Regulation of human 3-beta-hydroxysteroid dehydrogenase type-2 (3βHSD2) by molecular chaperones and the mitochondrial environment affects steroidogenesis

Overview of the Molecular Steps in Steroidogenesis of the GABAergic Neurosteroids Allopregnanolone and Pregnanolone

“…63 The 3b-HSD2 isoform is thought to be the most relevant for steroid biosynthesis, as it is expressed in the adrenals, ovaries, and testes-all traditionally steroidogenic tissues. 63 However, the 3b-HSD1 isoform is found in non-steroidogenic tissues 63 and therefore may play a role in steroidogenesis in the central nervous system (CNS). This is important as 3b-HSD1 has a significantly higher affinity for common substrates, coenzymes, and inhibitors than 3b-HSD2 64 and thus may have the ability to convert substantially lower concentrations of pregnenolone to progesterone as might be seen in the CNS.…”

“…3b-HSD2 is localized to the IMM in close association with P450scc but performs its catalytic function in the intermembrane space because it requires a low pH environment to function. 63,65,66 3b-HSD2 first performs a dehydrogenation reaction that converts NAD þ (nicotinamide adenine dinucleotide) to NADH. 62 NADH induces a conformational change in 3b-HSD2, thus creating a catalytic site for the isomerization reaction that converts pregnenolone to progesterone.…”

“…62,67 The catalytic part of the protein can exist in three forms: a highly folded form at physiological pH, a partially folded form (molten globule with a high degree of secondary structure but no defined tertiary structure) at about pH 4.5, or a completely unfolded form at about pH 3.5. 63,66 3b-HSD2 is most active when partially unfolded, a state stabilized by chaperone proteins that prevent 3b-HSD2 aggregation (in the case of denaturation) and facilitate recycling of the protein back to the less-active highly folded state during cell quiescence. 63,66,68 On both the OMM and IMM, 3b-HSD is tightly associated with P450scc and mitochondrial translocase proteins (Tom22, Tim50, and Tim23) that seem to be necessary for 3b-HSD2 function.…”

“…63,66 3b-HSD2 is most active when partially unfolded, a state stabilized by chaperone proteins that prevent 3b-HSD2 aggregation (in the case of denaturation) and facilitate recycling of the protein back to the less-active highly folded state during cell quiescence. 63,66,68 On both the OMM and IMM, 3b-HSD is tightly associated with P450scc and mitochondrial translocase proteins (Tom22, Tim50, and Tim23) that seem to be necessary for 3b-HSD2 function. 63,65 After synthesis, progesterone crosses the OMM into the cytosol via passive diffusion.…”

“…62 3β-HSD exists in two isoforms (3β-HSD1 and 3β-HSD2), which share 93% homology and a similar quaternary structure except for key residues that confer different ligand specificities. 63 The 3β-HSD2 isoform is thought to be the most relevant for steroid biosynthesis, as it is expressed in the adrenals, ovaries, and testes—all traditionally steroidogenic tissues. 63 However, the 3β-HSD1 isoform is found in non-steroidogenic tissues 63 and therefore may play a role in steroidogenesis in the central nervous system (CNS).…”