Anthrones, naturally occurring competitive inhibitors of adenosine‐triphosphate‐citrate lyase

Adenosine triphosphate (ATP)‐citrate lyase (ACL) is a homotetrameric liver enzyme which catalyzes the cytosolic formation of acetyl‐CoA. This reaction provides the major source of acetyl‐CoA for fatty acid and cholesterol biosynthesis. Inhibition of ACL offers a potentially unique way to control plasma cholesterol and triglyceride levels. In this study, we describe the activity of an active microbial metabolite derived from a soil fungus, Penicillium sp., SC2193. This culture produces a series of related anthrones and anthraquinones. We present evidence for one of these anthrones, 2‐chloro‐1, 3, 8‐trihydroxy‐6‐methyl‐9‐anthrone, as a specific and competitive inhibitor of ACL against the substrate Mg citrate and mixed noncompetitive inhibition against two other required substrates for this enzyme, Mg ATP and CoA. With an IC 50 of 283 nM in the primary assay and, more specifically, a K i of < 100 nM against the substrate Mg citrate, SC2193 represents the most potent competitive inhibitor of ACL yet described, and, as such, might prove very useful as a molecular tool for the discovery of selective, mechanistically novel hypolipidemic agents.