3α-Hydroxysteroid dehydrogenase (3α-HSD)

3α-Hydroxysteroid dehydrogenase (3α-HSD) is a soluble NAD(P)H-dependent oxidoreductase of the aldo-keto reductase (AKR) family that catalyzes the reversible conversion of 3-ketosteroids to their 3α-hydroxy analogs, playing a critical role in the metabolism and inactivation of potent steroid hormones such as dihydrotestosterone in humans and other species[1][2][3][4][5]. Several isoforms exist in humans, with the most prominent being types 1 (AKR1C4, predominantly hepatic) and 3 (AKR1C2, expressed broadly in steroid-sensitive tissues including skin, prostate, testis, adrenal, and brain)[1][4][5]. Through this activity, 3α-HSDs are key regulators of local steroid action and receptor signaling, influencing diverse physiological and pathological processes such as hormone-dependent cancers, skin function, and possibly neurosteroid signaling[1][3][4][5]. As a family, these enzymes are structurally defined by the typical (α/β)8-barrel fold of AKRs, with a conserved catalytic tetrad facilitating hydride transfer, and are notable for their functional plasticity and overlapping substrate specificities with other steroid and xenobiotic oxidoreductases[2][3][6]. 3α-HSD is considered a promising drug target for modulating steroid hormone effects, though therapeutic strategies must consider the extensive isoform diversity and physiological redundancy[3][4][5].

Other names

3-alpha-hydroxysteroid dehydrogenase3α-HSDAKR1C2 (type 3, human major cutaneous)AKR1C4 (type 1, human liver)3α/17β-hydroxysteroid dehydrogenaseDihydrodiol dehydrogenase

Competitive inhibition of the active site (preventing catalysis of steroid conversion); Modulation of NAD(P)H binding (as 3α-HSD is NAD(P)H-dependent); Pre-receptor regulation (shifting local equilibrium of active/inactive steroids in tissues)