's smallest molecular motor 547 development of cancer 515 Proton flow around the c ring powers ATP synthesis 548 17.4 The Citric Acid Cycle Is a Source of ATP synthase and G proteins have several common Biosynthetic Precursors 516 features 550 The citric acid cycle must be capable of being 18.5 Many Shuttles Allow Movement Across rapidly replenished 516 Mitochondrial Membranes 550 The disruption of pyruvate metabolism is the cause Electrons from cytoplasmic NADH enter of beriberi and poisoning by mercury and arsenic 517 mitochondria by shuttles 551 The citric acid cycle may have evolved from The entry of ADP into mitochondria is coupled to preexisting pathways 518 the exit of ATP by ATP-ADP translocase 552 17.5 The Glyoxylate Cycle Enables Plants Mitochondrial transporters for metabolites have a and Bacteria to Grow on Acetate 518 common tripartite structure 553 18.6 The Regulation of Cellular Respiration Is Chapter 18 Oxidative Phosphorylation 525 Governed Primarily by the Need for ATP 554 18.1 Eukaryotic Oxidative Phosphorylation The complete oxidation of glucose yields about 30 molecules of ATP 554 Takes Place in Mitochondria 526 The rate of oxidative phosphorylation is determined Mitochondria are bounded by a double membrane 526 by the need for ATP 555 Mitochondria are the result of an Regulated uncoupling leads to the generation of heat 556 endosymbiotic event 527 Oxidative phosphorylation can be inhibited at many stages 558 18.2 Oxidative Phosphorylation Depends on Mitochondrial diseases are being discovered 558 Electron Transfer 528 Mitochondria play a key role in apoptosis 559 The electron-transfer potential of an electron is Power transmission by proton gradients is a central measured as redox potential 528 motif of bioenergetics 559 A 1.14-volt potential difference between NADH and molecular oxygen drives electron transport through Chapter 19 The Light Reactions of the chain and favors the formation of a proton Photosynthesis 565 gradient 530 18.3 The Respiratory Chain Consists of Photosynthesis converts light energy into chemical energy 566 Four Complexes:Three Proton Pumps and 19.1 Photosynthesis Takes Place in Chloroplasts 567 a Physical Link to the Citric Acid Cycle 531 The primary events of photosynthesis take place in The high-potential electrons of NADH enter the thylakoid membranes 567 respiratory chain at NADH-Qoxidoreductase 533 Chloroplasts arose from an endosymbiotic event 568
Contents xxiii Mechanism: The mechanism of citrate synthase prevents undesirable reactions 504 Citrate is isomerized into isocitrate 506 Isocitrate is oxidized and decarboxylated to alpha-ketoglutarate 506 Succinyl coenzyme A is formed by the oxidative decarboxylation of alpha-ketoglutarate 507 A compound with high phosphoryl-transfer potential is generated from succinyl coenzyme A 507 Mechanism: Succinyl coenzyme A synthetase transforms types of biochemical energy 508 Oxaloacetate is regenerated by the oxidation of succinate 509 The citric acid cycle produces high-transfer-potential electrons, ATP, and CO2 510 17.3 Entry to the Citric Acid Cycle and Metabolism Through It Are Controlled 512 The pyruvate dehydrogenase complex is regulated allosterically and by reversible phosphorylation 513 The citric acid cycle is controlled at several points 514 Defects in the citric acid cycle contribute to the development of cancer 515 17.4 The Citric Acid Cycle Is a Source of Biosynthetic Precursors 516 The citric acid cycle must be capable of being rapidly replenished 516 The disruption of pyruvate metabolism is the cause of beriberi and poisoning by mercury and arsenic 517 The citric acid cycle may have evolved from preexisting pathways 518 17.5 The Glyoxylate Cycle Enables Plants and Bacteria to Grow on Acetate 518 Chapter 18 Oxidative Phosphorylation 525 18.1 Eukaryotic Oxidative Phosphorylation Takes Place in Mitochondria 526 Mitochondria