Aldose and aldehyde reductase are closely related members of the aldo-keto reductase superfamily. Aldose reductase is implicated in the pathogenesis of diabetic cataracts, retinopathy, neuropathy and nephropathy. Aldose reductase inhibitors, proposed for the prevention and therapy of those diabetic complications, are not specific and inhibit both enzymes as well as other members of the superfamily. The objectives of this proposal are to compare the atomic structure and the catalytic and inhibitory mechanisms of these two enzymes so as to obtain a better understanding of the enzymatic mechanism(s) in order to rationally develop highly specific inhibitors unique to each enzyme, as well as to better understand the normal operation of aldose reductase in the whole organism. It is proposed to: (1) investigate the joint role of the NADP-binding and C-terminal loops of aldose reductase in the regulation of catalysis and co-factor exchange, and particularly, the potential role of cysteine 298 in the thiol-mediated regulation of the enzyme; (2) determine the mechanism, structure, and inhibition of human aldehyde reductase in comparison to aldose reductase; (3) use the kinetic and crystallographic information obtained to design specific inhibitors for aldose and aldehyde reductase, respectively, using organic solvent mapping of enzyme surface, proprietary peptidomimetic compounds and knowledge of the mechanistic pathway; and (4) determine the basis for the significant decrease in activity of murine recombinant wild-type aldose reductase in preparation for future testing of the role of aldose reductase in diabetic retinopathy and other complications by introduction of appropriate mutations into the mouse germ-line.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY011018-05
Application #
2888468
Study Section
Visual Sciences C Study Section (VISC)
Project Start
1995-06-01
Project End
2002-07-31
Budget Start
1999-08-01
Budget End
2000-07-31
Support Year
5
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Pediatrics
Type
Schools of Medicine
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030
Bohren, Kurt M; Brownlee, June M; Milne, Amy C et al. (2005) The structure of Apo R268A human aldose reductase: hinges and latches that control the kinetic mechanism. Biochim Biophys Acta 1748:201-12
Barski, Oleg A; Siller-Lopez, Fernando; Bohren, Kurt M et al. (2004) Human aldehyde reductase promoter allows simultaneous expression of two genes in opposite directions. Biotechniques 36:382-4, 386, 388
Barski, Oleg A; Papusha, Victor Z; Kunkel, Gary R et al. (2004) Regulation of aldehyde reductase expression by STAF and CHOP. Genomics 83:119-29
Gabbay, Kenneth H (2004) Aldose reductase inhibition in the treatment of diabetic neuropathy: where are we in 2004? Curr Diab Rep 4:405-8
Sheikh-Hamad, D; Nadkarni, V; Choi, Y J et al. (2001) Cyclosporine A inhibits the adaptive responses to hypertonicity: a potential mechanism of nephrotoxicity. J Am Soc Nephrol 12:2732-41
Bohren, K M; Grimshaw, C E (2000) The sorbinil trap: a predicted dead-end complex confirms the mechanism of aldose reductase inhibition. Biochemistry 39:9967-74
Barski, O A; Gabbay, K H; Bohren, K M (1999) Characterization of the human aldehyde reductase gene and promoter. Genomics 60:188-98
Nadkarni, V; Gabbay, K H; Bohren, K M et al. (1999) Osmotic response element enhancer activity. Regulation through p38 kinase and mitogen-activated extracellular signal-regulated kinase kinase. J Biol Chem 274:20185-90
Harrison, D H; Bohren, K M; Petsko, G A et al. (1997) The alrestatin double-decker: binding of two inhibitor molecules to human aldose reductase reveals a new specificity determinant. Biochemistry 36:16134-40
Ko, B C; Ruepp, B; Bohren, K M et al. (1997) Identification and characterization of multiple osmotic response sequences in the human aldose reductase gene. J Biol Chem 272:16431-7

Showing the most recent 10 out of 15 publications