Navigating Metabolism

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Index

Page references followed by b denote boxes; those followed by f denote ﬁgures; those followed by t denote tables.

A Acyl-CoA synthetase, 110 Acyl transacylase, 107, 109f ACC (acetyl-CoA carboxylase), 105, 107, Adenine, 148, 149f, 155, 157f. 109f, 113, 115, 117, 173 See also Purines Acetate, 182, 193 Adenine nucleotide transporter (ANT), 38, Acetoacetate, 116b, 117b 47f, 53, 56–57 Acetone, 116b, 117b Adenosine, 142, 143f, 164–165, 164f Acetylation, 181–183, 184f Adenosine deaminase, 165 acetyl-CoA and, 9, 10f, 181–183, 184f Adenosine phosphoribosyltransferase (APRT), of lysine residues, 2, 183 155, 157f Acetyl-CoA, 2 Adenylate kinase, 16, 32, 112, 152, 154f allosteric regulation of pyruvate Adenylosuccinate, 152, 154f–155f carboxylase, 93 ADP from citrate, 43, 53, 56f, 59, 60f, 71, 72f, adenine nucleotide transporter (ANT), 38, 47f, 107, 108f 53, 56–57 citrate transporter and, 53–54, 56f adenylate kinase reaction, 16, 32, 112 entry into TCA cycle, 41, 42f energy charge, 18 in fatty acid synthesis, 107–110, 108f–109f P2 purinoreceptor activation, generation of, 39, 41, 42f, 43, 45, 45f, 164, 164f 53–54, 56f, 59 Aerobic glycolysis, 34–35, 190, 220 metabolic functions, 9, 10f, 53 Aging posttranslational modiﬁcations and, free radical theory of, 83b 181–183, 184f metabolism and, 212 Acetyl-CoA carboxylase (ACC), 105, 107, AKT, 120, 168f, 169–170, 199 109f, 113, 115, 117, 173 Alanine Acetylserotonin O-methyltransferase, β-alanine, 161–162, 163f 139, 140f conversion to pyruvate, 93 Aconitase, 60, 70 generation of, 130, 132f Activation energy, 13, 13f, 18 from pyruvate, 26 Active site, 20 urea cycle and, 134 Acyclglycerophosphate acyltransferase, 110, 111f Alanine aminotransferase, 134 ACYL (ATP-citrate lyase), 53, 56f, 59, 71, Albinism, 41 72f, 107, 108f, 182, 192 Alcohol dehydrogenase, 31f

233

234 Index

Aldolase B, 100, 101f fatty acid regulation, 117 Aldosterone, 121, 122f metformin and, 2, 209b Allopurinol, 156f, 157b nutrient sensing, 216–217 Allosteric enzymes, 20 salicylate inactivation of, 120 Allosteric regulation, 26, 27f, 32, 45, 93 SIRT1 phosphorylation by, 184 Allosteric site, 20, 21 Amphibolic pathway, 41 α-ketoglutarate Amylo-(1,4–1,6)-transglycosylase, 96 amino acid generation from, 130, 132f, 134 Anabolism from cystathionine, 142, 143f aberrant activation of signaling pathways in from glutaminolysis, 39, 44, 44f, 45, 59, 94–95 proliferating cells, 197–203, isocitrate conversion to, 70, 71f 198f–199f, 201f in TCA cycle, 39, 42f–45f, 43–45, 59–60, 60f acetyl-CoA role in, 10f α-ketoglutarate dehydrogenase, 41, 42f, 45, 45f, 77 entropy change in anabolic reactions, 11 α-ketoglutarate-dependent dioxygenase family, overview, 1, 2f, 9 4–5, 177, 186, 203, 221 Anaerobic glycolysis, 31 α-proteobacteria Analyzing metabolism, 223–231 endosymbiont theory and, 37 Anaplerosis, 43–44 proton pumps, 47 Anemia, 68, 70b Amino acids, 127–145 Angiogenesis, 202 arginine metabolism, 129, 144, 145f ANT (adenine nucleotide transporter), 38, 47f, 53, conversion to TCA cycle intermediates, 132, 56–57 133f Antimetabolite drug, 206 cysteine production, 142, 143f, 144 Antioxidants, 207, 209 degradation, 131–136, 133f, 135f, 137f Antiporters, 58 epigenetics and, 142 Apoptosis, 58 essential, 127, 128f, 129 APRT (adenosine phosphoribosyltransferase), feeding into TCA cycle, 39 155, 157f methionine metabolism, 128, 142–144, 143f Archaea for neurotransmission, 138–140, 139f–141f endosymbiont theory and, 37 overview of metabolism, 128f proton pumps, 47 production of nonessential, 129–131, 130f–132f Arginase, 134, 137f quick guide, 127–129, 128f Arginine tryptophan metabolism, 129 L-arginine, 144, 145f tyrosine metabolism, 128, 129, 139–142, 141f nitric oxide production, 144, 145f 4-Aminobutyrate aminotransferase, 138, 139f in urea cycle, 129, 134, 136b, 137f Amino sugars, 26, 27f Arginosuccinase, 134, 137f Ammonium ions, 128, 130, 131, 132f–133f, 134 Arginosuccinate, 134, 137f AMP Arginosuccinate synthetase, 134, 137f from adenine, 156, 157f Artiﬁcial sweeteners, 101b cAMP, 95, 97b, 162 Asparagine, 130 catabolism, 152, 156f Asparagine synthetase, 130, 132f energy charge, 18 Aspartate, 43, 44f increasing levels of, 16, 32, 45, 61, 95, 156, 172 in pyrimidine biosynthesis, 158, 159f from inosine 50-monophosphate, 152, 154f urea cycle and, 134, 135f, 136, 137f PFK1 regulation, 32 Aspartate aminotransferase, 130, 132f, 134 regulation of gluconeogenesis, 95, 96f Aspartate transcarboylase, 158 AMP-activated protein kinase (AMPK) Aspirin, 2 activation of, 16, 172–173, 173f, 181 Atkinson, Daniel, 18 autophagy regulation, 177 ATM, 218 in cancer cells, 200 ATP, 9, 11 catabolism induction by, 61, 172–173, adenine nucleotide transporter (ANT), 38, 47f, 173f–174f 53, 56–57 cholesterol regulation, 121, 123 allosteric regulation of TCA cycle, 45

