Enzymatic formation and chemical synthesis of an active metabolite of 3 beta-hydroxy-5 alpha-cholest-8(14)-en-15-one, a potent regulator of cholesterol metabolism.
The enzymatic (rat liver mitochondria) conversion of 3 beta-hydroxy-5 alpha-cholest-8(14)-en-15-one to 5 alpha-cholest-8(14)-ene-3 beta,26-diol-15-one is described. The enzymatic product was judged, on the basis of IH and 13C NMR studies, to be a 4:1 mixture of its 25R and 25S isomers. (25R)-5 alpha-Cholest-8(14)-ene-3 beta,26-diol-15-one was prepared through a five-step synthesis from (25R)-26-hydroxycholesterol. The (25R) isomer of the new compound was found to be highly active in the suppression of the levels of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in cultured mammalian cells and to inhibit the esterification of cholesterol in jejunal microsomes.
Schroepfer
G J
GJ
Department of Biochemistry, Rice University, Houston, Texas 77251.
Kim
H S
HS
Vermilion
J L
JL
Stephens
T W
TW
Pinkerton
F D
FD
Needleman
D H
DH
Wilson
W K
WK
St Pyrek
J
J
D000818:Animals; D002460:Cell Line; D055598:Chemical Phenomena; D002621:Chemistry; D002782:Cholestenes / Q000096:biosynthesis / Q000138:chemical synthesis / Q000378:metabolism; D002783:Cholestenones / Q000096:biosynthesis / Q000138:chemical synthesis / Q000378:metabolism; D002784:Cholesterol / Q000031:analogs & derivatives; D004952:Esters; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D007583:Jejunum / Q000378:metabolism; D008861:Microsomes / Q000378:metabolism; D008930:Mitochondria, Liver / Q000378:metabolism; D051381:Rats
D002782:Cholestenes; D002783:Cholestenones; D004952:Esters; C055090:cholest-8(14)-ene-3,26-diol-15-one; C015073:cholest-8(14)-en-3-ol-15-one; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases