Novel Substrates and Inhibitors of Human Liver Sorbitol Dehydrogenase

  • Wolfgang Maret
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 284)


The formation of D-fructose from sorbitol, first observed in perfused dog liver (Embden and Griesbach, 1914), was shown to be catalyzed by sorbitol dehydrogenase (SDH)1 from rat liver homogenates (Blakley, 1951). SDH was later purified to homogeneity from sheep liver (Smith, 1962). Several more recent findings prompted further investigation of structural features of this enzyme and the role of SDH in pathological conditions. First, the discovery of a sequence homology between sheep liver SDH and zinc-containing alcohol dehydrogenases (ADHs) (Jeffery et al., 1981) led to metal analyses that established SDH as a metalloenzyme with one zinc atom per subunit of the tetramer (Jeffery et al., 1984). In contrast, dimeric mammalian ADHs have two zinc atoms per subunit. Second, sorbitol accumulates in tissues affected by diabetes (Gabbay, 1973; Greene et al., 1987) and in the liver and kidney of copper-deficient male rats as a result of feeding fructose (Fields et al., 1989). The elevated levels of sorbitol can upset osmoregulation and result in cellular pathology (Burg and Kador, 1988). Also, the increased availability of fructose associated with these conditions causes fructosylation and crosslinking of proteins (Walton et al., 1989).