Index 235

amount generated by complete oxidation of 2,3-Bisphosphoglycerate, 25f, 26, 27f glucose, 54–55, 57f Body mass index (BMI), 103 discovery of, 24b Bond energy, 11, 12, 14 energy charge, 18 Branching enzyme, 96, 98f extracellularas signaling molecule, 162, 164, 164f Breast cancer, 100, 205 generation Brown, Michael, 124–125 in amino acid degradation, 132, 134 Brown fat cells, uncoupled respiration in, 49 in cancer cells, 198, 202 Butyric acid, 105, 106f in glycolysis, 23, 24, 25f, 26 in lipid catabolism, 111–113 C in NADH and FADH2 oxidation, 51 in proliferating cells, 193 Caffeine, 165b – oxidative phosphorylation, 38, 39, 46 51, 47f Calcium production by adenylate kinase, 16, 32 AMP-activated protein kinase (AMPK) – production in mitochondria, 23, 26, 38 39, 41 activation, 173, 173f – for proliferating cell metabolic needs, 189 190, homeostasis regulation by mitochondria, 57–58, 189f 59f – respiratory rate controlled by, 55 57 stimulation of TCA cycle by, 45–46, 45f uncoupling biosynthetic activity from ATP Calorie, 11 – generation in mitochondria, 58 60, 60f cAMP, 95, 97b, 162 use in glycolysis, 29 cAMP-dependent protein kinase A (PKA), 95, 97b ATP-citrate lyase (ACLY), 53, 56f, 59, 71, 72f, Cancer. See also Cancer metabolism 107, 108f, 182, 192 aberrant activation of signaling pathways, – ATP-coupled reaction, 15 16, 15f 197–203, 198f–199f, 201f ATP synthase, 39, 46, 47f, 49 breast, 100, 205 Autoimmunity, 215 genetic alterations driving tumorigenesis, – Autophagosome, 175 176, 175f 203–206, 204f – – Autophagy, 167, 174 177, 175f 176f glucose metabolism in cancer cells, 34–35, 34f hyaluronic acid expression in breast cancer stem B cells, 100 hypoxia and, 202–203 Beclin 1 interacting complex, 175–176, 176f metabolic plasticity, 206 Beer, 31 metformin as anticancer agent, 208b–209b, 208f β-alanine, 161–162, 163f non-small cell lung cancer, 206 β-aminoisobutyrate, 161–162, 163f prostate, 231 β-hydroxybutyrate, 116b, 117b therapeutic targets, 206–209, 220–221 Betaine-homocysteine S-methyl transferase, 142, Warburg effect, 190, 231 143f Cancer metabolism, 4–5 β-ketoacyl carrier protein reductase, 107, 109f fructose metabolism by tumor cells, 100b β-ketoacyl synthase, 107, 109f future perspectives, 213–214 β-oxidation, 103, 105, 111, 113, 114f glucose metabolism, 34–35, 34f Bicarbonate, 90 heterogeneity of, 197, 199, 206 Bile acid, 121 modern understanding of, 219–220 Biochemistry, deﬁned, 7 oncometabolites, 226 Biosynthesis one-carbon metabolism, 73, 205 biosynthetic capacity of glycolytic rebirth of, 218–219 intermediates, 24, 26, 27f, 29, 32, 35 as therapeutic target, 206–209, 220–221 NADPH and, 65, 66 Carbamoyl phosphate, 134, 135f, 137f, 158, 159f TCA cycle as biosynthetic hub, 42–44, 43f Carbamoyl phosphate synthetase I, 134, 137f uncoupling biosynthetic activity from ATP Carbamoyl phosphate synthetase II, 158, 160, 162f generation in mitochondria, 58–60, 60f Carbohydrate response elements, 180–181, 180f Biotin, 90 Carbohydrates, 85–101 1,3-Bisphosphoglycerate, 25f, 26, 27f, 29, 93 complex, 85

236 Index

Carbohydrates (Continued) generation by glutamine-dependent reductive metabolism of simple sugars, 87–90, 87f–89f carboxylation, 60, 60f overview of metabolism, 86f from glutamine-dependent reductive quick guide to, 85, 87 carboxylation, 203 signaling and, 87, 97–100 in TCA cycle, 39, 41, 42f, 43, 43f, 45 Carbon transport into cytosol, 43, 53–54, 54f, 59, 107, carbon substrate, cell choice of, 213 108f, 192 isotope tracing, 227–231, 228f Citrate synthase, 41, 42f, 45, 45f Carbon dioxide, release in TCA cycle, 41, 42f, 55 Citrate transporter, 53–54, 54f Carbonyl cyanide-p-triﬂuoromethoxyphenyl- Citric acid cycle. See TCA cycle hydrazone (FCCP), 49, 50b, 58 Citrulline, 134, 136b, 137f, 144, 145f Carnitine-acylcarnitine translocase, 103, 112f, 113 Coenzymes, 19 Carnitine acyltransferase I (CPTI), 103, 105, 112f, Cofactors, 19 113, 117 Common cold, 82 Carnitine acyltransferase II (CPTII), 103, 112f, 113 Competitive inhibition, 20, 21f Carnitine transport cycle, 103, 112f, 113 Concentration, affect on reaction rate, 19–20, 20f Catabolism Conservation of energy, law of, 10 acetyl-CoA role in, 10f Control coefﬁcient, respiratory rate, 57 AMPK induction of, 172–173, 173f–174f Cori, Carl and Gerty, 92b entropy change in catabolic reactions, 11 Cori cycle, 90, 92b, 192 lipid, 111–113, 114f Cortisol, 121, 122f overview, 1, 2f, 9 Coupled reactions, 15–16, 15f, 17b–18b purine, 152, 156f Coupled respiration, 49, 50b pyrimidine, 160–162, 163f Covicine, 70b Catalase, 74f, 75, 80 CPTI (carnitine acyltransferase I), 103, 105, 112f, Catalysts, enzymes as, 9–10, 13, 18–20 113, 117 Catecholamines, 140, 141f CPTII (carnitine acyltransferase II), 103, 112f, 113 CD44, 100 Crabtree effect, 31 Cell death, 58 Crick, Francis H.C., 147 Cells Cristae, 38 carbon substrate, choice of, 213 CTP, 159, 160f–161f energetic state of, 16, 18 CTP synthetase, 159, 160f–161f energy transformation in, 24b Currency exchange, 51 mitochondria number in, 29, 68 Cyclooxygenase enzymes, 120 Cell signaling. See Signaling Cystathionine, 129, 142, 143f β Cellular respiration, factors controlling, 55–57 Cystathionine synthase, 129 γ Cellulose, 85 Cystathionine- -lyase, 129, 142, 143f – Ceramide, 120 Cysteine, 80 81 cGMP, 144, 145f, 162 glutathione from, 129, 143f, 144 Chance, Britton, 55 production, 129, 142, 143f, 144 Chaperone-mediated autophagy, 175 thio group, 76 Chavez, Cesar, 116b Cystine, 144, 195 Chemiosmotic theory, 46–48, 48b, 51 Cytochrome c, 39, 46, 52 Cholesterol Cytochrome c oxidase, 39, 178 reduction with statins, 124b, 124–125 Cytochrome c reductase, 39 regulation of cellular levels, 121, 123–125 Cytosine, 149f, 150. See also Pyrimidines synthesis, 120–121, 122f – ChREBP, 180 181, 180f D Chronic obstructive pulmonary disease, 186 Citrate Deacetylation, 183–184, 184f conversion to acetyl-CoA and oxaloacetate, 43, Debranching enzyme, 96, 98f 53, 56f, 59, 60f, 107, 108f Decarboxylation, oxidative, 41 fatty acid metabolism regulation, 113, 115 de Duve, Christain, 174