are bounded by a double membrane 526 Mitochondria are the result of an endosymbiotic event 527 18.2 Oxidative Phosphorylation Depends on Electron Transfer 528 The electron-transfer potential of an electron is measured as redox potential 528 A 1.14-volt potential difference between NADH and molecular oxygen drives electron transport through the chain and favors the formation of a proton gradient 530 18.3 The Respiratory Chain Consists of Four Complexes: Three Proton Pumps and a Physical Link to the Citric Acid Cycle 531 The high-potential electrons of NADH enter the respiratory chain at NADH-Q oxidoreductase 533 Ubiquinol is the entry point for electrons from FADH2 of flavoproteins 535 Electrons flow from ubiquinol to cytochrome c through Q-cytochrome c oxidoreductase 535 The Q cycle funnels electrons from a two-electron carrier to a one-electron carrier and pumps protons 536 Cytochrome c oxidase catalyzes the reduction of molecular oxygen to water 537 Toxic derivatives of molecular oxygen such as superoxide radical are scavenged by protective enzymes 540 Electrons can be transferred between groups that are not in contact 542 The conformation of cytochrome c has remained essentially constant for more than a billion years 543 18.4 A Proton Gradient Powers the Synthesis of ATP 543 ATP synthase is composed of a proton-conducting unit and a catalytic unit 545 Proton flow through ATP synthase leads to the release of tightly bound ATP: The binding-change mechanism 546 Rotational catalysis is the world’s smallest molecular motor 547 Proton flow around the c ring powers ATP synthesis 548 ATP synthase and G proteins have several common features 550 18.5 Many Shuttles Allow Movement Across Mitochondrial Membranes 550 Electrons from cytoplasmic NADH enter mitochondria by shuttles 551 The entry of ADP into mitochondria is coupled to the exit of ATP by ATP-ADP translocase 552 Mitochondrial transporters for metabolites have a common tripartite structure 553 18.6 The Regulation of Cellular Respiration Is Governed Primarily by the Need for ATP 554 The complete oxidation of glucose yields about 30 molecules of ATP 554 The rate of oxidative phosphorylation is determined by the need for ATP 555 Regulated uncoupling leads to the generation of heat 556 Oxidative phosphorylation can be inhibited at many stages 558 Mitochondrial diseases are being discovered 558 Mitochondria play a key role in apoptosis 559 Power transmission by proton gradients is a central motif of bioenergetics 559 Chapter 19 The Light Reactions of Photosynthesis 565 Photosynthesis converts light energy into chemical energy 566 19.1 Photosynthesis Takes Place in Chloroplasts 567 The primary events of photosynthesis take place in thylakoid membranes 567 Chloroplasts arose from an endosymbiotic event 568
xxiv Contents 19.2 Light Absorption by Chlorophyll Induces 20.2 The Activity of the Calvin Cycle Depends Electron Transfer 568 on Environmental Conditions 597 A special pair of chlorophylls initiate charge separation 569 Rubisco is activated by light-driven changes in proton Cyclic electron flow reduces the cytochrome of the and magnesium ion concentrations 598 reaction center 572 Thioredoxin plays a key role in regulating the 19.3 Two Photosystems Generate a Proton Calvin cycle 598 Gradient and NADPH in Oxygenic The C4 pathway of tropical plants accelerates Photosynthesis 572 photosynthesis by concentrating carbon dioxide 599 Photosystem II transfers electrons from water to Crassulacean acid metabolism permits growth in 600 plastoquinone and generates a proton gradient 572 arid ecosystems Cytochrome bf links photosystem II to photosystem I 575 20.3 The Pentose Phosphate Pathway Photosystem I uses light energy to generate reduced Generates NADPH and Synthesizes ferredoxin,a powerful reductant 575 Five-Carbon Sugars 601 Ferredoxin-NADP+reductase converts NADP+ Two molecules of