Aldo-keto reductase family 1 member A1

Aldo-keto reductase family 1 member A1 (AKR1A1) is a 325-amino acid enzyme that catalyzes NADPH-dependent reduction of carbonyl-containing compounds to their corresponding alcohols (UniProt: P14550). It displays broad substrate specificity toward endogenous metabolites including aldehydes, ketones, monosaccharides, and bile acids, with particular activity toward negatively charged substrates such as glucuronate and succinic semialdehyde. The enzyme also functions in detoxification of toxic aldehydes, including methylglyoxal and lipid-derived species like acrolein.

Beyond detoxification, AKR1A1 plays roles in procarcinogen activation and xenobiotic metabolism, including processing of anthracycline drugs. A distinctive function involves inhibition of protein S-nitrosylation through degradation of S-nitroso-coenzyme A, thereby modulating metabolic reprogramming in renal proximal tubules.

AKR1A1 is upregulated in Alzheimer's disease brain tissue. Analysis of human post-mortem AD brain compared to age-matched controls using TMT-labeled proteomics across four subcellular fractions revealed a mean log2 fold-change of +0.6396 (Chaparral AD proteomics), indicating consistent elevation across fractions. The functional significance of this upregulation in AD pathogenesis remains to be elucidated.