Index 237 de Hevesy, György, 226 Endoplasmic reticulum, ROS generation, δ-aminolevulinic acid, 129, 131f 78, 80f δ-aminolevulinic acid synthase, 129, 131f Endosymbiont theory, 37 δ-pyrroline-5-carboxylate, 131, 132f Endothelial cells, ATP generation in, 193 Demethylation, 4, 185–186 Endothelium-derived relaxing factor, 144 Deoxyribonucleotides, 150–151, 150f Energy Diabetes, 208b, 225 change in reactions, 9–16 Diacylglycerol acyltransferase, 110, 111f conservation of, 10 Diacylglycerols, 110, 111f, 120 thermodynamics, 10–11 Diet, metabolism and, 211–212 Energy charge, 18 Diet soda, 101b Enoyl-ACP reductase, 107, 109f Dihydrofolate, 160 Enthalpy, 11 Dihydrofolate reductase, 160 Entropy, 11 Dihydroxyacetone phosphate, 25f, 26, 27f, 29, 90, Environment, metabolism and, 211–212 94, 100b, 101f Enzymes 2,4-Dinitrophenol (DNP), 50 activation energy lowered by, 13, 13f, 18 Disaccharides, 85, 87 allosteric, 20 Disease as catalysts, 9–10, 13, 18–20 integration of metabolism with diet and cofactors, 19 environment, 211–212 control of metabolic flux of pathways by, 21–22 metabolic disease, screening for, 225–226 genetic alterations driving tumorigenesis, metabolism linked to, 2, 4f 203–206, 204f mitochondria and, 62–63 glycolytic, regulation of, 31–34, 33f Disulfide bond, 76 isoforms, 218 Disulfide glutathione (GSSG), 76, 81, 82f posttranslational modifications, 219 DNA, 148, 150 reaction rate and, 13, 18–20, 20f deoxyribonucleotides, 150–151, 150f regulation, 20–21, 21f mitochondrial (mtDNA), 38, 61, 62 ribozyme, 18 DNP (2,4-dinitrophenol), 50 Enzyme–substrate complex, 19, 20 Dopamine, 139–140, 141f Epigenetics, 2, 5, 9 Dopaquinone, 139, 141f amino acids and, 128, 142 Double bonds, in fatty acids, 105, 106f oxygen levels and, 186 Dual oxidases, 78 threonine metabolism and, 185 Epinephrine, 140, 141f, 142 Equilibrium constant (Keq), 14–15 E ERK, 169 Easter Island, 172b Essential amino acids, 127 Eicosanoids, 119–120, 119f ETC. See Electron transport chain Electrons, flow of, 214–215 Ethanol, from fermentation, 31, 31f fi Electron transport chain (ETC) Eukaryote, evolution of rst, 37 ATP amount generated by, 51 Eumelanins, 41 complexes, 39, 40f, 46, 47f, 48–53 Evolution, 1, 23, 37 – efficiency of electron transfer, 51–52 Exergonic reaction, 12, 12f, 15 16, 23 NAD+ regeneration by, 30, 31, 46 overview of, 39 F oxidative phosphorylation, 38, 39, 46–51, 47f respiratory rate control by, 57 FAD, as coenzyme, 41 ROS generation, 51–52, 76–77, 77f, 179–180 FADH2 Embden, Gustav, 24b ATP amount generated in oxidation by ETC, Embden-Meyerhof-Parnas pathway, 23. 51–55 See also Glycolysis coupled reactions, 16 Endergonic reaction, 12, 12f, 15–16 electron transport chain and, 39, 40f, 46, Endo, Akira, 124b 47f, 49, 51

238 Index

FADH2 (Continued) Fructose 2,6-bisphosphatase-3, 68 generated Fructose 1-phosphate, 89, 89f, 100b, 101f in fatty acid oxidation, 113, 114f Fructose 6-phosphate in TCA cycle, 39, 41, 42f in glycolysis, 25f, 26, 27f glycerol–phosphate shuttle and, 53, 55f in pentose phosphate pathway, 67f, 68, 69f Fan, Teresa, 229 Fructose 1-phosphate aldolase B, 89f, 90 Farnesyl pyrophosphate, 121, 122f Fructose 6-phosphate amidotransferase, 193 FASN, 107 Fuel choice, cellular, 213 Fasting, ketone body production with, 116b–117b Fuel switches, 213 Fats. See Lipids Fumarase, 136 Fatty acids. See also Lipids Fumarate, 46, 134, 136, 137f, 156–167, 158f, double bonds in, 105, 106f 203–204 regulation of anabolism and catabolism, 105, Fumarate hydratase, 202–204, 204f 113, 115, 115f, 117 Furchgott, Robert F., 144 structure, 105–107, 106f Future pathways of metabolism research, 211–221 synthesis, 103, 105–110, 108f–109f, 111f transport, mitochondrial, 103, 111–113, 112f unsaturated and saturated, 105, 106f, 107 G Fatty acid synthase, 107, 109f, 110 GABA (γ-aminobutyric acid), 129, 138, 139f – Fatty acyl-CoA, 112 113, 112f Galactokinase, 88, 88f – Fatty acyl-CoA synthetase, 111 112 Galactose Favism, 70b catabolism, 88–89, 88f ﬂ FCCP (carbonyl cyanide-p-tri uoromethoxyphe- conversion to glucose 6-phosphate, 88–89 nylhydrazone), 49, 50b, 58 structure, 87f Fed-fast cycle, 97b Galactose-1-P-uridyl transferase, 88, 88f Feedback inhibition, 20, 32 GalNAc (N-acetylgalactosamine), 97–98 Feed-forward activation mechanism, 32 γ-aminobutyric acid (GABA), 129, 138, 139f Fermentation γ-glutamyl kinase, 130, 132f homolactic, 31 Gandhi, Mahatma, 116b in mammals and yeast, 31, 31f GCN2, 216–217 Pasteur effect, 31 Gene expression, 1–2, 9, 217–218 Fialuridine, 62 Genetic alterations driving tumorigenesis, Final electron acceptor, 46, 47f 203–206, 204f Fischer, Hermann Emil, 165b Gerszten, Robert, 225 – FKBP12, 169 170 GFAT (glutamine fructose 6-phosphate 5-Fluorouracil, 160 amidotransferase), 98, 99, 99f – Folate, 72 74, 73f, 142, 143f, 205 Gibbs, Josiah Willard, 11 F1-ATPase, 49, 51 Gibbs free energy, 11–16, 18 F1F0-ATP synthase (F1F0-ATPase), 39, 49 in glycolytic reactions, 27–29, 28f, 28t Formate, 73, 73f in TCA cycle reactions, 41, 44–45 Franklin, Rosalind, 147 GlcNAc (N-acetylglucosamine), 97–100 Free radical theory of aging, 83b Global proﬁling, 226 Fructokinase, 89, 89f, 100 Glucagon, 32, 95, 97b Fructose Glucocorticoids, 121 entry into glycolysis, 100b, 101f Glucokinase, 32 metabolism, 89–90, 89f, 100b–101b, 101f Gluconeogenesis, 28, 32, 43–44, 68, 90–95, 91f obesity epidemic and, 90, 100b blood glucose levels maintained by, 90 structure, 87f as endergonic process, 94 sweetness, 88 enzymes shared with glycolysis, 91f transporter, 100b location of, 90 Fructose 1,6-bisphosphatase, 32, 33f, 94, 95, 96f, 97b overview, 85–86 Fructose 1,6-bisphosphate, 29 regulation of, 95, 96f Fructose 2,6-bisphosphate, 29, 95, 96f sources of carbons for, 90–95, 94f

Index 239

Glucosamine 6-phosphate, 98, 99f, 193 Glutamine-dependent reductive carboxylation, 60, Glucosamine 6-P-N-acetyltransferase, 98, 99f 60f, 203 Glucose Glutamine fructose 6-phosphate ATP amount generated by complete amidotransferase (GFAT), 98, 99, 99f oxidation of, 54–55, 57f Glutamine gluconeogenesis, 94–95 blood concentration of, 27, 90 Glutamine synthetase, 130, 132f, 134 cancer metabolism, 34–35, 34f, 198 Glutaminolysis, 39, 44, 44f, 45, 59, 94–95, 193 carbon isotope tracing, 227 Glutaredoxins (GRXs), 76 Crabtree effect, 31 Glutathione (GSH), 65, 66, 81, 129, 144 fructose metabolism compared, 100b–101b Glutathione peroxidases (GPXs), 74f, 75, 80–82, in glycolysis, 23, 25f, 27f, 88 82f glycosylation of growth factors, 186–187 GLUT5 transporter, 100b homeostasis Glycans, 97 during fed-fast cycle, 97b Glyceraldehyde, 90 glycogen synthesis and degradation, 95–97, Glyceraldehyde 3-phosphate 97b dihydroxyacetone phosphate converted to, 100b, inhibition of metabolism as cancer 101f therapy, 207 in gluconeogenesis, 91f, 93 phosphorylation, 29 in glycolysis, 24, 25f, 26, 29 structure, 87f in pentose phosphate pathway, 67f, 68, 69f transcriptional network regulation, 180–181, Glyceraldehyde 3-phosphate dehydrogenase, 29, 180f 53, 54f, 77, 93 Glucose 6-phosphatase, 94, 97 Glycerol Glucose 1-phosphate, 96–97, 98f in gluconeogenesis, 94 Glucose 6-phosphate in lipids, 105, 110 conversion from glucose 1-phosphate, 97 Glycerol kinase, 94 galactose conversion to, 88–89 Glycerol 3-phosphate, 26, 27f, 94, 110, 111f in glycolysis, 25f, 26, 27f, 88 Glycerol 3-phosphate acyltransferase, 110, 111f hexokinase inhibition, 32 Glycerol 3-phosphate dehydrogenase, 53, 55f, 94 in pentose phosphate pathway, 65, 66, Glycerol–phosphate shuttle, 53, 55f 67f, 68, 69f Glycine, 72–73, 73f Glucose 6-phosphate dehydrogenase glutathione from, 129 deﬁciency, 68, 70b in heme synthesis, 129, 131f in pentose phosphate pathway, 67f, 68 as neurotransmitter, 129 Glucose transporters, 194, 195f from 3-phosphoglycerate, 129, 130f Glutamate, 39, 43–44, 43f, 44f, 60, 128 S-adenosylmethionine (SAM) generation, 185 amino acid generation from, 130, 132f Glycine decarboxylation, 205–206 glutathione from, 129 Glycoconjugates, 85 glycosylation of growth factors, 186–187 Glycogen, 26, 85, 87 neurotransmission and, 129, 138, 139f degradation, 96–97, 98f transporters, 194–195, 195f glucose homeostasis and, 95–97, 97b urea cycle and, 134, 135f synthesis, 95–96, 98f Glutamate-cysteine ligase, 144 Glycogenolysis, 90, 96–97, 98f Glutamate dehydrogenase, 130, 132f, 134 Glycogen phosphorylase, 96–97, 97b, 98f Glutamate 5-phosphate, 130, 132f Glycogen synthase, 95, 97b, 98f Glutamic acid decarboxylase, 138, 139f Glycolipid, 85 Glutaminase, 132f, 134, 135f Glycolysis Glutamine, 5, 39, 43–44, 44f, 60, 60f aerobic, 34–35, 190, 220 fuel for cancer cells, 198 anaerobic, 31 inhibition of metabolism as cancer therapy, 207 ATP-coupled reactions, 15–16, 15f in proliferating cells, 193 ATP use in, 29 transporters, 194–195, 195f biosynthetic capacity of glycolytic urea cycle and, 134, 135f intermediates, 24, 26, 27f, 29, 32, 35

240 Index

Glycolysis (Continued) Hedgehog acyltransferase, 119 in cancer cells, 200, 201f, 202 Heme, 19, 43, 44f, 129, 131f control by pyruvate kinases, 5 Henseleit, Kurt, 134, 136b energy-generating capacity of, 24–26, 25f Hexokinase, 25f, 26, 31–32, 33f, 88, 94, 169, 207 entry of simple sugars into, 88–90, 88f–89f Hexosamine pathway, 26, 27f, 35, 87 enzymes shared with gluconeogenesis, 91f glyconjugate generation, 98–99, 99f evolution of, 23 in proliferating cells, 190 fructose entry into, 100b, 101f Hexose monophosphate shunt. See Pentose Gibbs free energy change in, 27–29, 28f, 28t phosphate pathway irreversible reactions, 31–32, 87, 90 HGPRT (hypoxanthine-guanine lipid synthesis and, 105, 111f phosphoribosyltransferase), 155, 157b, major features of, 23–24 157f metabolic flux quantification, 229 HIF (hypoxia-inducible factor), 76, 138, 169, origin of term, 23 177–180, 178f–179f, 197, 202, 204–205, overall reaction, 23 204f in proliferating cells, 190, 191f, 192, 196–197 HIG-1 (hypoxia-inducible gene-1), 52 regulation, 31–34, 33f High-fructose corn syrup, 100 steps in, 23, 24, 25f, 87 Hill, Archibald Vivian, 24b Glycolytic intermediates Histone demethylases, 142 amino acids from, 129, 130f Histone methyltransferases, 128, 142 biosynthetic capacity of, 24, 26, 27, 29, 32, 35 Histones, 142, 183, 184 NADPH generation from, 65, 66, 67f, 68, 69f HMG-CoA reductase (3-hydroxy-3- Glycoproteins, 85, 97–100, 99f methylglutaryl CoA reductase), 105, Glycosidic bonds, 95, 97 121–125, 122f, 173 Glyoxylate cycle, 136b Homocysteine, 142, 143f, 185, 186f GMP Homolactic fermentation, 31 catabolism, 152, 156f Hyaluronic acid, 100 cGMP, 144, 145f, 162 Hydrogen isotope tracing, 228–230 from guanine, 156, 157f Hydrogen peroxide, 51–52, 65, 74–78, 74f, from inosine 50-monophosphate, 152, 154f 75f, 77f, 79f, 80–81 Goldstein, Joseph, 124–125 Hydrogen-peroxide-dependent signaling, 75, 75f Gout, 157b Hydroperoxides, 80, 81 G-protein-coupled receptors, 88, 164, 164f 3-Hydroxyacyl-ACP dehydratase, 107, 109f GPXs (glutathione peroxidases), 74f, 75, 2-Hydroxyglutarate, 5, 204f, 205, 221, 226 80–82, 82f Hydroxyl radical, 74, 74f, 75 Growth factors 3-Hydroxy-3-methylglutaryl CoA reductase glycosylation of, 186–187 (HMG-CoA reductase), 105, 121–125, signaling, 169–170, 171f 122f, 173 GRXs (glutaredoxins), 76 Hydroxytmethyltransaminase, 129, 130f GSH (glutathione), 65, 66, 81, 129, 144 5-Hydroxytryptophan, 138–139, 140f GSH peroxidases, 51 Hyperpolarization of 12C, 230–231 GSH reductase, 81 Hypoxanthine, 148, 152, 156f, 157b GSSG (disulfide glutathione), 76, 81, 82f Hypoxanthine-guanine phosphoribosyltransferase GTP, 41, 42f, 55, 113, 152 (HGPRT), 155, 157b, 157f GTPase, 119, 217 Hypoxia-inducible factor (HIF), 76, 138, 169, Guanine, 148, 149f, 156, 157f. See also Purines 177–180, 178f–179f, 197, 202, 204–205, Guanylate kinase, 152, 154f 204f Hypoxia-inducible gene-1 (HIG-1), 52 H I H+, and proton motive force, 39, 46–51, 47f Harman, Denham, 83b Ignarro, Louis J., 144 Hedgehog, 119 Immunity, metabolic links to, 215