NADPH are generated in the into NADPH 576 conversion of glucose 6-phosphate into ribulose 601 19.4 A Proton Gradient Across the Thylakoid 5-phosphate Membrane Drives ATP Synthesis 577 The pentose phosphate pathway and glycolysis are linked by transketolase and transaldolase 601 The ATP synthase of chloroplasts closely resembles Mechanism:Transketolase and transaldolase stabilize those of mitochondria and prokaryotes 578 carbanionic intermediates by different mechanisms 604 Cyclic electron flow through photosystem I leads to the production of ATP instead of NADPH 579 20.4 The Metabolism of Glucose 6-phosphate The absorption of eight photons yields one O2,two by the Pentose Phosphate Pathway Is NADPH,and three ATP molecules 580 Coordinated with Glycolysis 606 19.5 Accessory Pigments Funnel Energy into The rate of the pentose phosphate pathway is controlled by the level of NADP+ 606 Reaction Centers 581 Resonance energy transfer allows energy to move The flow of glucose 6-phosphate depends on the need for NADPH,ribose 5-phosphate,and ATP 607 from the site of initial absorbance to the reaction Through the looking-glass:The Calvin cycle and the center 581 Light-harvesting complexes contain additional pentose phosphate pathway are mirror images 609 chlorophylls and carotinoids 582 20.5 Glucose 6-phosphate Dehydrogenase The components of photosynthesis are highly organized 583 Plays a Key Role in Protection Against Reactive Many herbicides inhibit the light reactions of Oxygen Species 609 photosynthesis 584 Glucose 6-phosphate dehydrogenase deficiency causes a drug-induced hemolytic anemia 609 19.6 The Ability to Convert Light into Chemical Energy Is Ancient 584 A deficiency of glucose 6-phosphate dehydrogenase confers an evolutionary advantage in some circumstances 611 Chapter 20 The Calvin Cycle and Pentose Phosphate Pathway 589 Chapter 21 Glycogen Metabolism 615 20.1 The Calvin Cycle Synthesizes Hexoses Glycogen metabolism is the regulated release and from Carbon Dioxide and Water 590 storage of glucose 616 Carbon dioxide reacts with ribulose 1,5-bisphosphate 21.1 Glycogen Breakdown Requires the to form two molecules of 3-phosphoglycerate 591 Interplay of Several Enzymes 617 Rubisco activity depends on magnesium and Phosphorylase catalyzes the phosphorolytic cleavage carbamate 592 of glycogen to release glucose 1-phosphate 617 Rubisco also catalyzes a wasteful oxygenase reaction: Mechanism:Pyridoxal phosphate participates in the Catalytic imperfection 593 phosphorolytic cleavage of glycogen 618 Hexose phosphates are made from phosphoglycerate, A debranching enzyme also is needed for the and ribulose 1,5-bisphosphate is regenerated 594 breakdown of glycogen 619 Three ATP and two NADPH molecules are used to Phosphoglucomutase converts glucose 1-phosphate bring carbon dioxide to the level of a hexose 597 into glucose 6-phosphate 620 Starch and sucrose are the major carbohydrate The liver contains glucose 6-phosphatase,a stores in plants 597 hydrolytic enzyme absent from muscle 621
xxiv Contents 19.2 Light Absorption by Chlorophyll Induces Electron Transfer 568 A special pair of chlorophylls initiate charge separation 569 Cyclic electron flow reduces the cytochrome of the reaction center 572 19.3 Two Photosystems Generate a Proton Gradient and NADPH in Oxygenic Photosynthesis 572 Photosystem II transfers electrons from water to plastoquinone and generates a proton gradient 572 Cytochrome bf links photosystem II to photosystem I 575 Photosystem I uses light energy to generate reduced ferredoxin, a powerful reductant 575 Ferredoxin–NADP1 reductase converts NADP1 into NADPH 576 19.4 A Proton Gradient Across the Thylakoid Membrane Drives ATP Synthesis 577 The ATP synthase of chloroplasts closely resembles those of mitochondria and prokaryotes 578 Cyclic electron flow through photosystem I leads to the production of ATP instead of NADPH 