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Amino Acids

, Volume 6, Issue 1, pp 15–23 | Cite as

Methylglyoxal, glyoxalases and the development of diabetic complications

  • P. J. Thornalley
Review Article

Summary

The formation of the reactiveα,β-dicarbonyl metabolite, methylglyoxal, is increased during hyperglycaemia associated with diabetes mellitus. Methylglyoxal is metabolised to S-D-lactoylglutathione and D-lactate by the glyoxalase system and to hydroxyacetone (95%) and D-lactaldehyde by aldose reductase. Methylglyoxal and hydroxyacetone bind and modify protein, producing fluorescent products. Red blood cell activities of glyoxalase enzymes are risk factors for the development of clinical complications of diabetes. Aldose reductase inhibitors decrease the concentration of methylglyoxal in experimental diabetic rats to normal levels, aminoguanidine and L-arginine scavenge methylglyoxal; these effects may be involved in their prospective preventive therapy of diabetic complications. Biochemical and clinical evidence suggests that the metabolism of methylglyoxal in diabetes mellitus is linked to the development of diabetic complications. A causal relationship may involve modification of protein by methylglyoxal and hydroxyacetone.

Keywords

Amino acids Methylglyoxal Glyoxalase Hydroxyacetone Aldose reductase Aminoguanidine Diabetic complications 

