InterPro domain: IPR044485

In general, the aldo-keto reductase (AKR) protein superfamily members reduce carbonyl substrates such as: sugar aldehydes, keto-steroids, keto-prostaglandins, retinals, quinones, and lipid peroxidation by-products [ 1 , 2 ]. However, there are some exceptions, such as the reduction of steroid double bonds catalysed by AKR1D enzymes (5beta-reductases); and the oxidation of proximate carcinogen trans-dihydrodiol polycyclic aromatic hydrocarbons; while the beta-subunits of potassium gated ion channels (AKR6 family) control Kv channel opening [ 3 ].

Structurally, they contain an (alpha/beta)8-barrel motif, display large loops at the back of the barrel which govern substrate specificity, and have a conserved cofactor binding domain. The binding site is located in a large, deep, elliptical pocket in the C-terminal end of the beta sheet, the substrate being bound in an extended conformation. The hydrophobic nature of the pocket favours aromatic and apolar substrates over highly polar ones [ 3 ]. They catalyse an ordered bi bi kinetic mechanism in which NAD(P)H cofactor binds first and leaves last [ 4 ]. Binding of the NADPH coenzyme causes a massive conformational change, reorienting a loop, effectively locking the coenzyme in place. This binding is more similar to FAD- than to NAD(P)-binding oxidoreductases [ 4 ].

This entry represents aldo-keto reductase family 2A (AKR2A), which includes NADP-S6PDH from Malus domestica (Apple) [ 5 ], and AKR2A2 (or NADPH-M6PR) from Apium graveolens (Celery) [ 6 ].

1. The aldo-keto reductase superfamily. cDNAs and deduced amino acid sequences of human aldehyde and aldose reductases. J. Biol. Chem. 264, 9547-51
2. The aldo-keto reductases (AKRs): Overview. Chem Biol Interact 234, 236-46
3. An unlikely sugar substrate site in the 1.65 A structure of the human aldose reductase holoenzyme implicated in diabetic complications. Science 257, 81-4
4. The crystal structure of the aldose reductase.NADPH binary complex. J. Biol. Chem. 267, 24841-7
5. Nucleotide Sequence of a cDNA Encoding NADP-Sorbitol-6-Phosphate Dehydrogenase from Apple. Plant Physiol 100, 1607-8
6. Molecular cloning of mannose-6-phosphate reductase and its developmental expression in celery. Plant Physiol 113, 1427-35