579 The absorption of eight photons yields one O2, two NADPH, and three ATP molecules 580 19.5 Accessory Pigments Funnel Energy into Reaction Centers 581 Resonance energy transfer allows energy to move from the site of initial absorbance to the reaction center 581 Light-harvesting complexes contain additional chlorophylls and carotinoids 582 The components of photosynthesis are highly organized 583 Many herbicides inhibit the light reactions of photosynthesis 584 19.6 The Ability to Convert Light into Chemical Energy Is Ancient 584 Chapter 20 The Calvin Cycle and Pentose Phosphate Pathway 589 20.1 The Calvin Cycle Synthesizes Hexoses from Carbon Dioxide and Water 590 Carbon dioxide reacts with ribulose 1,5-bisphosphate to form two molecules of 3-phosphoglycerate 591 Rubisco activity depends on magnesium and carbamate 592 Rubisco also catalyzes a wasteful oxygenase reaction: Catalytic imperfection 593 Hexose phosphates are made from phosphoglycerate, and ribulose 1,5-bisphosphate is regenerated 594 Three ATP and two NADPH molecules are used to bring carbon dioxide to the level of a hexose 597 Starch and sucrose are the major carbohydrate stores in plants 597 20.2 The Activity of the Calvin Cycle Depends on Environmental Conditions 597 Rubisco is activated by light-driven changes in proton and magnesium ion concentrations 598 Thioredoxin plays a key role in regulating the Calvin cycle 598 The C4 pathway of tropical plants accelerates photosynthesis by concentrating carbon dioxide 599 Crassulacean acid metabolism permits growth in arid ecosystems 600 20.3 The Pentose Phosphate Pathway Generates NADPH and Synthesizes Five-Carbon Sugars 601 Two molecules of NADPH are generated in the conversion of glucose 6-phosphate into ribulose 5-phosphate 601 The pentose phosphate pathway and glycolysis are linked by transketolase and transaldolase 601 Mechanism: Transketolase and transaldolase stabilize carbanionic intermediates by different mechanisms 604 20.4 The Metabolism of Glucose 6-phosphate by the Pentose Phosphate Pathway Is Coordinated with Glycolysis 606 The rate of the pentose phosphate pathway is controlled by the level of NADP1 606 The flow of glucose 6-phosphate depends on the need for NADPH, ribose 5-phosphate, and ATP 607 Through the looking-glass: The Calvin cycle and the pentose phosphate pathway are mirror images 609 20.5 Glucose 6-phosphate Dehydrogenase Plays a Key Role in Protection Against Reactive Oxygen Species 609 Glucose 6-phosphate dehydrogenase deficiency causes a drug-induced hemolytic anemia 609 A deficiency of glucose 6-phosphate dehydrogenase confers an evolutionary advantage in some circumstances 611 Chapter 21 Glycogen Metabolism 615 Glycogen metabolism is the regulated release and storage of glucose 616 21.1 Glycogen Breakdown Requires the Interplay of Several Enzymes 617 Phosphorylase catalyzes the phosphorolytic cleavage of glycogen to release glucose 1-phosphate 617 Mechanism: Pyridoxal phosphate participates in the phosphorolytic cleavage of glycogen 618 A debranching enzyme also is needed for the breakdown of glycogen 619 Phosphoglucomutase converts glucose 1-phosphate into glucose 6-phosphate 620 The liver contains glucose 6-phosphatase, a hydrolytic enzyme absent from muscle 621
Contents xxv 21.2 Phosphorylase Is Regulated by Allosteric The complete oxidation of palmitate yields Interactions and Reversible Phosphorylation 621 106 molecules of ATP 647 Muscle phosphorylase is regulated by the intracellular 22.3 Unsaturated and Odd-Chain Fatty Acids energy charge 621 Require Additional Steps for Degradation 648 Liver phosphorylase produces glucose for use by other An isomerase and a reductase are required for tissues 623 the oxidation of unsaturated fatty acids 648 Phosphorylase kinase is activated by phosphorylation Odd-chain fatty acids yield propionyl CoA in the and calcium ions 623 final thiolysis