Catalysis of reduction of aldos-2-uloses (‘osones’) by aldose reductase: selectivity for the aldehydic carbonyl group

Abstract

In mammalian tissues, reducing sugars and N-(1-deoxyfructosyl) groups of glycated proteins undergo non-enzymatic reactions to form aldos-2-uloses, or ‘osones’. These compounds, which occur in relatively high concentrations in diabetic animals, are harmful in that they react with side-chain groups of proteins, adversely affecting their functions. However, there is evidence for the reduction of aldos-2-uloses in vivo, a process which would be expected to result in a lowering of reactivity, and serve as a detoxification mechanism. We report that, on incubation with aldose reductase and NADPH, d- arabino-hexos-2-ulose ( 1; ‘glucosone’), 3-deoxy- d- glycero-pentos-2-ulose ( 2; ‘3-deoxyxylosone’) and 3-deoxy- d- erythro-hexos-2-ulose ( 3; ‘3-deoxyglucosone’) gave the corresponding 2-ketoses, 4, 5, and 6. These results suggest that aldose reductase contributes to the conversion of 3 into 6 in vivo, thus accounting for the coexistence of both compounds in human blood and urine [K.J. Knecht et al., Arch. Biochem. Biophys., 294 (1992) 130–137]. No aldoses or alditols were formed in the enzymatic reactions of 1, 2, and 3, indicating that reduction had occurred exclusively at the C-1 (aldehydic) carbonyl, in contrast to the aldose reductase catalysed reduction of methylglyoxal, which was reported to occur at the C-1 (aldehydic) carbonyl, and, to a small extent, at the C-2 (ketone) carbonyl [D.L. Vander Jagt et al., J. Biol. Chem., 267 (1992) 4364–4369]. The high selectivity towards the C-1 carbonyl group is discussed in the light of recent information on possible modes of binding of sugars to aldose reductase.