Novel Substrates and Inhibitors of Human Liver Sorbitol Dehydrogenase
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).
KeywordsHuman Liver Secondary Alcohol Zinc Atom Mandelic Acid Sorbitol Dehydrogenase
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