step 649 21.3 Epinephrine and Glucagon Signal the Vitamin B12 contains a corrin ring and a cobalt atom 650 Need for Glycogen Breakdown 624 Mechanism:Methylmalonyl CoA mutase catalyzes a G proteins transmit the signal for the initiation of rearrangement to form succinyl CoA 651 glycogen breakdown 624 Fatty acids are also oxidized in peroxisomes 652 Glycogen breakdown must be rapidly turned off Ketone bodies are formed from acetyl CoA when when necessary 626 fat breakdown predominates 653 The regulation of glycogen phosphorylase became Ketone bodies are a major fuel in some tissues 654 more sophisticated as the enzyme evolved 627 Animals cannot convert fatty acids into glucose 656 21.4 Glycogen Is Synthesized and Degraded 22.4 Fatty Acids Are Synthesized by Fatty by Different Pathways 627 Acid Synthase 656 UDP-glucose is an activated form of glucose 627 Fatty acids are synthesized and degraded by different Glycogen synthase catalyzes the transfer of glucose pathways 656 from UDP-glucose to a growing chain 628 The formation of malonyl CoA is the committed step A branching enzyme forms o-1,6 linkages 629 in fatty acid synthesis 657 Glycogen synthase is the key regulatory enzyme in Intermediates in fatty acid synthesis are attached to glycogen synthesis 629 an acyl carrier protein 657 Glycogen is an efficient storage form of glucose 629 Fatty acid synthesis consists of a series of condensation, 21.5 Glycogen Breakdown and Synthesis Are reduction,dehydration,and reduction reactions 658 Reciprocally Regulated 630 Fatty acids are synthesized by a multifunctional Protein phosphatase 1 reverses the regulatory effects enzyme complex in animals 659 of kinases on glycogen metabolism 631 The synthesis of palmitate requires 8 molecules of acetyl Insulin stimulates glycogen synthesis by inactivating CoA,14 molecules of NADPH,and 7 molecules of ATP 661 glycogen synthase kinase 632 Citrate carries acetyl groups from mitochondria to Glycogen metabolism in the liver regulates the the cytoplasm for fatty acid synthesis 662 blood-glucose level 633 Several sources supply NADPH for fatty acid synthesis 662 A biochemical understanding of glycogen-storage Fatty acid synthase inhibitors may be useful drugs 663 diseases is possible 634 22.5 The Elongation and Unsaturation of Chapter 22 Fatty Acid Metabolism 639 Fatty Acids Are Accomplished by Accessory Enzyme Systems 663 Fatty acid degradation and synthesis mirror each Membrane-bound enzymes generate unsaturated fatty acids 664 other in their chemical reactions 640 Eicosanoid hormones are derived from polyunsaturated 22.1 Triacylglycerols Are Highly Concentrated fatty acids 664 Energy Stores 641 22.6 Acetyl CoA Carboxylase Plays a Key Role Dietary lipids are digested by pancreatic lipases 641 in Controlling Fatty Acid Metabolism 666 Dietary lipids are transported in chylomicrons 642 Acetyl CoA carboxylase is regulated by conditions in 22.2 The Use of Fatty Acids As Fuel Requires the cell 666 Three Stages of Processing 643 Acetyl CoA carboxylase is regulated by a variety of hormones 666 Triacylglycerols are hydrolyzed by hormone-stimulated lipases 643 Chapter 23 Protein Turnover and Amino Fatty acids are linked to coenzyme A before they Acid Catabolism 673 are oxidized 644 Carnitine carries long-chain activated fatty acids 23.1 Proteins Are Degraded to Amino Acids 674 into the mitochondrial matrix 645 The digestion of dietary proteins begins in the Acetyl CoA,NADH,and FADH2 are generated in stomach and is completed in the intestine 674 each round of fatty acid oxidation 646 Cellular proteins are degraded at different rates 675