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References

  1. Aleksandrovskii YA (1992) Antithrombin III, CI inhibitor, methylglyoxal, and polymorphonuclear leukocytes in the development of vascular complications of diabetes. Thromb Res 67: 179–189Google Scholar
  2. Bayne S, Fewster JA (1956) The osones. Adv Carbohydr Chem 2: 43–96Google Scholar
  3. Baynes JW (1991) Role of oxidative stress in the development of complications in diabetes. Diabetes 40: 405–412Google Scholar
  4. Brownlee M, Vlassara H, Kooney A, Ulrich P, Cerami A (1986) Aminoguanidine prevents diabetes-induced arterial wall protein cross-linking. Science 232: 1629–1632Google Scholar
  5. Brownlee M, Cerami A, Vlassara H (1988) Advanced glycation endproducts in tissue and the biochemical basis of diabetic complications. N Engl J Med 318: 1315–1321Google Scholar
  6. Bunzli HF, Bosshard HR (1971) Modification of a single arginine residue in insulin with phenylglyoxal. Hoppe-Seyler's Z Physiol Chem 352: 1180–1182Google Scholar
  7. Cameron NE, Cotter MA, Love A (1992) Effects of aminoguanidine on peripheral nerve function and polyol pathway metabolites in streptozotocin-diabetic rats. Diabetologia 35: 946–950Google Scholar
  8. Cheung ST, Fonda ML (1979) Reaction of phenylglyoxal with arginine. Effect of buffers and pH. Biochem Biophys Res Comm 90: 940–947Google Scholar
  9. Fuller JH, Kean H, Jarret RJ, Omer V, Meade TW, Chakrabart R, North WRS, Stirting Y (1979) Hemostatic variables associated with diabetes and its complications. Br Med J 2: 964–966Google Scholar
  10. Gabbay KH (1973) The sorbitol pathway and the complications of diabetes. N Engl J Med 288: 831–836Google Scholar
  11. Gonzalez AV, Sochor M, McLean P (1982) The effect of an aldose reductase inhibitor (sorbinil) on the level of metabolites in lens of diabetic rats. Diabetes 32: 482–485Google Scholar
  12. Hallfrisch J (1990) Metabolic effects of dietary fructose. FASEB J 4: 2652–2660Google Scholar
  13. Hirsch J, Petrakova E, Feather MS (1992) The reaction of dicarbonyl sugars with aminoguanidine. Carbohydr Res 232: 125–130Google Scholar
  14. Horiuchi S, Murakami M, Takata K, Morimo Y (1986) Scavenger receptor for aldehydemodified proteins. J Biol Chem 261: 4962–4966Google Scholar
  15. Janne J, Alhonen-Hongisto L, Nikula P, Elo H (1985) S-Adenosylmethionine decarboxylase as a target of chemotherapy. Adv Enzyme Regul 24: 125–139Google Scholar
  16. Lo TWC, Selwood T, Thornalley PJ (1993) Modification of plasma protein by methylglyoxal under physiological conditions. Prevention by aminoguanidine and L-arginine. Amino Acids 5: 172 (abstract)Google Scholar
  17. Lubec G, Vierhapper H, Bailey AJ, Damjanic P, Fasching P, Sims TJ, Kampel D, Popow C, Bartosch B (1991) Influence of L-arginine on glucose-mediated collagen cross link precursors in patients with diabetes mellitus. Amino Acids 1: 73–80Google Scholar
  18. McCann VJ, Davis RE, Welborn TA, Constable J, Beale DJ (1981) Glyoxalase phenotypes in patients with diabetes mellitus. Aust NZ J Med 11: 380–382Google Scholar
  19. McLellan AC, Phillips SA, Thornalley PJ (1992) Fluorimetric assay of D-lactate. Anal Biochem 206: 12–16Google Scholar
  20. McLellan AC, Thornalley PJ, Benn J, Sonksen PH (1993) The glyoxalase system in clinical diabetes mellitus and correlation with clinical complications. Clin Sci (submitted)Google Scholar
  21. Menzel EJ, Reihsner R (1991) Alterations of biochemical and biomechanical properties of rat tail tendons caused by non-enzymatic glycation and their inhibition by dibasic amino acids arginine and lysine. Diabetologia 43: 12–16Google Scholar
  22. Phillips SA, Thornalley PJ (1993a) The formation of methylglyoxal from triose phosphates. Investigation using a specific assay for methylglyoxal. Eur J Biochem 212: 101–105Google Scholar
  23. Phillips SA, Thornalley PJ (1993b) Formation of methylglyoxal and D-lactate in human red blood cellsin vitro. Biochem Soc Trans 21: 163SGoogle Scholar
  24. Phillips SA, Mirrlees D, Thornalley PJ (1993) Modification of the glyoxalase system in streptozotocin-induced diabetic rats. Effect of the aldose reductase inhibitor Statil. Biochem Pharmacol 46: 805–811Google Scholar
  25. Pompliano DL, Peyman A, Knowles JR (1990) Stabilization of a reaction intermediate as a catalytic device: definition of the functional role of the flexible loop in triosephosphate isomerase. Biochemistry 29: 3186–3194Google Scholar
  26. Ray S, Ray M (1983) Formation of methylglyoxal from aminoacetone by amine oxidase from goat plasma. J Biol Chem 258: 3461–3462Google Scholar
  27. Ray M, Ray S (1987) Aminoacetone oxidase from goat liver. J Biol Chem 262: 5974–5977Google Scholar
  28. Reichard GA, Skutches CL, Hoeldtke RD, Owen OE (1986) Acetone metabolism in humans during diabetic ketoacidosis. Diabetes 35: 668–674Google Scholar
  29. Richard JP (1991) Kinetic parameters for the elimination reaction catalyzed by triosephosphate isomerase and an estimation of the reaction's physiological significance. Biochemistry 30: 4581–4585Google Scholar
  30. Selwood T, Thornalley PJ (1993) Binding of methylglyoxal to albumin and formation of fluorescent adducts. Inhibition by arginine,N α-acetylarginine and aminoguanidine. Biochem Soc Trans 21: 170FGoogle Scholar
  31. Smith PR, Thornalley PJ (1992) Mechanism of the degradation of non-enzymatically glycated proteins under physiological conditions. Studies with the model fructosamine,N ε-(1-deoxy-D-fructos-l-yl)hippuryl-lysine. Eur J Biochem 210: 729–739Google Scholar
  32. Smith PR, Saeed S, Selwood T, Thornalley PJ (1992) Pharmacological intervention to prevent the development of diabetic complications. Aminoguanidine diverts the degradation of lysyl-fructosamine to produce unmodified lysine and scavenges methylglyoxal. Diabetic Med 9 [Suppl] 1: 31AGoogle Scholar
  33. Soulis-Liparota T, Cooper M, Parazoglou D, Clarke B, Jerums G (1991) Retardation by aminoguanidine of development of albuminuria, mesangial expansion, and tissue fluorescence in streptozotocin-induced diabetic rat. Diabetes 40: 1328–1334Google Scholar
  34. Takahashi K (1977a) The reaction of phenylglyoxal and related reagents with amino acids. J Biochem 81: 395–402Google Scholar
  35. Takahashi K (1977b) Further studies on the reaction of phenylglyoxal related reagents with proteins. J Biochem 81: 403–414Google Scholar
  36. Thornalley PJ (1985) Monosaccharide autoxidation in health and disease. Environ Health Perspect 64: 297–307Google Scholar
  37. Thornalley PJ (1988) Modification of the glyoxalase system in human red blood cells by glucosein vitro. Biochem J 254: 751–755Google Scholar
  38. Thornalley PJ (1990) The glyoxalase system: new developments towards functional characterisation of a metabolic pathway fundamental to biological life. Biochem J 269: 1–11Google Scholar
  39. Thornalley PJ, Hooper NI, Jennings PE, Florkowski CM, Jones AF, Lunec J, Barnett AH (1989) The human red blood cell glyoxalase system in diabetes mellitus. Diab Res Clin Pract 7: 115–120Google Scholar
  40. Vander Jagt DL (1993) Glyoxalase II: molecular characteristics, kinetics and mechanism. Biochem Soc Trans 21: 522–527Google Scholar
  41. Vander Jagt DL, Robinson B, Taylor KT, Hunsaker LA (1992) Reduction of trioses by NADPH-dependent aldo-keto reductase. J Biol Chem 267: 4364–4369Google Scholar
  42. Vlassara H, Brownlee M, Manogue KR, Dinarello CA, Pasagain A (1988) Cachectin/TNF and IL-1 induced by glucose-modified proteins: role in normal tissue remodelling. Science 240: 1546–1548Google Scholar

Copyright information

© Springer-Verlag 1994

Authors and Affiliations

  • P. J. Thornalley
    • 1
  1. 1.Department of Chemistry and Biological ChemistryUniversity of EssexColchesterUK

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