AKR1C2

Aldo-keto reductase family 1 member C2, also known as bile acid binding protein, 3α-hydroxysteroid dehydrogenase type 3 (3α-HSD3), and dihydrodiol dehydrogenase type 2, is an enzyme that in humans is encoded by the AKR1C2 gene.

Superfamily of enzymes
This gene encodes a member of the aldo/keto reductase superfamily, which consists of more than 40 known enzymes and proteins. These enzymes catalyze the conversion of aldehydes and ketones to their corresponding alcohols using NADH and/or NADPH as cofactors. The enzymes display overlapping but distinct substrate specificity. This particular enzyme, AKR1C2, binds bile acid with high affinity, and shows minimal 3α-hydroxysteroid dehydrogenase activity. The AKR1C2 gene shares high sequence identity with three other gene members and is clustered with those three genes at chromosome 10p15-p14. Three transcript variants encoding two different isoforms have been found for this gene. The AKR1C2 enzyme catalyzes reactions at specific positions on the steroid nucleus. Specifically, AKR enzymes, including AKR1C2, act as 3α/β-HSDs, 17β-HSDs, and 20α-HSDs, catalyzing NAD(P)(H)-dependent oxidoreduction of substituents at the C3, C17, and C20 positions of the steroid nucleus.

Aldo-keto reductase activity
AKR1C2 binds bile acid with high affinity catalyzing aldo-keto reduction reaction.

Aldo-keto reductases, including AKR1C2, are NAD(P)H-linked oxidoreductases that primarily catalyze the reduction of aldehydes and ketones to primary and secondary alcohols. This reduction is dependent on NADPH.

In the context of bile acids, the AKR1C2 enzyme would bind to the bile acid (a type of steroid molecule) and catalyze the reduction of a carbonyl group (C=O) present in the bile acid to a hydroxy group (-OH), using NADPH as a cofactor. This reaction is part of the broader metabolic processes that these enzymes are involved in, which include biosynthesis, intermediary metabolism, and detoxification.

3α-hydroxysteroid dehydrogenase activity
The AKR1C2 enzyme is also known as 3α-hydroxysteroid dehydrogenase type 3 (3α-HSD3), meaning that the enzyme possesses 3α-hydroxysteroid dehydrogenase activity, i.e. it can hydroxylate steroids at a carbon position 3α of the steroid nucleus, attaching the hydroxy group (-OH) to carbon 3 in α stereiodirection. 3α-hydroxysteroid dehydrogenases, including AKR1C2, are NAD(P)H-linked oxidoreductases that primarily catalyze the oxidation of 3α-hydroxysteroids to their corresponding 3-ketosteroids. This oxidation is dependent on NAD+. The substrates for the 3α-HSD3 enzyme are steroids such as androgens, estrogens, and progestins, which regulate various sex functions. For example, 3α-HSD3 can catalyze the conversion of the potent androgen 5α-dihydrotestosterone (DHT) into its much less active form, 5α-androstan-3α,17β-diol (3α-diol), effectively deactivating biological action of DHT.