Microbial Metabolites Inhibiting Sterol Biosynthesis: Their Chemical Diversity and Characteristics of the Mechanism of Action

摘要

Inhibitors of sterol biosynthesis (ISB) are widespread in nature and characterized by appreciable diversity both in their chemical structure and mechanism of action. Many of these inhibitors express pronounced biological activity and approved themselves in the development of various pharmaceuticals. In this review, there is a detailed description of biologically active microbial metabolites with established chemical structure that have ability to inhibit sterol biosynthesis. Inhibitors of mevalonate pathway in fungal and mammalian cells, exhibiting hypolipidemic or antifungal activity, as well as inhibitors of alternative nonmevalonate (pyruvate–gliceraldehyde phosphate) isoprenoid pathway, which are promising in the development of effective antimicrobial or antiparasitic drugs, are under consideration in this review. Chemical formulas of the main natural inhibitors and their semisynthetic derivatives are represented. Mechanism of their action at cellular and biochemical level is discussed. Special attention is given to inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (lovastatin group) and inhibitors of acyl-CoA:cholesterol acyltrans-ferase (ACAT) that possess hypolipidemic activity and could be affective in the treatment of atherosclerosis. In case of inhibitors of late stages of sterol biosynthesis (after squalene formation), special attention is paid to compounds possessing evident antifungal and antitumoral activity. Explanation of the mechanism of anticancer and antiviral action of microbial ISB, as well as the description of their ability to induce apoptosis, is given.