The inhibition of cytoplasmic acetoacetyl-CoA thiolase by a triyne carbonate (L-660, 631).
The compound L-660, 631 (2-oxo-5-(1-hydroxy-2,4,6-heptatriynyl)-1,3-dioxolane-4 heptanoic acid), a natural product isolated from an Actinomycete culture, was found to inhibit rat liver cytosolic acetoacetyl-CoA thiolase, the first step in the cholesterol biosynthesis pathway, with an IC50 of 1.0 x 10(-8) M. The inhibitor had no effect on other sulfhydryl containing enzymes of lipid synthesis such as HMG-CoA synthase, HMG-CoA reductase, and fatty acid synthase. When tested in cultured human liver Hep G2 cells the compound inhibited the incorporation of 14C-acetate and 14C-octanoate into sterols 56% and 48% respectively at 3 x 10(-6) M with no effect on fatty acid synthesis. No noticeable effect was seen on fatty acid biosynthesis. This strongly suggests that the locus of inhibition of acetate incorporation into sterols found with this compound is the acetoacetyl-CoA thiolase step in the cholesterol biosynthesis pathway.
Greenspan
M D
MD
Merck Sharp & Dohme Research Laboratories, Rahway, New Jersey 07065.
Yudkovitz
J B
JB
Chen
J S
JS
Hanf
D P
DP
Chang
M N
MN
Chiang
P Y
PY
Chabala
J C
JC
Alberts
A W
AW
D000101:Acetyl-CoA C-Acetyltransferase / Q000037:antagonists & inhibitors*; D000123:Acetyltransferases / Q000037:antagonists & inhibitors*; D000192:Actinomycetales / Q000032:analysis; D000818:Animals; D002784:Cholesterol / Q000096:biosynthesis; D003593:Cytoplasm / Q000201:enzymology; D004148:Dioxolanes / Q000494:pharmacology*; D004149:Dioxoles / Q000494:pharmacology*; D005227:Fatty Acids / Q000096:biosynthesis; D006538:Heptanoic Acids / Q000494:pharmacology*; D008099:Liver / Q000201:enzymology*; D051381:Rats
D004148:Dioxolanes; D004149:Dioxoles; D005227:Fatty Acids; D006538:Heptanoic Acids; C056803:Sch 31828; D002784:Cholesterol; D000123:Acetyltransferases; D000101:Acetyl-CoA C-Acetyltransferase