GAPDH and Intermediary Metabolism

  • Norbert W. Seidler
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 985)


GAPDH plays a major enzymatic role in the intermediary metabolism of human tissues. In fact, the cells of all organisms require the catalytic capability of GAPDH in order to maintain adequate glycolytic flux. Even the primitive archaea rely on GAPDH in a pivotal step in the Entner-Doudoroff pathway, which is a series of reactions that resembles glycolysis. GAPDH catalyzes the sixth reaction of glycolysis in eukaryotic cells and represents a regulatory hurdle in anaerobic glycolysis. The triose substrate of GAPDH is actually a product of several important metabolic pathways: stage one of glycolysis, fructose catabolism, pentose phosphate pathway and glycerol metabolism. The GAPDH reaction is reversible, hence, necessary for hepatic gluconeogenesis. The chapter discusses GAPDH as being a metabolic ‘switching station’, diverting carbon flow appropriately. There is discussion regarding the experimental analysis of GAPDH’s enzymatic function, particularly in the use of inhibitors. The GAPDH gene is portrayed in the context of the enzyme’s role in metabolism. The observed intolerance to genetic mutation suggests that the genetic changes (i.e. those seen across species) may provide a treasure of information regarding the limits of genetic variability that can be tolerated and still allow for the protein to conduct essential glycolytic – as well as non-glycolytic – functions.


Autosomal Dominant Polycystic Kidney Disease Glycolytic Flux Dihydroxyacetone Phosphate NADH Ratio Gymnemic Acid 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Williamson JR (1965) Glycolytic control mechanisms. J Biol Chem 240:2308–2321PubMedGoogle Scholar
  2. 2.
    Velick SF, Furfine C (1963) Glyceraldehyde 3-phosphate dehydrogenase. In: Boyer PD (ed) The enzymes, vol 7. Academic, New YorkGoogle Scholar
  3. 3.
    Klingenberg M, Slenczka W, Ritt E (1959) Comparative biochemistry of the pyridine nucleotide system in the mitochondria of various organs. Biochem Z 332:47–66PubMedGoogle Scholar
  4. 4.
    Williamson JR, Krebs HA (1961) Acetoacetate as fuel of respiration in the perfused rat heart. Biochem J 80:540–547PubMedGoogle Scholar
  5. 5.
    Godon C, Lagniel G, Lee J et al (1998) The H2O2 stimulon in Saccharomyces cerevisiae. J Biol Chem 273:22480–22489PubMedCrossRefGoogle Scholar
  6. 6.
    Desaint S, Luriau S, Aude JC et al (2004) Mammalian antioxidant defenses are not inducible by H2O2. J Biol Chem 279:31157–31163PubMedCrossRefGoogle Scholar
  7. 7.
    Ravichandran V, Seres T, Moriguchi T et al (1994) S-thiolation of glyceraldehyde-3-phosphate dehydrogenase induced by the phagocytosis-associated respiratory burst in blood monocytes. J Biol Chem 269:25010–25015PubMedGoogle Scholar
  8. 8.
    Newman SF, Sultana R, Perluigi M et al (2007) An increase in S-glutathionylated proteins in the Alzheimer’s disease inferior parietal lobule, a proteomics approach. J Neurosci Res 85:1506–1514PubMedCrossRefGoogle Scholar
  9. 9.
    Chuang DM, Hough C, Senatorov VV (2005) Glyceraldehyde-3-phosphate dehydrogenase, apoptosis, and neurodegenerative diseases. Annu Rev Pharmacol Toxicol 45:269–290PubMedCrossRefGoogle Scholar
  10. 10.
    Shenton D, Grant CM (2003) Protein S-thiolation targets glycolysis and protein synthesis in response to oxidative stress in the yeast Saccharomyces cerevisiae. Biochem J 374:513–519PubMedCrossRefGoogle Scholar
  11. 11.
    Colussi C, Albertini MC, Coppola S et al (2000) H2O2-induced block of glycolysis as an active ADP-ribosylation reaction protecting cells from apoptosis. FASEB J 14:2266–2276PubMedCrossRefGoogle Scholar
  12. 12.
    Dastoor Z, Dreyer JL (2001) Potential role of nuclear translocation of glyceraldehyde-3-phosphate dehydrogenase in apoptosis and oxidative stress. J Cell Sci 114:1643–1653PubMedGoogle Scholar
  13. 13.
    Ralser M, Wamelink MM, Kowald A et al (2007) Dynamic rerouting of the carbohydrate flux is key to counteracting oxidative stress. J Biol 6:10PubMedCrossRefGoogle Scholar
  14. 14.
    Daly ME, Vale C, Walker M et al (1998) Acute effects on insulin sensitivity and diurnal metabolic profiles of a high-sucrose compared with a high-starch diet. Am J Clin Nutr 67:1186–1196PubMedGoogle Scholar
  15. 15.
    van der Meer R, Akerboom TP, Groen AK et al (1978) Relationship between oxygen uptake of perifused rat-liver cells and the cytosolic phosphorylation state calculated from indicator metabolites and a redetermined equilibrium constant. Eur J Biochem 84:421–428PubMedCrossRefGoogle Scholar
  16. 16.
    Pette D, Dölken G (1975) Some aspects of regulation of enzyme levels in muscle energy-supplying metabolism. Adv Enzyme Regul 13:355–377PubMedCrossRefGoogle Scholar
  17. 17.
    Bünger R, Mukohara N, Kang YH et al (1991) Combined glyceraldehyde-3-phosphate dehydrogenase/phosphoglycerate kinase in catecholamine-stimulated guinea-pig cardiac muscle. Comparison with mass-action ratio of creatine kinase. Eur J Biochem 202:913–921PubMedCrossRefGoogle Scholar
  18. 18.
    Scrutton MC, Utter MF (1968) The regulation of glycolysis and gluconeogenesis in animal tissues. In: Boyer PD, Meister A, Sinsheimer RL, Snell EE (eds) Annual review of biochemistry, vol 37. Annual Reviews, Palo AltoGoogle Scholar
  19. 19.
    Habenicht A (1997) The non-phosphorylating glyceraldehyde-3-phosphate dehydrogenase: biochemistry, structure, occurrence and evolution. Biol Chem 378:1413–1419PubMedGoogle Scholar
  20. 20.
    Chance B, Estabrook RW, Ghosh A (1964) Damped sinusoidal oscillations of cytoplasmic reduced pyridine nucleotide in yeast cells. Proc Natl Acad Sci USA 51:1244–1251PubMedCrossRefGoogle Scholar
  21. 21.
    Hommes FA, Schuurmansstekhoven FM (1964) Aperiodic changes of reduced nicotinamide-adenine dinucleotide during anaerobic glycolysis in brewer’s yeast. Biochim Biophys Acta 86:427–428PubMedCrossRefGoogle Scholar
  22. 22.
    Duysens LN, Amesz J (1957) Fluorescence spectrophotometry of reduced phosphopyridine nucleotide in intact cells in the near-ultraviolet and visible region. Biochim Biophys Acta 24:19–26PubMedCrossRefGoogle Scholar
  23. 23.
    Chance B, Schoener B, Elsaesser S (1965) Metabolic control phenomena involved in damped sinusoidal oscillations of reduced diphosphopyridine nucleotide in a cell-free extract of Saccharomyces carlsbergensis. J Biol Chem 240:3170–3181PubMedGoogle Scholar
  24. 24.
    Tilton WM, Seaman C, Carriero D et al (1991) Regulation of glycolysis in the erythrocyte: role of the lactate/pyruvate and NAD/NADH ratios. J Lab Clin Med 118:146–152PubMedGoogle Scholar
  25. 25.
    Smythe CV (1936) The reactions of iodoacetate and of iodoacetamide with various sulfhydryl groups, with urease, and with yeast preparations. J Biol Chem 114:601–612Google Scholar
  26. 26.
    Williamson JR (1967) Glycolytic control mechanisms. 3. Effects of iodoacetamide and fluoroacetate on glucose metabolism in the perfused rat heart. J Biol Chem 242:4476–4485PubMedGoogle Scholar
  27. 27.
    Dioudis C, Dimitrios G, Thomas TH et al (2008) Abnormal glyceraldehyde-3-phosphate dehydrogenase binding and glycolytic flux in autosomal dominant polycystic kidney disease after a mild oxidative stress. Hippokratia 12:162–167PubMedGoogle Scholar
  28. 28.
    Brodie AE, Reed DJ (1990) Cellular recovery of glyceraldehyde-3-phosphate dehydrogenase activity and thiol status after exposureto hydroperoxides. Arch Biochem Biophys 276:212–218PubMedCrossRefGoogle Scholar
  29. 29.
    Sakai K, Hasumi K, Endo A (1991) Identification of koningic acid (heptelidic acid)-modified site in rabbit muscle glyceraldehyde-3-phosphate dehydrogenase. Biochim Biophys Acta 1077:192–196PubMedCrossRefGoogle Scholar
  30. 30.