Index 241

IMP dehydrogenase, 152, 155f Lane, Andrew, 229 Inﬂammation, metabolic links to, 215 Lane, Nick, 37 Inosine 50-monophosphate, 151–152, 153f–155f Lanosterol, 123–124 Insulin, 32, 97b, 168, 208b–209b L-arginine, 144, 145f Insulin resistance, 101b Law of mass action, 14 Isocitrate, 70, 71f LDL (low-density lipoprotein), 124–125 Isocitrate dehydrogenase (IDH) L-DOPA, 139–140, 141f IDH1, 4–5, 65, 70, 71f Le Chatelier’s principle, 14 IDH2, 4–5, 60, 60f, 65, 70, 71f, 203 Leigh syndrome, 62 IDH3, 70, 71f Leloir, Luis Federico, 88f mutations, 4–5, 204f, 205, 206–207, 220–221, Leloir pathway, 88–89, 88f 226 Lesch-Nyhan syndrome, 157b NADPH generation, 65, 70, 71f Leukotrienes, 120 in TCA cycle, 41, 42f, 45–46 Linoleic acid, 105, 106f Isopentenyl pyrophosphate, 121, 122f Lipids, 103–125 Isotope carbon-labeling techniques, 5 cholesterol, synthesis and regulation of, Isotope tracing, 224, 226–231, 228f 120–125, 122f ketone body production with fasting, 116b–117b, 116f J overview of metabolism, 104f production of, 105–110, 108f–109f, 111f Johnson, William, 39 quick guide to, 103–105 Joule (J), 11 regulation of fatty acid anabolism and Jumonji-domain (JmjC) histone catabolism, 113, 115, 115f, 117 demethylase enzymes, 203–204, 204f, 205 roles in body, 103 signaling pathway activation by, 105, 117–120, K 119f structure, 106f Kelch-like ECH-associated protein 1 (KEAP1), Lipins, 110 203, 204 Liver Ketone bodies, 116b–117b, 116f fructose metabolism in, 100b–101b, 101f Kinases, 76 nonalcoholic fatty liver disease, 230 Kinetic energy, 10–11 LKB1, 200 Kinetics, enzyme, 19 Lohman, Karl, 24b Kornberg, Arthur, 150 Lovastatin, 124b Kornberg, Hans, 136b Low-density lipoprotein (LDL), 124–125 K-ras oncogene, 194, 200 L-tryptophan hydrolase, 138, 140f Krebs, Hans, 6, 39, 42, 134, 136b Lustig, Robert H., 100b Krebs cycle. See TCA cycle Lysine, acetylation of, 2, 183 Lysine-speciﬁc demethylases, 185, 187f Lysosomes, 175, 175f L

Lactase, 23, 88 M Lactate converted to pyruvate, 90, 92b, 93, 192 Macroautophagy, 175–176 pyruvate conversion to, 17b–18b, 23, 30f, 31, Magnetic resonance spectroscopy (MRS), 226 31f, 202 Malaria, 70b release/uptake, 192 Malate Lactate dehydrogenase, 17b, 30–31, 30f, 31f, 93, citrate transporter and, 53, 55f 179–180, 192, 231 conversion to pyruvate, 71, 72f, 192 Lactic acidosis, 62 fumarate conversion to, 136 Lactose, 23, 87f in NADPH generation, 70–71, 72f Lactose intolerance, 88 oxaloacetate conversion to, 93

242 Index

Malate-aspartate shuttle, 53, 54f, 136 Metabolites Malate dehydrogenases, 41, 42f, 53, 54f, 93, 107, control of metabolic flux of pathways by, 108f, 136 21–22, 45 Malic enzymes, 56f, 66, 71, 72f, 107, 108f, defined, 9 192, 194 intracellular metabolite control of signaling, Malonyl-CoA, 107–108, 109f, 110, 117 181–188, 182f, 184f–187f Malonyl transacylase, 107 measuring, 223–226 Maltose, 87f oncometabolites, 226 Mammalian target of rapamycin (mTOR), 2 regulation of glycolysis, 32, 33f, 34 MAPK (mitogen-activated protein kinase), regulation of TCA cycle, 45 164–165 TCA cycle provision of, 43 Mass action, law of, 14 Metabolomics, 214, 223, 225–226, 231 Mass-action ratio, 15 Metal ions, as cofactors, 19 Mass spectroscopy (MS), 224–229, 231 Metformin, 2, 208b–209b, 208f MAX protein, 169 Methionine, 72, 128, 142–144, 143f, 185, 186f MCU (mitochondrial calcium uniporter), 58, 59f Methionine adenosyltransferase, 142, 143f Melanins, 140–141, 141f Methionine synthase, 142, 143f MELAS (mitochondrial encephalopathy, lactic Methotrexate, 160, 206 acidosis, and stroke-like episodes), 62 Methylation, 4, 184–185, 186f Melatonin, 129, 139, 140f 5-Methyl-tetrahydrofolate, 142, 143f Membrane potential, 49 Methyltransferases, 142, 143f, 184–185, 186f Metabolic disease, screening for, 225–226 Mevalonate, 121 Metabolic flux Meyerhof, Otto Fritz, 24b

factors controlling, 22 Michaelis–Menten constant (Km), 19–20 illustration of control, 21 Michaelis–Menten equation, 19 increase in cancer cells and proliferating cells, 35 Microautophagy, 175 isotope tracers to quantify, 229–231 Microbiome, 212 in TCA cycle, control of, 45 Mitchell, Peter, 46, 48b, 51 Metabolic flux analysis, 224, 229–231 Mitochondria, 37–63 Metabolic pathways. See also specific pathway ATP production in, 23, 26, 38–39, 41 amphibolic, 41 calcium homeostasis regulation, 57–58, 59f analyzing, 223, 226–229 cells with none or few, 29, 68 conserved, 212 degradation of, 51 direction of, 9–10 disease and, 62–63 enzyme catalysis in, 9–10, 13, 18–20 dynamics, 61 factors controlling metabolic flux, 22 electron transport chain (see Electron illustration of control of flux through, 21 transport chain) metabolic flux analysis, 224, 229–231 energy-generating capacity of, 38–41 + NAD -generating, 183, 185f quick guide to, 38–39 overview, 5–6, 6f TCA cycle and, 39–41, 40f, 42f Metabolic switches, 212 essential features of, 38 Metabolism evolutionary origin of, 37 aging and, 212 fission and fusion, 61 analyzing, 223–231 heme synthesis, 129, 131f essential functions of cells, 9, 10f metabolism in proliferating cells, 190, integration with diet and environment, 191f, 192–193 211–212 nuclear gene expression controlled by introduction to, 1–7 metabolic signals, 217–218 reciprocal control of metabolism and cellular oxidative phosphorylation in, 38, 39, 46–51, 47f decisions, 216 oxygen consumption, 49, 50b as therapeutic target in cancer, 206–209, ROS in, 51–52 220–221 as signaling organelles, 5, 38, 61–62 Metabolism research, future pathways of, 211–221 structure, 38, 40f

