Biocatalytic synthesis of 4-pregnen-20,21-diol-3-one, a selective inhibitor of human 5alpha-reductase type II.
Biocatalysis, the conversion of substrates into valuable products by the use of enzymes, has some striking advantages in comparison to standard organic chemistry for drug synthesis. By biocatalysis, substrates that contain several identical reactive groups at different positions can be converted with high regio-selectivity and enantio-selectivity. In this study, an E. coli isolate (E132) was identified which was able to convert the steroid desoxycorticosterone into the product 4-pregnen-20,21-diol-3-one in real terms. The product was purified from the cell culture supernatant by HPLC and its structure was demonstrated by mass spectrometry and NMR spectroscopy. It was tested on inhibition of human 5alpha-reductases type I and type II. At a concentration of 10 microM, inhibition was 49.0% for type I and 81.8% for type II, whereas there was no inhibition of human aromatase (CYP19) at 20 microM and human 17alpha-hydroxylase-C17,20-lyase (CYP17) at 2.5 microM detectable. The IC50 value of 4-pregnen-20,21-diol-3-one for human 5alpha-reductase type II was determined to be 1.56 microM.
Hannemann
Frank
F
Biochemistry, Saarland University, PO. Box 151150, D-66041 Saarbrücken, Germany.
Bernhardt
Rita
R
Jose
Joachim
J
D002478:Cells, Cultured; D042944:Cholestenone 5 alpha-Reductase / Q000037:antagonists & inhibitors / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D004926:Escherichia coli / Q000378:metabolism*; D006801:Humans; D006908:Hydroxyprogesterones / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D015394:Molecular Structure
C527598:4-pregnen-20,21-diol-3-one; D004791:Enzyme Inhibitors; D006908:Hydroxyprogesterones; D042944:Cholestenone 5 alpha-Reductase