| HSD3B2 encodes the type 2 isoform of 3β-hydroxysteroid dehydrogenase/Δ5-Δ4 isomerase, a short-chain dehydrogenase/reductase family member predominantly expressed in steroidogenic tissues such as the adrenal gland, ovary, and testis. The enzyme localizes to the endoplasmic reticulum and inner mitochondrial membrane as a homodimeric NAD+-dependent bifunctional catalyst featuring conserved YXXXK motifs critical for substrate recognition and proton transfer. It oxidizes the 3β-hydroxyl group of Δ5-3β-hydroxysteroids like pregnenolone, 17α-hydroxypregnenolone, and dehydroepiandrosterone using NAD+ to yield NADH, followed by spontaneous or enzyme-facilitated Δ5-Δ4 isomerization to produce progesterone, 17α-hydroxyprogesterone, and androstenedione, respectively, channeling flux through glucocorticoid, mineralocorticoid, androgen, and estrogen biosynthetic pathways. This sequential dehydrogenation-isomerization supports adrenal cortisol and aldosterone production alongside gonadal sex steroid synthesis, with kinetic preference for Δ5 substrates ensuring efficient progression from cholesterol-derived precursors. Transcriptional control involves orphan nuclear receptors steroidogenic factor-1 and DAX-1 binding promoter elements, alongside STAT5/STAT6 activation by cytokines like IL-4/IL-13 and EGF signaling. In steroidogenic cells, cyclic AMP stimulation differentially modulates activity, with acute exposure inhibiting via cofactor adjustments and chronic induction enhancing through promoter transactivation by Nur77 at NBRE sites synergizing with coactivators. Loss-of-function mutations disrupt these conversions, elevating Δ5 precursors and depleting active steroids, manifesting as salt-wasting congenital adrenal hyperplasia with ambiguous genitalia in males and partial androgenization in females. |