Index 243

TCA cycle (see TCA cycle) electron transport chain and, 39, 40f, 46, 47f, transporters, 38, 52–54, 54f–56f, 58, 59f, 107, 49, 51 111–113, 112f, 192 generated uncoupling biosynthetic activity from in fatty acid oxidation, 113, 114f ATP-generation, 58–60, 60f in glycolysis, 23, 25f, 26 urea cycle (see Urea cycle) by lactate generation from pyruvate, 93 Mitochondrial antiviral-signaling protein, 61 in TCA cycle, 39, 41, 42f Mitochondrial calcium uniporter (MCU), 58, 59f inhibition of TCA cycle by, 45, 45f Mitochondrial DNA (mtDNA), 38, 61, 62 oxidation to NAD+, 30, 46, 47f, 49, 107, 108f Mitochondrial permeability transition pore respiratory rate control by, 57 (MPTP), 58 transport into mitochondria, 30, 53, 54f Mitogen-activated protein kinase (MAPK), 164–165 NADH dehydrogenase, 39, 46 Mitophagy, 51 NADPH, 65–83 Moncada, Salvador, 144 in citrate formation, 60, 60f Mondo transcription factors, 180–181, 180f coupled reactions, 16, 105, 110 Monocarboxylate transporters, 192 fatty acid synthesis, 105, 107, 110 Monosaccharides, 85, 87. See also Simple sugars generation Monounsaturated fatty acids, 105, 106f by isocitrate dehydrogenase, 65, 70, 71f MPTP (mitochondrial permeability transition by malic enzymes, 66, 71, 72f, 107, 108f, 194 pore), 58 by one-carbon metabolism, 66, 72–74, 73f MS (mass spectroscopy), 224–229, 231 overview, 65–66, 66f mtDNA (mitochondrial DNA), 38, 61, 62 by pentose phosphate pathway, 65–66, 67f, mTOR, 169–170, 171f, 172b, 199 68, 69f, 70b mTORC1 (rapamycin complex 1), 168f, 169–170, by TCA-cycle intermediates, 70–71, 71f, 72f 171f, 173, 177, 179 in proliferating cells, 189–190, 189f, 194 mTORC2 (rapamycin complex 2), 169–170 quick guide to, 65–66, 66f Murad, Ferid, 144 roles in metabolism, 65–66, 66f Muscle cells, purine nucleotide cycle in, 156–157 ROS detoxiﬁcation, 79–82 Mutations, IDH, 4–5, 204f, 205, 206–207, NADPH/NADP+ ratio, 65 220–221, 226 NADPH oxidases (NOXs), 65, 66, 74f, 76, 78, MYC protein, 169, 199f, 200 79f, 198 Myoadenylate deaminase, 157 Nernst equation, 18b Myristoylation, 118–119, 119f Neurons, glycolysis control in, 68 Neurotransmitters, 129, 138–140, 139f–141f N Nicotinamide, 183 Nicotinamide mononucleotide, 183 N-acetylgalactosamine (GalNAc), 97–98 Nicotinamide phosphoribosyltransferase, 183 N-acetylglucosamine (GlcNAc), 97–100 Nitric oxide, 144, 145f N-acetylglucosamine 1-phosphate, 98 Nitric oxide synthases, 129, 144, 145f N-acetylglucosamine 6-phosphate, 98 Nitrogen bases, 148–150, 149f NAD+ Nitrogen isotope tracing, 229 as coenzyme, 19, 41 NMR (nuclear magnetic resonance) spectroscopy, deacetylation and, 183–184, 184f 224–225, 227–229 generated by malate dehydrogenase 1, 93, 107, N-myristoylation, 118–119, 119f 108f Nobel Prize, metabolism-related, 1, 3b–4b metabolic pathways generating, 183, 185f Nonalcoholic fatty liver disease, 230 in proliferating cells, 190, 192 Noncompetitive inhibition, 20–21, 21f regeneration, 30–31, 30f, 31f Non-small cell lung cancer, 206 transport out of mitochondria, 30 Nonsteroidal anti-inﬂammatory drugs (NSAIDs), NADH 120 ATP amount generated in oxidation by ETC, Norepinephrine, 140, 141f, 142 51, 55 NOXs (NADPH oxidases), 65, 66, 74f, coupled redox reactions, 16, 17b–18b 76, 78, 79f, 198

244 Index

N-palmitoylation, 119, 119f Oxidation reaction, 2, 16. See also specific NRF2 (nuclear factor erythroid 2-related factor 2), reactions 81, 203, 207 Oxidation-reduction (redox) reactions, 16, NSAIDs (nonsteroidal anti-inflammatory drugs), 17b–18b. See also specific reactions 120 Oxidative damage, 75 Nuclear factor erythroid 2-related factor 2 (NRF2), Oxidative phosphorylation, 38, 39, 46–51, 47f 81, 203, 207 Oxidative stress, in red blood cells, 68, 70b Nuclear factor NF-κB, 76 Oxidative stress-induced cell death, 198 Nuclear magnetic resonance (NMR) spectroscopy, Oxidoreductin 1 (ERO1), 78, 80f 224–225, 227–229 Oxygen Nucleosides, 148, 149f, 150 as final electron acceptor in ETC, 46, 47f Nucleotides, 147–165 levels and epigenetics, 186 deoxyribonucleotides, 150–151, 150f mitochondrial/cellular consumption, 49, overview of metabolism, 147f 50b, 56, 178 purine biosynthesis, 151–152, 153f–155f reactive oxygen species ( see ROS) purine degradation, 152, 156f transcriptional network regulation, 177–180, purine salvage, 155–157, 157f–158f 178f–179f pyrimidine biosynthesis, 158–160, 159f Oxygen conformance, 178 pyrimidine catabolism, 160–162, 163f quick guide to, 148 signaling and, 162, 164–165, 164f P – structure, 148 150, 149f Palmitate, 103, 104f, 105, 110, 113, 115 – Nutrient sensing, 216 217 Palmitoylation, 118–119, 119f Nutrient uptake Palmitoyl-CoA, 113, 114f–115f, 115, 120 – in proliferating cells, 194 195, 195f Paracoccus denitrificans, 37 – signal transduction regulation of, 168 169, 168f Parkin, 51 Parkinson’s disease, 58, 140, 165b O Parnas, Jakub, 24b Pasteur, Louis, 31 Obesity, 90, 100b, 103 Pasteur effect, 31 Ochoa, Severo, 150 PDI (protein disulfide isomerase), 78, 80f O-GlcNAcase, 99 Pentose phosphate pathway O-GlcNAc transferase (OGT), 97, 99, 99f galactose entry into, 89 Oleic acid, 105, 106f glycolytic intermediates and, 26, 27f, 35 OMP decarboxylase, 162f NADPH generation, 65–66, 67f, 68, 69f, 70b Oncogenes, 197, 202–203, 219 in proliferating cells, 190, 191f Oncometabolites, 226 PEPCK (phosphoenolpyruvate carboxykinase), One-carbon metabolism 93, 94f fueled by serine, 205 Peroxiredoxins (PRXs), 51, 74f, 75, 80–82, NADPH generation in, 66, 72–74, 73f 81f, 209 in proliferating cells, 190, 191f PET (positron emission tomography), 34, 34f Organic cation transporters, 209b Peutz-Jeghers syndrome, 200 Ornithine, 130, 132f, 134, 136b, 137f PFK1 (phosphofructokinase-1), 25f, 26, 31–32, Ornithine aminotransferase, 130, 132f 33f, 34, 94, 95, 96f, 97b, 100b Ornithine transcarbamoylase, 134, 137f PFK2 (phosphofructokinase-2), 32, 33f, 95, 97b Orotate, 158, 159f Phenomelanins, 41 Oxaloacetate, 39, 41, 42f, 43–45, 43f, 59, 60f Phenotype, metabolism and, 1–2 from citrate, 43, 53, 56f, 59, 60f, 107, 108f Phenylalanine, 129, 141f, 142, 225 citrate conversion to, 71, 72f Phenylalanine hydroxylase, 129, 141f, 142 conversion to malate, 71, 93 Phenylketonuria (PKU), 142, 225 conversion to PEP, 93, 93f Phosphatases, 76, 92b malate conversion to, 136 Phosphate dehydrogenase, 77 pyruvate conversion to, 44, 45, 90, 93–94, 93f Phosphate transporter, 53

