PHAR 430 Lecture Notes - Lecture 9: Hmg-Coa Reductase, Lovastatin, Statin
Document Summary
Blocked here because it"s the rate limiting step, and can be feedback inhibited by cholesterol itself. Also, it"s better blocking earlier because the other compounds are toxic metabolites. Blocking the enzymes further down can cause build up of toxic metabolites. Stereospecific conversion of 3-hydroxy-3-methylglutaric acid (hmg) to mevalonic acid. = the rate limiting step of cholesterol biosynthesis. Hmg is bound to coenzyme a = activated. Hmg-coa reductase reduces hmg by transferring 4 electrons from 2 molecules of naph onto hmg. One domain binds to the hmg portion of the substrate = ionic interactions. The other domain binds to the coenzyme a portion = hydrophobic pocket lockated adjacent to the active site. Statins reduce plasma cholesterol by 3 related mechanisms. Increased expression of hepatic ldl receptors = enhanced clearance of ldl: reduction of vldl precursors. First isolated from fungi (aspergillus, penicillium and monascus species) Found to be competitive inhibitors of hmg-coa reductase.
