STRUCTURE FUNCTION STUDIES OF OXIDOREDUCTASES

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Aldose reductase (AR) is an NADPH dependent oxidoreductase that catalyzes the reduction of a wide variety of aldehydes including glucose. It has been shown that increased flux of hexoses via the AR catalyzed pathway is one of the underlying causes of tissue injury and dysfunction associated with hyperglycemic states such as diabetes mellitus. Clinical trials with AR inhibitors have yielded uncertain results and the long-term efficacy of these drugs in treating diabetic complications remains to be demonstrated. AR has been crystallized with several compounds which, are members of polyol pathway (part of glucose metabolism) in more than one crystal form. Our studies show that AR is an efficient catalyst for the reduction of compounds like 4-hydroxy-trans-2-nonenal, which, are products of lipid peroxidation (Dixit et al., (2000) J Bio Chem 275, 21587). In addition 4-hydroxy-trans-2-nonenal is a better substrate than all the known glucose metabolism related compounds. Further exploiting structure function studies we have demonstrated that the lipid based compounds could bind in the active site of AR in more than one orientation (Ramana et al. (2000) Biochemistry 39, 12172). Crystal structures of AR with the lipid based compounds will provide the specific interactions between AR residues and these compounds. This will help to distinguish between different orientations of binding.