The aldo-keto reductase superfamily is a class of monomeric NADPH-dependent oxidoreductases with molecular masses of about 35 kDa (7). This group includes aldehyde and aldose reductases (8-14), prostaglandin F synthase (EC 220.127.116.11) (15), 2,5-diketogluconate reductase (16,17), morphine dehydrogenase (EC 18.104.22.168) (18), chlordecone reductase (EC 22.214.171.124) (19), a number of hydroxysteroid dehydrogenases (EC 126.96.36.199, 188.8.131.52,184.108.40.206) (20-25), plant chalcone reductases (26,27), and so on. From the strong similarity in their amino acid sequences, q-crystallin (28) and a yeast protein encoded by the GCY gene (29), which do not exhibit oxidoreductase activity, are also included in this superfamily. (A list of current members of the aldo-keto reductase superfamily can be seen on the AKR Web page at http://pharme26.med.upenn.edu./.) Among them, aldehyde reductase and aldose reductase catalyze the NADPH-dependent reduction of a wide range of aromatic and aliphatic aldehydes, such as p-nitroben-zaldehyde, pyridine-3-aldehyde, and glyceraldehyde, to the corresponding alcohols (8-14). These two enzymes are widely distributed in various kinds of mammals including humans, cows, pigs, rats, and mice.
Because aldose and aldehyde reductases cause complications in diabetes (30), the crystal structures of human and pig aldose reductases and aldehyde reductases have been determined by X-ray diffraction methods (31-34). As oxidoreductases, the enzymes are unique in that they have a //a-triosephosphate isomerase (TIM) barrel structure, and are the first oxidoreductases known to possess such a structure instead of a dinucleotide, or Rossmann, binding fold. Elucidation of the tertiary structures and reaction mechanisms of these enzymes will facilitate the design of specific inhibitors that may be used as drugs for the treatment of diabetic complications.
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