Type 10 17beta-hydroxysteroid dehydrogenase catalyzing the oxidation of steroid modulators of γ-aminobutyric acid type A receptors

Abstract: The steroids allopregnanolone and allotetrahydrodeoxycorticosterone (3α,5α-THDOC) are positive allosteric modulators of GABAA receptors, generated by the reduction of 5α-dihydroprogesterone (5α-DHP) and 5α-DHDOC, respectively, under the catalysis of human type 3 3α-hydroxysteroid dehydrogenase (HSD). However, brain enzymes catalyzing the conversion of such tetrahydrosteroids back to the corresponding 5α-dihydrosteroids remain to be identified. Characterization of human type 10 17β-HSD provides a new insight into its importance for the oxidation of steroid modulators of GABAA receptors. The apparent catalytic efficiency (kcat/Km) of this enzyme for the oxidation of allopregnanolone and 3α,5α-THDOC are 432 and 1381min-1mM-1, respectively. This enzyme has negligible 3-ketosteroid reductase activity for 5α-DHP and 5α-DHDOC even in an acidic environment. Immunoreactivity against 17β-HSD10 was found in a number of neuronal populations. Taken together, evidence suggests that 17β-HSD10 is the brain enzyme capable of catalyzing the oxidation of steroid modulators of GABAA receptors. [Copyright &y& Elsevier]