    Sakai K, Hasumi K, Endo A (1990) Two glyceraldehyde-3-phosphate dehydrogenase isozymes from the koningic acid (heptelidic acid) producer Trichoderma koningii. Eur J Biochem 193:195–202PubMedCrossRefGoogle Scholar
  31. 31.
    Sakai K, Hasumi K, Endo A (1988) Inactivation of rabbit muscle glyceraldehyde-3-phosphate dehydrogenase by koningic acid. Biochim Biophys Acta 952:297–303PubMedCrossRefGoogle Scholar
  32. 32.
    Izutani Y, Murai T, Imoto T et al (2005) Gymnemic acids inhibit rabbit glyceraldehyde-3-phosphate dehydrogenase and induce a smearing of its electrophoretic band and dephosphorylation. FEBS Lett 579:4333–4336PubMedCrossRefGoogle Scholar
  33. 33.
    Medvedev A, Buneeva O, Gnedenko O et al (2006) Isatin interaction with glyceraldehyde-3-phosphate dehydrogenase, a putative target of neuroprotective drugs: partial agonism with deprenyl. J Neural Transm Suppl 71:97–103PubMedCrossRefGoogle Scholar
  34. 34.
    Kondo S, Kubota S, Mukudai Y et al (2011) Binding of glyceraldehyde-3-phosphate dehydrogenase to the cis-acting element of structure-anchored repression in ccn2 mRNA. Biochem Biophys Res Commun 405:382–387PubMedCrossRefGoogle Scholar
  35. 35.
    Eaton P, Wright N, Hearse DJ et al (2002) Glyceraldehyde phosphate dehydrogenase oxidation during cardiac ischemia and reperfusion. J Mol Cell Cardiol 34:1549–1560PubMedCrossRefGoogle Scholar
  36. 36.
    Bruice PY, Wilson SC, Bruice TC (1978) Inactivation of glyceraldehyde-3-phosphate dehydrogenase and yeast alcohol dehydrogenase by arene oxides. Biochemistry 17:1662–1669PubMedCrossRefGoogle Scholar
  37. 37.
    Chernorizov KA, Elkina JL, Semenyuk PI et al (2010) Novel inhibitors of glyceraldehyde-3-phosphate dehydrogenase: covalent modification of NAD-binding site by aromatic thiols. Biochemistry (Mosc) 75:1444–1449CrossRefGoogle Scholar
  38. 38.
    McCaul S, Byers LD (1976) The reaction of epoxides with yeast glyceraldehyde-3-phosphate dehydrogenase. Biochem Biophys Res Commun 72:1028–1034PubMedCrossRefGoogle Scholar
  39. 39.
    Tang Z, Yuan S, Hu Y et al (2012) Over-expression of GAPDH in human colorectal carcinoma as a preferred target of 3-Bromopyruvate Propyl Ester. J Bioenerg Biomembr 44:117–125PubMedCrossRefGoogle Scholar
  40. 40.
    Sansbury BE, Riggs DW, Brainard RE et al (2011) Responses of hypertrophied myocytes to reactive species: implications for glycolysis and electrophile metabolism. Biochem J 435:519–528PubMedCrossRefGoogle Scholar
  41. 41.
    Wick AN, Drury DR, Nakada HI et al (1957) Localization of the primary metabolic block produced by 2-deoxyglucose. J Biol Chem 224:963–969PubMedGoogle Scholar
  42. 42.
    Sols A, Crane RK (1954) Substrate specificity of brain hexokinase. J Biol Chem 210:581–595PubMedGoogle Scholar
  43. 43.
    Fahien LA (1966) A study of the reaction of glyceraldehyde with glyceraldehyde 3-phosphate dehydrogenase. J Biol Chem 241:4115–4123PubMedGoogle Scholar
  44. 44.
    Krimsky I, Racker E (1963) Separation of oxidative from phosphorylative activity by proteolysis of glyceraldehyde-3-phosphate dehydrogenase. Biochemistry 2:512–518PubMedCrossRefGoogle Scholar
  45. 45.
    Velick SF, Hayes JE Jr (1953) Phosphate binding and the glyceraldehyde-3-phosphate dehydrogenase reaction. J Biol Chem 203:545–562PubMedGoogle Scholar
  46. 46.