Contents xxv 21.2 Phosphorylase Is Regulated by Allosteric Interactions and Reversible Phosphorylation 621 Muscle phosphorylase is regulated by the intracellular energy charge 621 Liver phosphorylase produces glucose for use by other tissues 623 Phosphorylase kinase is activated by phosphorylation and calcium ions 623 21.3 Epinephrine and Glucagon Signal the Need for Glycogen Breakdown 624 G proteins transmit the signal for the initiation of glycogen breakdown 624 Glycogen breakdown must be rapidly turned off when necessary 626 The regulation of glycogen phosphorylase became more sophisticated as the enzyme evolved 627 21.4 Glycogen Is Synthesized and Degraded by Different Pathways 627 UDP-glucose is an activated form of glucose 627 Glycogen synthase catalyzes the transfer of glucose from UDP-glucose to a growing chain 628 A branching enzyme forms a-1,6 linkages 629 Glycogen synthase is the key regulatory enzyme in glycogen synthesis 629 Glycogen is an efficient storage form of glucose 629 21.5 Glycogen Breakdown and Synthesis Are Reciprocally Regulated 630 Protein phosphatase 1 reverses the regulatory effects of kinases on glycogen metabolism 631 Insulin stimulates glycogen synthesis by inactivating glycogen synthase kinase 632 Glycogen metabolism in the liver regulates the blood-glucose level 633 A biochemical understanding of glycogen-storage diseases is possible 634 Chapter 22 Fatty Acid Metabolism 639 Fatty acid degradation and synthesis mirror each other in their chemical reactions 640 22.1 Triacylglycerols Are Highly Concentrated Energy Stores 641 Dietary lipids are digested by pancreatic lipases 641 Dietary lipids are transported in chylomicrons 642 22.2 The Use of Fatty Acids As Fuel Requires Three Stages of Processing 643 Triacylglycerols are hydrolyzed by hormone-stimulated lipases 643 Fatty acids are linked to coenzyme A before they are oxidized 644 Carnitine carries long-chain activated fatty acids into the mitochondrial matrix 645 Acetyl CoA, NADH, and FADH2 are generated in each round of fatty acid oxidation 646 The complete oxidation of palmitate yields 106 molecules of ATP 647 22.3 Unsaturated and Odd-Chain Fatty Acids Require Additional Steps for Degradation 648 An isomerase and a reductase are required for the oxidation of unsaturated fatty acids 648 Odd-chain fatty acids yield propionyl CoA in the final thiolysis step 649 Vitamin B12 contains a corrin ring and a cobalt atom 650 Mechanism: Methylmalonyl CoA mutase catalyzes a rearrangement to form succinyl CoA 651 Fatty acids are also oxidized in peroxisomes 652 Ketone bodies are formed from acetyl CoA when fat breakdown predominates 653 Ketone bodies are a major fuel in some tissues 654 Animals cannot convert fatty acids into glucose 656 22.4 Fatty Acids Are Synthesized by Fatty Acid Synthase 656 Fatty acids are synthesized and degraded by different pathways 656 The formation of malonyl CoA is the committed step in fatty acid synthesis 657 Intermediates in fatty acid synthesis are attached to an acyl carrier protein 657 Fatty acid synthesis consists of a series of condensation, reduction, dehydration, and reduction reactions 658 Fatty acids are synthesized by a multifunctional enzyme complex in animals 659 The synthesis of palmitate requires 8 molecules of acetyl CoA, 14 molecules of NADPH, and 7 molecules of ATP 661 Citrate carries acetyl groups from mitochondria to the cytoplasm for fatty acid synthesis 662 Several sources supply NADPH for fatty acid synthesis 662 Fatty acid synthase inhibitors may be useful drugs 663 22.5 The Elongation and Unsaturation of Fatty Acids Are Accomplished by Accessory Enzyme Systems 663 Membrane-bound enzymes generate unsaturated fatty acids 664 Eicosanoid hormones are derived from polyunsaturated fatty acids 664 22.6 Acetyl CoA Carboxylase Plays a Key Role in Controlling Fatty Acid Metabolism 666 Acetyl CoA carboxylase is regulated by conditions in the cell 666 Acetyl CoA carboxylase is regulated by a variety of hormones 666 Chapter 23 Protein Turnover and Amino Acid Catabolism 673 23.1 Proteins Are Degraded to Amino Acids 674 The digestion of dietary proteins begins in the stomach and is completed in the intestine 674 Cellular proteins are degraded at different rates 675
