Type 10 17beta-hydroxysteroid dehydrogenase catalyzing the oxidation of steroid modulators of gamma-aminobutyric acid type A receptors.
The steroids allopregnanolone and allotetrahydrodeoxycorticosterone (3alpha,5alpha-THDOC) are positive allosteric modulators of GABA(A) receptors, generated by the reduction of 5alpha-dihydroprogesterone (5alpha-DHP) and 5alpha-DHDOC, respectively, under the catalysis of human type 3 3alpha-hydroxysteroid dehydrogenase (HSD). However, brain enzymes catalyzing the conversion of such tetrahydrosteroids back to the corresponding 5alpha-dihydrosteroids remain to be identified. Characterization of human type 10 17beta-HSD provides a new insight into its importance for the oxidation of steroid modulators of GABA(A) receptors. The apparent catalytic efficiency (k(cat)/K(m)) of this enzyme for the oxidation of allopregnanolone and 3alpha,5alpha-THDOC are 432 and 1381 min(-1) mM(-1), respectively. This enzyme has negligible 3-ketosteroid reductase activity for 5alpha-DHP and 5alpha-DHDOC even in an acidic environment. Immunoreactivity against 17beta-HSD10 was found in a number of neuronal populations. Taken together, evidence suggests that 17beta-HSD10 is the brain enzyme capable of catalyzing the oxidation of steroid modulators of GABA(A) receptors.
He
Xue-Ying
XY
Department of Neuropharmacology, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA.
Wegiel
Jerzy
J
Yang
Ying-Zi
YZ
Pullarkat
Raju
R
Schulz
Horst
H
Yang
Song-Yu
SY
D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000378:metabolism*; D043582:5-alpha-Dihydroprogesterone / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014151:Anti-Anxiety Agents / Q000737:chemistry / Q000378:metabolism*; D001921:Brain / Q000201:enzymology*; D002384:Catalysis; D003900:Desoxycorticosterone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism*; D005260:Female; D006801:Humans; D006913:Hydroxysteroid Dehydrogenases / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010084:Oxidation-Reduction; D011963:Receptors, GABA-A / Q000378:metabolism*
D014151:Anti-Anxiety Agents; D011963:Receptors, GABA-A; D003900:Desoxycorticosterone; C009413:tetrahydrodeoxycorticosterone; D043582:5-alpha-Dihydroprogesterone; D006913:Hydroxysteroid Dehydrogenases; D015094:3-Hydroxyacyl CoA Dehydrogenases; C108634:HSD17B10 protein, human