    Meunier JC, Dalziel K (1978) Kinetic studies of glyceraldehyde-3-phosphate dehydrogenase from rabbit muscle. Eur J Biochem 82:483–492PubMedCrossRefGoogle Scholar
  47. 47.
    Chen YH, He RQ, Liu Y et al (2000) Effect of human neuronal tau on denaturation and reactivation of rabbit muscle D-glyceraldehyde-3-phosphate dehydrogenase. Biochem J 351:233–240PubMedCrossRefGoogle Scholar
  48. 48.
    Nygaard AP, Sumner JB (1952) D-glyceraldehyde 3-phosphate dehydrogenase; a comparison with liver aldehyde dehydrogenase. Arch Biochem Biophys 39:119–128PubMedCrossRefGoogle Scholar
  49. 49.
    Velick SF, Baggott JP, Sturtevant JM (1971) Thermodynamics of nicotinamide-adenine dinucleotide addition to the glyceraldehyde 3-phosphate dehydrogenases of yeast and of rabbit skeletal muscle. Biochemistry 10:779–786PubMedCrossRefGoogle Scholar
  50. 50.
    Conway A, Koshland DE Jr (1968) Negative cooperativity in enzyme action. Biochemistry 7:4011–4023PubMedCrossRefGoogle Scholar
  51. 51.
    Smith CM, Velick SF (1972) The glyceraldehyde 3-phosphate dehydrogenases of liver and muscle. J Biol Chem 247:273–284PubMedGoogle Scholar
  52. 52.
    Swearengin TA, Fibuch EE, Seidler NW (2006) Sevoflurane modulates the activity of glyceraldehyde 3-phosphate dehydrogenase. J Enzyme Inhib Med Chem 21:575–579PubMedCrossRefGoogle Scholar
  53. 53.
    Hohorst HJ, Reim M, Bartels H (1962) Studies on the creatine kinase equilibrium in muscle and the significance of ATP and ADP levels. Biochem Biophys Res Commun 7:142–146PubMedCrossRefGoogle Scholar
  54. 54.
    Hohorst HL, Reim M, Bartels H (1962) Equilibria of two-partner reactions of energy supplying metabolism in muscle. Biochem Biophys Res Commun 7:137–141PubMedCrossRefGoogle Scholar
  55. 55.
    Oguchi M, Gerth E, Fitzgerald B et al (1973) Regulation of glyceraldehyde 3-phosphate dehydrogenase by phosphocreatine and adenosine triphosphate. IV. Factors affecting in vivo control of enzymatic activity. J Biol Chem 248:5571–5576PubMedGoogle Scholar
  56. 56.
    Lowry OH, Passonneau JV, Hasselberger FX et al (1964) Effect of ischemia on known substrates and cofactors of the glycolytic pathway in brain. J Biol Chem 239:18–30PubMedGoogle Scholar
  57. 57.
    Lowry OH, Passonneau JV (1964) The relationships between substrates and enzymes of glycolysis in brain. J Biol Chem 239:31–42PubMedGoogle Scholar
  58. 58.
    Portera-Cailliau C, Weimer RM, De Paola V et al (2005) Diverse modes of axon elaboration in the developing neocortex. PLoS Biol 3:e272PubMedCrossRefGoogle Scholar
  59. 59.
    (2005) Creating a window into the developing brain: observing axon growth in live mice. PLoS Biol 3:e301. Accessed 1 July 2011Google Scholar
  60. 60.
    Mosconi L, Pupi A, De Leon MJ (2008) Brain glucose hypometabolism and oxidative stress in preclinical Alzheimer's disease. Ann N Y Acad Sci 1147:180–195PubMedCrossRefGoogle Scholar
  61. 61.
    Li Y, Nowotny P, Holmans P et al (2004) Association of late-onset Alzheimer’s disease with genetic variation in multiple members of the GAPD gene family. Proc Natl Acad Sci USA 101:15688–15693PubMedCrossRefGoogle Scholar
  62. 62.
    Yun M, Park CG, Kim JY et al (2000) Structural analysis of glyceraldehydes 3-phosphate dehydrogenase from Escherichia coli: direct evidence of substrate binding and cofactor-induced conformational changes. Biochemistry 39:10702–10710PubMedCrossRefGoogle Scholar
  63. 63.
    Skarzynski T, Moody PC, Wonacott AJ (1987) Structure of holo-glyceraldehyde-3-phosphate dehydrogenase from Bacillus stearothermophilus at 1.8 A resolution. J Mol Biol 193:171–187PubMedCrossRefGoogle Scholar
  64. 64.