Index 245

Phosphatidic acid, 110, 111f N-palmitoylation, 119, 119f Phosphatidic acid phosphohydrolases, 110, 111f S-palmitoylation, 118–119, 119f Phosphatidylinositol 4,5-bisphosphate, 120, 169 S-prenylation, 119, 119f Phosphatidylinositol 3,4,5-trisphosphate, 120, 169 Potential energy, 10–11 Phosphoacetylglucosamine mutase, 98, 99f P2 purinoreceptors, 162, 164, 164f Phosphodiestase type 5, 144, 145f Prokaryotes, endosymbiont theory and, 37 Phosphoenolpyruvate, 29, 43–44, 43f, 90, 93, 93f Proliferating cells, metabolism of, 189–209, 216 Phosphoenolpyruvate carboxykinase (PEPCK), aberrant activation of signaling pathways, 93, 94f 197–203, 198f–199f, 201f Phosphofructokinase-1 (PFK1), 25f, 26, 31–32, NADPH, 194 33f, 34, 94, 95, 96f, 97b, 100b nutrient uptake, 194–195, 195f Phosphofructokinase-2 (PFK2), 32, 33f, 95, 97b overview, 189–190, 189f 6-Phosphofructo-2-kinase, 68 T cells, 195–197, 196f Phosphoglucomutase, 88, 88f Proline dehydrogenase, 77 6-Phosphogluconate dehydrogenase, 67f, 68 Prolyl hydrolases, 177, 178f, 203, 205 Phosphogluconate pathway. See Pentose phosphate Prostaglandins, 120 pathway Prostate cancer, 231 3-Phosphoglycerate, 25f, 26, 27f, 29, 129, 130f Prosthetic groups, 19 Phosphoglycerate dehydrogenase, 129, 130f, 204f, Protein disulfide isomerase (PDI), 78, 80f 205 Protein kinase A (PKA), 95, 97b 3-Phosphohydroxypyruvate, 129, 130f Protein kinase C, 120 Phosphoinositide-dependent kinase 1, 169 Proteins Phosphoinositide 3-kinase, 168f, 169 amino acids (see Amino acids) Phosphoinositides, 119f, 120 posttranslational modifications, 167, 181–187, Phospholipase A2, 120 182f Phospholipase C, 120 Proteoglycans, 99–100 Phospholipids, 105, 106f Proton gradient, 46–48, 47f 5-Phosphoribosyl-1-pyrophosphate (PRPP), Proton leakage, 49–50, 57 151–152, 153f, 155–156, 155f, 157b, 157f, Proton motive force (pmf), 39, 46–51, 47f 158, 159f, 160, 162f Protonophore, 49–50, 50b, 58 Phosphorylation Proton pumps, 39, 46–51, 47f oxidative, 38, 39, 46–51, 47f PRPP (5-phosphoribosyl-1-pyrophosphate), substrate-level, 26, 29 151–152, 153f, 155–156, 155f, 157b, 157f, 3-Phosphoserine, 129, 130f 158, 159f, 160, 162f Phosphoserine phosphatase, 129, 130f PRPP synthetase, 157b Phosphoserine transaminase, 129, 130f PRXs (peroxiredoxins), 51, 80–82, 81f PI3K, 197, 199–200, 199f, 208b PTEN, 199, 199f PKA (protein kinase A), 95, 97b PTEN-induced putative linase 1, 51 PKU (phenylketonuria), 142, 225 p53 transcription factor, 200 Polyunsaturated fatty acids, 105, 106f Purines, 43 Porcupine, 119 biosynthesis, 151–152, 153f–155f Porins, 39 caffeine, 165b Porphyrins, 43, 44f catabolism, 152, 156f Positron emission tomography (PET), 34, 34f salvage, 155–157, 157f–158f Posttranslational modifications, 167, 181–187, structure, 148–150, 149f 182f, 218 Pyrimidines, 43 acetylation, 181–183, 184f biosynthesis, 158–160, 159f deacetylation, 183–184, 184f catabolism, 160–162, 163f demethylation, 185–186 regulation of synthesis, 160, 162f glycosylation of, 186–187 structure, 148–150, 149f by lipids, 105, 117–119, 119f Pyrroline-5-carboxylate reductase, 131, 132f methylation, 184–185, 186f Pyruvate N-myristoylation, 118–119, 119f acetyl-CoA from, 39, 41, 42f, 45, 45f

246 Index

Pyruvate (Continued) Ribozyme, 18 alanine conversion to, 93 Ribulose 5-phosphate, 66, 67f, 68, 69f alanine from, 26, 134 Rickettsia prowazekii, 37 conversion to glucose, 28 RNA, 18, 148, 150 conversion to lactate, 17b–18b, 23, 30f, 31, 31f, ROS, 2, 65, 214–215 202 in cancer cells, 197, 198, 198f, 207, 209 conversion to oxaloacetate, 44, 45, 90, 93–94, detoxiﬁcation by NADPH, 79–82 93f generation by electron transport chain, 51–52, entry into mitochondria, 23, 26, 29, 30, 53, 192 179–180 from glycolysis, 23, 25f, 26, 29 in hypoxia, 179–180 lactate conversion to, 90, 92b, 93, 192 pathology and, 82–83 malate conversion to, 71, 72f, 192 sources of, 74, 74f, 76–78, 77f, 79f, 80f Pyruvate carboxylase, 44, 45, 45f, 90, 93, 93f stress signaling, 218 Pyruvate decarboxylase, 31f targets of, 76 Pyruvate dehydrogenase, 39, 41, 45, 45f, 54, 77, T-cell activation and proliferation, 196 179–180, 192 thio-dependent redox signaling, 74–78, 75f Pyruvate dehydrogenase kinase, 179–180 Pyruvate kinases, 5, 25f, 26, 31–32, 33f, 34, 200–202, 201f S Pythagoras, 70b S-adenosylhomocysteine (SAH), 142, 143f, 185, 186f R S-adenosylmethionine (SAM), 142, 143f, 184–185, 186f Radioisotopes, 226–227 Saturated fatty acids, 105, 106f Rag GTPase, 170, 217 SCAP, 123 Rapamycin, 169–170, 171f, 172b Sehgal, Suren, 172b Rapamycin complex 1 (mTORC1), 168f, 169–170, Serine, 72–73, 73f 171f, 173, 177, 179, 216–217 one-carbon metabolism fueled by, 190, 205 Rapamycin complex 2 (mTORC2), 169–170 3-phosphoglycerate converted to, 26 Ras, 119, 121, 169 production of, 129, 130f, 190 Ras homolog enriched in brain (RHEB), 170 sphingolipids production from, 120 Reactions Serotonin, 129, 138–139, 140f coupled, 15–16, 15f, 17b–18b Serotonin N-acetyltransferase, 139, 140f direction, 9–10, 27 Signaling, 1–2, 9, 167–188 energy change in, 9–16 aberrant activation of signaling pathways in equilibrium constant (Keq), 14–15 proliferating cells, 197–203, 198f–199f, Michaelis–Menten constant (Km), 19–20 201f rate, 13, 18–20, 20f AMPK induction of catabolism, 172–173, Reactive oxygen species. See ROS 173f–174f Receptor tyrosine kinases, 168–169, 168f autophagy, 167, 174–177, 175f–176f Redox balance in cancer cells, 197, 198, 198f carbohydrates and, 87, 97–100 Redox signaling, 74–78, 75f, 214 growth factor, 169–170, 171f Reduction potential, 17b, 46 hydrogen peroxide-dependent, 75, 75f Reduction reaction, 16. See also speciﬁcreactions intracellular metabolite control of, 181–188, Respiration, 10–11 182f, 184f–187f coupled, 49, 50b lipids, signaling pathway activation by, 105, uncoupled, 49–50, 50b 117–120, 119f Respiratory chain. See Electron transport chain mitochondria as signaling organelles, 5, 38, RHEB (Ras homolog enriched in brain), 170 61–62 Rheb GTPase, 217 mTOR and, 169–170, 171f, 172b Ribonucleotide reductase, 150f, 151, 160, 161f nuclear gene expression controlled by Ribonucleotides, 151 metabolic signals, 217–218 Ribose 5-phosphate, 89, 152, 153f, 155f nucleotides and, 162, 164–165, 164f

