AKRs

Aldo-keto reductases (AKRs) are a diverse superfamily of NADPH-dependent oxidoreductases that catalyze the stereospecific reduction of aldehydes and ketones to their corresponding alcohols. They participate in metabolism, detoxification of reactive carbonyl species, and the processing of endogenous and xenobiotic compounds across tissues and species.

AKRs share a conserved structural framework, typically a (β/α)8-barrel catalytic domain, and possess a broad substrate-binding pocket that accommodates sugars, steroids, prostaglandins, and aldehydes. The catalytic mechanism generally involves hydride transfer from NADPH to the carbonyl carbon, followed by protonation to generate the alcohol.

In humans, the AKR family includes several genes such as AKR1A1, AKR1B1 (aldose reductase), AKR1B10, and AKR1C1–AKR1C4. These enzymes show tissue-specific expression patterns and participate in sugar metabolism, steroid conversion, and prostaglandin metabolism.

Physiological roles of AKRs include detoxification of lipid peroxidation–derived aldehydes, metabolism of sugar alcohols (for example, conversion of glucose to sorbitol by aldose reductase), and regulation of bioactive lipid and steroid molecules. Their activity influences oxidative stress responses and hormone signaling.

Clinical and pharmacological relevance centers on the development of AKR inhibitors. Aldose reductase inhibitors have been investigated for diabetic complications, while other AKRs are studied as targets in cancer, fibrosis, and inflammatory diseases due to their roles in steroid and prostaglandin metabolism.

AKRs are widespread and evolutionarily conserved, with diverse members across bacteria, plants, and animals, reflecting adaptation to distinct physiological substrates and environmental challenges.