    Yamada K, Hara N, Shibata T et al (2006) The simultaneous measurement of nicotinamide adenine dinucleotide and related compounds by liquid chromatography/electrospray ionization tandem mass spectrometry. Anal Biochem 352:282–285PubMedCrossRefGoogle Scholar
  65. 65.
    Yang H, Yang T, Baur JA et al (2007) Nutrient-sensitive mitochondrial NAD+ levels dictate cell survival. Cell 130:1095–1107PubMedCrossRefGoogle Scholar
  66. 66.
    Fitzgerald C, Swearengin TA, Yeargans G (1999) Non-enzymatic glycosylation (or glycation) and inhibition of the pig heart cytosolic aspartate aminotransferase by glyceraldehyde 3-phosphate. J Enzyme Inhib 15:79–89PubMedGoogle Scholar
  67. 67.
    Rossman M, Liljas A, Branden C et al (1975) Evolutionary and structural relationship among dehydrogenases. In: Boyer PD (ed) The enzymes, vol 11. Academic, OrlandoGoogle Scholar
  68. 68.
    Adams MJ, Buehner M, Chandrasekhar K et al (1973) Structure-function relationships in lactate dehydrogenase. Proc Natl Acad Sci USA 70:1968–1972PubMedCrossRefGoogle Scholar
  69. 69.
    Webb LE, Hill EJ, Banaszak LJ (1973) Conformation of nicotinamide adenine dinucleotide bound to cytoplasmic malate dehydrogenase. Biochemistry 12:5101–5109PubMedCrossRefGoogle Scholar
  70. 70.
    Brändén CI, Eklund H, Nordström B et al (1973) Structure of liver alcohol dehydrogenase at 2.9-angstrom resolution. Proc Natl Acad Sci USA 70:2439–2442PubMedCrossRefGoogle Scholar
  71. 71.
    Buehner M, Ford GC, Moras D et al (1973) D-glyceraldehyde-3-phosphate dehydrogenase: three-dimensional structure and evolutionary significance. Proc Natl Acad Sci USA 70:3052–3054PubMedCrossRefGoogle Scholar
  72. 72.
    Nagy E, Henics T, Eckert M et al (2000) Identification of the NAD(+)-binding fold of glyceraldehyde-3-phosphate dehydrogenase as a novel RNA-binding domain. Biochem Biophys Res Commun 275:253–260PubMedCrossRefGoogle Scholar
  73. 73.
    Mygind T, Zeuthen Søgaard I, Melkova R et al (2000) Cloning, sequencing and variability analysis of the gap gene from mycoplasma hominis. FEMS Microbiol Lett 183:15–21PubMedCrossRefGoogle Scholar
  74. 74.
    Pancholi V, Fischetti VA (1992) A major surface protein on group A streptococci is a glyceraldehyde-3-phosphate-dehydrogenase with multiple binding activity. J Exp Med 176:415–426PubMedCrossRefGoogle Scholar
  75. 75.
    Suzuki K, Imahori K (1973) Glyceraldehyde 3-phosphate dehydrogenase of Bacillus stearothermophilus. Kinetics and physicochemical studies. J Biochem 74:955–970PubMedGoogle Scholar
  76. 76.
    Tsai IH, Murthy SN, Steck TL (1982) Effect of red cell membrane binding on the catalytic activity of glyceraldehyde-3-phosphate dehydrogenase. J Biol Chem 257:1438–1442PubMedGoogle Scholar
  77. 77.
    Jia B, le Linh T, Lee S et al (2011) Biochemical characterization of glyceraldehyde-3-phosphate dehydrogenase from Thermococcus kodakarensis KOD1. Extremophiles 15:337–346PubMedCrossRefGoogle Scholar
  78. 78.
    Branlant G, Branlant C (1985) Nucleotide sequence of the Escherichia coli gap gene. Different evolutionary behavior of the NAD+ -binding domain and of the catalytic domain of D-glyceraldehyde-3-phosphate dehydrogenase. Eur J Biochem 150:61–66PubMedCrossRefGoogle Scholar
  79. 79.
    Nelson K, Whittam TS, Selander RK (1991) Nucleotide polymorphism and evolution in the glyceraldehyde-3-phosphate dehydrogenase gene (gapA) in natural populations of Salmonella and Escherichia coli. Proc Natl Acad Sci USA 88:6667–6671PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  • Norbert W. Seidler
    • 1
  1. 1.Department of BiochemistryKansas City University of Medicine and BiosciencesKansas CityUSA

Personalised recommendations