xxvi Contents 23.2 Protein Turnover Is Tightly Regulated 675 Part III SYNTHESIZING THE MOLECULES Ubiquitin tags proteins for destruction 675 OF LIFE The proteasome digests the ubiquitin-tagged proteins 677 Chapter 24 The Biosynthesis of Amino Acids 705 The ubiquitin pathway and the proteasome have prokaryotic counterparts 677 Amino acid synthesis requires solutions to three key biochemical problems 706 Protein degradation can be used to regulate biological function 678 24.1 Nitrogen Fixation:Microorganisms Use 23.3 The First Step in Amino Acid Degradation ATP and a Powerful Reductant to Reduce Is the Removal of Nitrogen 680 Atmospheric Nitrogen to Ammonia 706 Alpha-amino groups are converted into The iron-molybdenum cofactor of nitrogenase binds ammonium ions by the oxidative deamination and reduces atmospheric nitrogen 707 of glutamate 680 Ammonium ion is assimilated into an amino acid Mechanism:Pyridoxal phosphate forms Schiff-base through glutamate and glutamine 709 intermediates in aminotransferases 681 24.2 Amino Acids Are Made from Intermediates Aspartate aminotransferase is an archetypal of the Citric Acid Cycle and Other Major pyridoxal-dependent transaminase 682 Pathways 711 Pyridoxal phosphate enzymes catalyze a wide array Human beings can synthesize some amino acids but of reactions 683 must obtain others from the diet 711 Serine and threonine can be directly Aspartate,alanine,and glutamate are formed by the deaminated 684 addition of an amino group to an alpha-ketoacid 712 Peripheral tissues transport nitrogen to the A common step determines the chirality of all liver 684 amino acids 713 23.4 Ammonium lon Is Converted into Urea The formation of asparagine from aspartate requires in Most Terrestrial Vertebrates 685 an adenylated intermediate 713 The urea cycle begins with the formation of Glutamate is the precursor of glutamine,proline, carbamoyl phosphate 685 and arginine 714 The urea cycle is linked to gluconeogenesis 687 3-Phosphoglycerate is the precursor of serine, Urea-cycle enzymes are evolutionarily related to cysteine,and glycine 714 enzymes in other metabolic pathways 688 Tetrahydrofolate carries activated one-carbon units Inherited defects of the urea cycle cause at several oxidation levels 715 hyperammonemia and can lead to brain damage 688 S-Adenosylmethionine is the major donor of Urea is not the only means of disposing of methyl groups 716 excess nitrogen 689 Cysteine is synthesized from serine and homocysteine 718 23.5 Carbon Atoms of Degraded Amino Acids Emerge As Major Metabolic High homocysteine levels correlate with vascular disease 719 Intermediates 690 Shikimate and chorismate are intermediates in the Pyruvate is an entry point into metabolism for a biosynthesis of aromatic amino acids 719 number of amino acids 691 Tryptophan synthase illustrates substrate channeling Oxaloacetate is an entry point into metabolism for in enzymatic catalysis 722 aspartate and asparagine 692 Alpha-ketoglutarate is an entry point into metabolism 24.3 Feedback Inhibition Regulates Amino for five-carbon amino acids 692 Acid Biosynthesis 723 Succinyl coenzyme A is a point of entry for several Branched pathways require sophisticated nonpolar amino acids 693 regulation 723 Methionine degradation requires the formation of a An enzymatic cascade modulates the activity of key methyl donor,S-adenosylmethionine 693 glutamine synthetase 725 The branched-chain amino acids yield acetyl CoA, 24.4 Amino Acids Are Precursors of Many acetoacetate,or propionyl CoA 693 Biomolecules 726 Oxygenases are required for the degradation of Glutathione,a gamma-glutamyl peptide,serves as aromatic amino acids 695 a sulfhydryl buffer and an antioxidant 727 23.6 Inborn Errors of Metabolism Can Nitric oxide,a short-lived signal molecule,is formed Disrupt Amino Acid Degradation 697 from arginine 727
