Aldose reductase enzyme (AR)

Aldose reductase is a cytosolic NADPH-dependent oxidoreductase that catalyzes the first step in the polyol pathway by reducing glucose to sorbitol. It also reduces various other aldehyde substrates derived from lipid peroxidation and environmental sources. The enzyme consists of approximately 315–316 amino acids forming an eight-stranded β/α-barrel structure with its active site located within this barrel. Its physiological roles extend beyond carbohydrate metabolism; it participates in cellular defense against oxidative stress by detoxifying reactive carbonyl compounds. Pathologically, excessive activity under hyperglycemic conditions leads to accumulation of intracellular sorbitol—a process implicated in secondary diabetic complications such as neuropathy, retinopathy, nephropathy, and cardiovascular disorders due to osmotic imbalance and increased production of reactive oxygen species. Additionally, overexpression has been linked with inflammation-related diseases and several cancers. Therapeutically targeting aldose reductase aims primarily at preventing or slowing progression of microvascular/macrovascular diabetes complications but also holds promise for treating certain rare metabolic disorders and inflammatory conditions through new generations of selective inhibitors currently under development.

Other names

Aldose reductaseARALR2AKR1B1Aldo-keto reductase family 1 member B1

Drugs targeting aldose reductase typically act as competitive inhibitors at the active site of the enzyme. They block NADPH-dependent reduction of glucose to sorbitol and/or inhibit reduction of toxic aldehydes generated by oxidative stress. This reduces accumulation of sorbitol and mitigates downstream tissue damage associated with hyperglycemia or oxidative injury