NEW METABOLITES AND PATHWAYS IN THE MAMMALIAN LENS

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Identification of sorbitol-3-phosphate (S3P) and fructose-3-phosphate (F3P) in the mammalian lens suggests a possible new pathway for glucose metabolism in this tissue. This pathway appears to be connected with the aldose reductase pathway since the elevation in the concentration of S3P (and to a lesser extent F3P) in the diabetic lens is inhibited by the aldose reductase inhibitor sorbinil. The purpose of this proposal is to determine if the compounds associated with the new pathway are involved in the cytopathy observed the diabetic lens. One of the newly identified compounds, fructose-3-phosphate, is a member of a class of phosphate monoesters which include glyceraldehyde phosphate, dihhydroxyacetone phosphate and glucose-3-phosphate. Compounds of this type are relatively labile and dephosphorylate easily forming inorganic phosphate and alpha dicarbonyl compounds known to be potent crosslinking agents. We propose that some of the accelerated cell damage in the diabetic lens may result from increased concentrations of fructose- 3-phosphate and its breakdown product 3-deoxy-glucosone, which cause increased crosslinking of lenticular proteins. In this study we intend to test this hypothesis and to identify and characterize the metabolites, reactions and enzymes involved in the new pathway.