Index 247

nutrient uptake, regulation of, 168–169, 168f as biosynthetic hub, 42–44, 43f redox, 74–78, 75f, 214 biosynthetic intermediates generated by, 58–60, thio-dependent redox signaling, 74–78, 75f 60f transcriptional network regulation, 177–181, discovery of, 39, 41 178f–180f Gibbs free energy and, 41, 44–45 Simple sugars, 23, 85 glycolysis regulation by intermediates, 32, 34 in glycoproteins, 98 lipid synthesis and, 105, 111f metabolism of, 87–90, 87f–89f overall reaction, 41 sweetness, 88 overview, 39, 41, 42f Sirtuin family of deacetylases, 183–184, 184f in proliferating cells, 191f, 192–193, 196 SLC25A1 transporter, 53, 56f regulation of, 44–46, 45f SNAT transporters, 194, 195f TCA-cycle intermediates S-nitrosothiol, 144, 145f amino acids converted to, 132, 133f Sodium-glucose transporters, 194, 195f amino acids generated from, 129–130, 131f SODs, 51, 74, 77–78, 77f, 80 NADPH generation, 70 –71, 71f, 72f Solute carrier family of transporters, 194–195, 195f production from purine nucleotide salvage, S-palmitoylation, 118–119, 119f 156–157, 158f Sphingolipids, 119f, 120 in proliferating cells, 192–193 Sphingosine 1-phosphate, 120 T cells, 195–197, 196f, 229 S-prenylation, 119, 119f TET (ten-eleven translocation) DNA hydrolases, Squalene, 121, 122f 203, 204f, 205 SREBP, 123–125 Tetrahydrofolate (TFH), 73, 73f, 129, 130f, 142, Stable isotopes, 227, 230 143f, 152, 160, 161f Standard free-energy change, 14 Thermodynamics, 10–11 Starch, 85 Thio-dependent redox signaling, 74–78, 75f Statins, 2, 124–125, 124b Thioesterase, 107, 109f Steric acid, 105 Thiolate anion, 76 Stress signaling pathways, 218 Thioredoxin (TRX), 65, 66, 76, 80, 81f Substrate-level phosphorylation, 26, 29 Threonine, 185, 193 Succinate Threonine dehydrogenase, 185 GABA shunt generation of, 138, 139f Thromboxanes, 120 in TCA cycle, 41, 42f, 46 Thymidylate synthase, 160, 161f in tumorigenesis, 203–204 Thymine, 149f, 150. See also Pyrimidines Succinate dehydrogenase, 39, 45, 46, 202–204, 204f Toll-like receptor signaling, 61–62 Succinic semialdehyde, 138, 139f Transaldolase, 68 Succinic semialdehyde dehydrogenase, 138, 139f Transcriptional network regulation, 177–181, Succinyl-CoA, 41, 42f, 43, 43f, 45, 129, 131f 178f–180f – Sucrase, 23, 87 88 by glucose, 180–181, 180f Sucrose, 23, 87f by oxygen, 177–180, 178f–179f Sulfenic acid, 76 Transition state, 13, 13f – Sulfenic amide bond, 76 Transketolase, 68 fi Sul nic acid, 76 Transporters. See also specific transporters Sulfonic acid, 76 calcium, 58, 59f – – – Superoxide, 51 52, 65, 66, 74 75, 74f, 77 78, 77f, carnitine-acylcarnitine translocase, 103, 79f 112f, 113 fi Sweeteners, arti cial, 101b citrate, 192 Sweetness, of simple sugars, 88 cystine, 144 fructose, 100b T glucose (GLUTs), 194, 195f glutamine and glutamate, 194–195, 195f TCA cycle mitochondrial, 38, 52–54, 54f–56f, 58, 59f, 107, as amphibolic pathway, 41 111–113, 112f, 192 anaplerosis, 43–44 monocarboxylate, 192

248 Index

Transporters (Continued) UDP-N-acetylglucosamine pyrophosphatase, 99, nutrient, 194–195, 195f 99f organic cation transporters, 209b ULK1, 177 pyruvate, 5, 38, 192 Uncoupled respiration, 49–50, 50b sodium-glucose, 194, 195f Unsaturated fatty acids, 105, 106f, 107 solute carrier family, 194–195, 195f Uracil, 149f, 150. See also Pyrimidines trans-sulfuration, 142, 143f Urea cycle, 131–136, 133f, 135f, 136b, 137f Triacylglycerols (triglycerides), 100b–101b, 101f, Uric acid, 152, 156f, 157b 103, 105, 106f, 110 Uridine nucleotides, generation of, 160, 161f Tricarboxylic cycle. See TCA cycle Triose kinase, 89f, 90 Triparanol, 124b V TRX (thioredoxin), 65, 66, 80, 81f Viagra, 144 TRX reductase (TR1 or TR2), 76, 80, 81f Vicine, 70b Tryptophan Vitamin C, 82 metabolism, 129 Voltage-dependent anion channel (VDAC), 39, 53, – serotonin generation from, 138 139, 77 140f von Hippel-Lindau tumor suppressor (VHL), 177, Tuberous sclerosis 1 and 2, 170 178f Tumor-initiating cells, 206 Tumor suppressors, 197, 202–203, 219 Tyrosinase, 41 W Tyrosine maintenance of levels within cells, Wang, Thomas, 225 141–142 Warburg, Otto, 34, 136b, 190, 220 – metabolism, 128, 139–142, 141f Warburg effect, 34 35, 92b, 190, 231 from phenylalanine, 129, 141f, 142 Watson, James, 147 Tyrosine hydroxylase, 139–140, 141f Wilkins, Maurice, 147 Williams, G.R., 55 Wnt, 119 U

Ubiquinol, 46 X Ubiquinone (Q), 39, 46, 52 UDP-galactose 4-epimerase, 99 Xanthine, 148, 152, 156f, 157b UDP-glucose, 95, 98f UDP-glucose pyrophosphorylase, 95, 98f Y UDP-N-acetylgalactosamine, 99, 99f UDP-N-acetylglucosamine, 99, 99f, 187 Yeast, fermentation in, 31, 31f