Human Liver Secondary Alcohol Zinc Atom Mandelic Acid Sorbitol Dehydrogenase 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Bagnasco, S. M., Uchida, S., Balaban, R. S., Kador, P. F., and Burg, M. B., 1987, Induction of aldose reductase and sorbitol in renal medullary cells by elevated extracellular NaCl, Proc. Natl. Acad. Sci. USA, 84:1718.PubMedCrossRefGoogle Scholar
  2. Blakley, R. L., 1951, The metabolism and antiketogenic effects of sorbitol. Sorbitol dehydrogenase, Biochem. J., 49:257.PubMedGoogle Scholar
  3. Bublitz, C., and Steavenson, S., 1988, The pentose phosphate pathway in the endoplasmic reticulum, J. Biol. Chem., 263:12849.PubMedGoogle Scholar
  4. Burg, M. B., and Kador, P. F., 1988, Sorbitol, osmoregulation, and the complications of diabetes, J. Clin. Invest., 81:635.PubMedCrossRefGoogle Scholar
  5. Christensen, U., Tüchsen, E., and Andersen, B., 1975, Initial velocity and product inhibition studies on L-iditol:NAD oxidoreductase, Acta Chem. Scand., Ser. B. 29:81.CrossRefGoogle Scholar
  6. Cleland, W. W., 1979, Substrate inhibition, Methods Enzymol., 63:500.PubMedCrossRefGoogle Scholar
  7. Dills, W. L., and Meyer, W. L., 1976, Studies on 1-deoxy-D-fructose, 1-deoxy-D-glucitol, and 1-deoxy-D-mannitol as antimetabolites, Biochemistry. 15:4506.Google Scholar
  8. Donald, L. J., Wang, H. S., and Hamerton, J. L., 1980, Assignment of sorbitol dehydrogenase locus to human chromosome 15PTER-+Q21, Biochem. Genet. . 18:425.PubMedCrossRefGoogle Scholar
  9. Drummond, L., Caldwell, J., and Wilson, H. K., 1989, The metabolism of ethylbenzene and styrene to mandelic acid: stereochemical considerations, Xenobiotica. 19:199.PubMedCrossRefGoogle Scholar
  10. Drummond, L., Caldwell, J., and Wilson, H. K., 1990, The stereoselectivity of 1,2-phenylethanediol and mandelic acid metabolism and disposition in the rat, Xenobiotica. 20:159.Google Scholar
  11. Eklund, H., Horjales, E., Jörnvall, H., Bränden, C.-I., and Jeffery, J., 1985, Molecular aspects of functional differences between alcohol and sorbitol dehydrogenases, Biochemistry. 24:8005.PubMedCrossRefGoogle Scholar
  12. Embden, G., and Griesbach, W., 1914, Über Milchsäure-und Zuckerbildung in der isolierten Leber, Hoppe-Sevler’s Z. Physiol. Chem.. 91:251.CrossRefGoogle Scholar
  13. .Gabbay, K. H., 1973, The sorbitol pathway and the complications of diabetes, NE J. Med., 288:831.CrossRefGoogle Scholar
  14. Fields, M., Lewis, C. G., and Beal, T., 1989, Accumulation of sorbitol in copper deficiency: Dependency on gender and type of dietary carbohydrate, Metab., Clin. Exp., 38:371.CrossRefGoogle Scholar
  15. Graham, J., 1984, Isolation of subcellular organelles and membranes, in: Centrifugation, Rickwood, D., ed., p. 161, IRL Press, Oxford, U.K.Google Scholar
  16. Greene, D. L., Lattimer, S. A., and Sima, A. A. F., 1987, Sorbitol, phosphoinositides, and sodium-potassium-ATPase in the pathogenesis of diabetic complications, NE J. Med., 316:599.CrossRefGoogle Scholar
  17. Jeffery, J., Cummins, L., Carlquist, M., and Jörnvall, H., 1981, Properties of sorbitol dehydrogenase and characterization of a reactive cysteine residue reveal unexpected similarities to alcohol dehydrogenases, Eur. J. Biochem., 120:229.PubMedCrossRefGoogle Scholar
  18. Jeffery, J., Chesters, J., Mills, C., Sadler, P. J., and Jörnvall, H., 1984, Sorbitol dehydrogenase is a zinc enzyme, EMBO J.. 3:357.Google Scholar
  19. Jeffery, J., and Jörnvall, H., 1988, Sorbitol dehydrogenase, Adv. Enzymol.. 61:47.PubMedGoogle Scholar
  20. Karlsson, C., Maret, W., Auld, D. S., Höög, J.-O., and Jörnvall, H., 1989, Variability within mammalian sorbitol dehydrogenases. The primary structure of the human liver enzyme, Eur. J. Biochem., 186:543.PubMedCrossRefGoogle Scholar
  21. Lange, L. G., and Vallee, B. L., 1976, Double-ternary complex affinity chromatography: Preparation of alcohol dehydrogenases, Biochemistry, 15:4681.PubMedCrossRefGoogle Scholar
  22. Maret, W., and Auld, D. S., 1988, Purification and characterization of human liver sorbitol dehydrogenase, Biochemistry. 27:1622.PubMedCrossRefGoogle Scholar
  23. Maret, W., 1989, Cobalt(II)-substituted class III alcohol and sorbitol dehydrogenases from human liver, Biochemistry. 28:9944.PubMedCrossRefGoogle Scholar
  24. McCorkindale, J., and Edson, N. L., 1954, Polyol dehydrogenases. The specificity of rat-liver polyol dehydrogenase, Biochem. J., 57:518.PubMedGoogle Scholar
  25. Nealon, D. A., and Rej, R., 1983, Human liver sorbitol dehydrogenase -Evidence for two forms, in: Selected Topics in Clinical Enzymology, Werner, M., and Goldberg, D. M., eds., Vol. 2, p. 535, de Gruyter, New York.Google Scholar
  26. Perea, F. J., Vaca, G., Alvarez, C., Cantu, J. M., and Ibarra, B., 1989, Electrophoretic pattern of sorbitol dehydrogenase (EC in human seminal plasma and spermatozoa, Ann. Genet.. 32:33.PubMedGoogle Scholar
  27. Smith, M. G., 1962, Polyol dehydrogenases. Crystallization of the L-iditol dehydrogenase of sheep liver, Biochem. J., 83:135.PubMedGoogle Scholar
  28. Sullivan, H. R., Miller, W. M., and McMahon, R. E., 1976, Reaction pathways of in vivo stereoselective conversion of ethylbenzene to (-)mandelic acid, Xenobiotica. 6:49.PubMedCrossRefGoogle Scholar
  29. Vallee, B. L., and Bazzone, T. J., 1983, Isozymes of human liver alcohol dehydrogenase, in: Current Topics in Biological & Medical Research, Rattazzi, M. C., Scandalios, J. G., and Witt, G. S., eds., Vol. 8, p. 219, Liss, New York.Google Scholar
  30. Vallee, B. L., and Auld, D. S., 1990, Zinc coordination, function, and structure of zinc enzymes and other proteins, Biochemistry. 29:5647.PubMedCrossRefGoogle Scholar
  31. Walton, D. J., McPherson, J. D., and Shilton, B. H., 1989, Fructose mediated crosslinking of proteins, in: The Maillard Reaction in Aging, Diabetes and Nutrition, Baynes, J. W., and Monnier, V. M., eds., p. 163, Liss, New York.Google Scholar

Copyright information

© Plenum Press, New York 1990

Authors and Affiliations

  • Wolfgang Maret
    • 1
  1. 1.Center for Biochemical and Biophysical Sciences and MedicineHarvard Medical School Brigham and Women’s HospitalBostonUK

Personalised recommendations