xxvi Contents 23.2 Protein Turnover Is Tightly Regulated 675 Ubiquitin tags proteins for destruction 675 The proteasome digests the ubiquitin-tagged proteins 677 The ubiquitin pathway and the proteasome have prokaryotic counterparts 677 Protein degradation can be used to regulate biological function 678 23.3 The First Step in Amino Acid Degradation Is the Removal of Nitrogen 680 Alpha-amino groups are converted into ammonium ions by the oxidative deamination of glutamate 680 Mechanism: Pyridoxal phosphate forms Schiff-base intermediates in aminotransferases 681 Aspartate aminotransferase is an archetypal pyridoxal-dependent transaminase 682 Pyridoxal phosphate enzymes catalyze a wide array of reactions 683 Serine and threonine can be directly deaminated 684 Peripheral tissues transport nitrogen to the liver 684 23.4 Ammonium Ion Is Converted into Urea in Most Terrestrial Vertebrates 685 The urea cycle begins with the formation of carbamoyl phosphate 685 The urea cycle is linked to gluconeogenesis 687 Urea-cycle enzymes are evolutionarily related to enzymes in other metabolic pathways 688 Inherited defects of the urea cycle cause hyperammonemia and can lead to brain damage 688 Urea is not the only means of disposing of excess nitrogen 689 23.5 Carbon Atoms of Degraded Amino Acids Emerge As Major Metabolic Intermediates 690 Pyruvate is an entry point into metabolism for a number of amino acids 691 Oxaloacetate is an entry point into metabolism for aspartate and asparagine 692 Alpha-ketoglutarate is an entry point into metabolism for five-carbon amino acids 692 Succinyl coenzyme A is a point of entry for several nonpolar amino acids 693 Methionine degradation requires the formation of a key methyl donor, S-adenosylmethionine 693 The branched-chain amino acids yield acetyl CoA, acetoacetate, or propionyl CoA 693 Oxygenases are required for the degradation of aromatic amino acids 695 23.6 Inborn Errors of Metabolism Can Disrupt Amino Acid Degradation 697 Part III SYNTHESIZING THE MOLECULES OF LIFE Chapter 24 The Biosynthesis of Amino Acids 705 Amino acid synthesis requires solutions to three key biochemical problems 706 24.1 Nitrogen Fixation: Microorganisms Use ATP and a Powerful Reductant to Reduce Atmospheric Nitrogen to Ammonia 706 The iron–molybdenum cofactor of nitrogenase binds and reduces atmospheric nitrogen 707 Ammonium ion is assimilated into an amino acid through glutamate and glutamine 709 24.2 Amino Acids Are Made from Intermediates of the Citric Acid Cycle and Other Major Pathways 711 Human beings can synthesize some amino acids but must obtain others from the diet 711 Aspartate, alanine, and glutamate are formed by the addition of an amino group to an alpha-ketoacid 712 A common step determines the chirality of all amino acids 713 The formation of asparagine from aspartate requires an adenylated intermediate 713 Glutamate is the precursor of glutamine, proline, and arginine 714 3-Phosphoglycerate is the precursor of serine, cysteine, and glycine 714 Tetrahydrofolate carries activated one-carbon units at several oxidation levels 715 S-Adenosylmethionine is the major donor of methyl groups 716 Cysteine is synthesized from serine and homocysteine 718 High homocysteine levels correlate with vascular disease 719 Shikimate and chorismate are intermediates in the biosynthesis of aromatic amino acids 719 Tryptophan synthase illustrates substrate channeling in enzymatic catalysis 722 24.3 Feedback Inhibition Regulates Amino Acid Biosynthesis 723 Branched pathways require sophisticated regulation 723 An enzymatic cascade modulates the activity of glutamine synthetase 725 24.4 Amino Acids Are Precursors of Many Biomolecules 726 Glutathione, a gamma-glutamyl peptide, serves as a sulfhydryl buffer and an antioxidant 727 Nitric oxide, a short-lived signal molecule, is formed from arginine 727