Aldosereductase: structure, mechanism of action, biological role and functioning according to normo and hyperglycemia

The review summarizes the literature on the structure, biological role and mechanism of action of aldose reductase at different blood glucose levels. Aldosereductase is the first enzyme of the sorbitol (polyol) pathway to glucose metabolism. In mammals, it is a monomeric protein with a molecular weight of 32–56 kDa, has 347–370 amino acid remainders. Its secondary structure consists of α-helices and β-bends, which alternate in 8 units. The active site of the enzyme is located at the C-terminus of the β-bend and contains a glutathione-binding domain. The active site of aldose reductase consists of two sites: substrate-binding and catalytic. The first is formed mainly by the residues of hydrophilic amino acids, and the second, by hydrophobic ones. The interaction of the enzyme with a coenzyme causes conformational changes in aldose reductase. It is believed that the enzyme functions according to the principle of an ordered “bi-bi” mechanism, that is, the coenzyme binds first, and the oxidized product is released last. The reduction of aldehydes of aldose reductase includes several stages: the interaction of the enzyme with NADPH and the formation of a binary complex, the acceptance of the substrate and the formation of a ternary complex (enzyme-coenzyme-substrate) and the separation of the alcohol-reaction product and the oxidized coenzyme. According to normoglycemia in mammalian cells via the sorbitol pathway, up to 1–3 % of intracellular glucose is restored. Under these conditions, it reduces the content of toxic and reactive aldehydes such as: 4-hydroxy-trans-2-nonenal, malondialdehyde, glyoxal, acrolein and their conjugates with reduced glutathione and carnosine, which are also toxic. Before being excreted from the body, they are reduced by aldose reductase to non-toxic compounds. Thus, the enzyme is one of the components of the body's antioxidant system. Hyperglycemia, which is most pronounced in diabetes, significantly increases the flow of glucose through the sorbitol pathway. The activation of aldosereductase and sorbitol dehydrogenase causes the use of a significant amount of NADPH, which leads to a decrease in antioxidant protection, and the excessive formation of NADH leads to a violation of the ratio of reduced and oxidized forms, known as “pseudohypoxia”. Metabolites of the sorbitol pathway, which are formed in excessive amounts, get toxic effects on metabolism and cellular structures, in particular: sorbitol, as an osmotically active component, causes lens edema, leads to the formation of cataracts, and fructose, fructose-phosphate and 3-deoxyglucasone underlie the pathogenesis of secondary diabetic complications.