Alternative titles; symbols
HGNC Approved Gene Symbol: AKR1A1
Cytogenetic location: 1p34.1 Genomic coordinates (GRCh38) : 1:45,550,826-45,570,049 (from NCBI)
Aldehyde reductase (EC 1.1.1.2) and aldose reductase (EC 1.1.1.21; 103880) are monomeric NADPH-dependent oxidoreductases having wide substrate specificities for carbonyl compounds (summary by Bohren et al., 1989).
By screening a liver library with degenerate oligonucleotide primers based on the protein sequence of liver aldehyde reductase, Bohren et al. (1989) isolated aldehyde reductase cDNAs. The predicted protein contains 325 amino acids. Aldose reductase and aldehyde reductase share 3 homology domains and are 51% identical overall.
Fujii et al. (1999) determined that the AKR1A1 gene spans 16 kb and contains 8 exons which encode the entire coding region and the 3-prime-untranslated sequences.
By fluorescence in situ hybridization, Fujii et al. (1999) mapped the AKR1A1 gene to chromosome 1p33-p32.
AKR1A1 is the functional mammalian homolog of S. cerevisiae S-nitroso-CoA (SNO-CoA) reductase (SCoR), which removes S-nitrosothiols from proteins in nitric oxide-based cellular signaling. Zhou et al. (2019) reported that the SNO-CoA-AKR1A1 system is highly expressed in renal proximal tubules, where it transduces the activity of endothelial nitric oxide synthase (ENOS; 163729) in reprogramming intermediary metabolism, thereby protecting kidneys against acute kidney injury. Specifically, deletion of Akr1a1 in mice to reduce SCoR activity increased protein S-nitrosylation, protected against acute kidney injury, and improved survival, whereas this protection was lost when Enos was also deleted. Metabolic profiling coupled with unbiased mass spectrometry-based SNO-protein identification revealed that protection by the SNO-CoA-SCoR system is mediated by inhibitory S-nitrosylation of pyruvate kinase M2 (PKM2; see 179050) through a novel locus of regulation, thereby balancing fuel utilization (through glycolysis) with redox protection (through the pentose phosphate shunt). Targeted deletion of PKM2 from mouse proximal tubules recapitulated precisely the protective and mechanistic effects of S-nitrosylation in Akr1a1-null mice, whereas cys-mutant PKM2, which is refractory to S-nitrosylation, negated SNO-CoA bioactivity. Zhou et al. (2019) concluded that their results identified a physiologic function of the SNO-CoA-SCoR system in mammals, described new regulation of renal metabolism and of PKM2 in differentiated tissues, and offered a novel perspective on kidney injury with therapeutic implications.
Bohren, K. M., Bullock, B., Wermuth, B., Gabbay, K. H. The aldo-keto reductase superfamily: cDNAs and deduced amino acid sequences of human aldehyde and aldose reductases. J. Biol. Chem. 264: 9547-9551, 1989. [PubMed: 2498333]
Fujii, J., Hamaoka, R., Matsumoto, A., Fujii, T., Yamaguchi, Y., Egashira, M., Miyoshi, O., Niikawa, N., Taniguchi, N. The structural organization of the human aldehyde reductase gene, AKR1A1, and mapping to chromosome 1p33-p32. Cytogenet. Cell Genet. 84: 230-232, 1999. [PubMed: 10393438] [Full Text: https://doi.org/10.1159/000015265]
Zhou, H. L., Zhang, R., Anand, P., Stomberski, C. T., Qian, Z., Hausladen, A., Wang, L., Rhee, E. P., Parikh, S. M., Karumanchi, S. A., Stamler, J. S. Metabolic reprogramming by the S-nitroso-CoA reductase system protects against kidney injury. Nature 565: 96-100, 2019. Note: Erratum: Nature 570: E23, 2019. [PubMed: 30487609] [Full Text: https://doi.org/10.1038/s41586-018-0749-z]