Oxidative 3alpha-hydroxysteroid dehydrogenase activity of human type 10 17beta-hydroxysteroid dehydrogenase.
In vitro enzyme assays have demonstrated that human type 10 17beta-hydroxysteroid dehydrogenase (17beta-HSD10) catalyzes the oxidation of 5alpha-androstane-3alpha,17beta-diol (adiol), an almost inactive androgen, to dihydrotestosterone (DHT) rather than androsterone or androstanedione. To further investigate the role of this steroid-metabolizing enzyme in intact cells, we produced stable transfectants expressing 17beta-HSD10 or its catalytically inactive Y168F mutant in human embryonic kidney (HEK) 293 cells. It was found that DHT levels in HEK 293 cells expressing 17beta-HSD10, but not its catalytically inactive mutant, will dramatically increase if adiol is added to culture media. Moreover, certain malignant prostatic epithelial cells have more 17beta-HSD10 than normal controls, and can generate DHT, the most potent androgen, from adiol. This event might promote prostate cancer growth. Analysis of the 17beta-HSD10 sequence shows that this enzyme does not have any ER retention signal or transmembrane segments and has not originated by divergence from a retinol dehydrogenase. The data suggest that the unique mitochondrial location of this HSD [Eur. J. Biochem. 268 (2001) 4899] does not prevent it from oxidizing the 3alpha-hydroxyl group of a C19 sterol in living cells. The experimental results lead to the conclusion that mitochondrial 17beta-HSD10 plays a significant part in a non-classical androgen synthesis pathway along with microsomal retinol dehydrogenases.
He
Xue-Ying
XY
Department of Pharmacology, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA.
Yang
Ying-Zi
YZ
Peehl
Donna M
DM
Lauderdale
Alexander
A
Schulz
Horst
H
Yang
Song-Yu
SY
D015067:17-Hydroxysteroid Dehydrogenases / Q000235:genetics / Q000378:metabolism*; D015094:3-Hydroxyacyl CoA Dehydrogenases; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific) / Q000378:metabolism*; D000429:Alcohol Oxidoreductases / Q000378:metabolism; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D002460:Cell Line; D013196:Dihydrotestosterone / Q000378:metabolism; D004847:Epithelial Cells / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D010084:Oxidation-Reduction; D011467:Prostate / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D014162:Transfection
D011994:Recombinant Proteins; D013196:Dihydrotestosterone; D015067:17-Hydroxysteroid Dehydrogenases; D000429:Alcohol Oxidoreductases; D015094:3-Hydroxyacyl CoA Dehydrogenases; C022520:retinol dehydrogenase; C108634:HSD17B10 protein, human; C458480:Hsd17b10 protein, mouse; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific)