The participation of malonyl coenzyme A in the biosynthesis of mevalonic acid.

A number of laboratories (l-4) have investigated the biosynthesis of mevalonic acid from acetate or acetyl coenzyme ,4 by yeast and animal enzyme systems. These investigations have indicated that acetoacetyl coenzyme A and P-hydroxy-P-methylglutaryl coenzyme A glutaryl are intermediates in the formation of mevalonic acid. However, the synthesis in vitro of sterols from acetate by subcellular, reconstituted animal enzyme syeterns is too low to account for t,he production in viva of cholesterol (4, 5). Therefore we have explored the possibility that another pathway might exist, for the formation of the early intermediates in cholesterol biogenesis. The establishment of ncetyland malonyl-CoA as intermediates in the biosynthesis of fatty acids (6-8) suggested the possibility of an alternate route for the biosynthesis of acetoacetyl-CoA and thus of sterols. However, the synthesis of acetoacetyl-CoA from malonyl-CoA has not been observed. Some evidence has been presented that an acetoacetyl-S-enzyme complex is formed (9, lo), and it has been suggested (11) that enzyme-bound acetoacetate is an intermediate in the biosynthesis of fatty acids whereas acetoacetyl-CoA is an intermediate in the biosynthesis of sterols. ‘The first hint that this suggested distinction might not be warranted came from the observation that a purified fatty acid-synthesizing enzyme, obtained from pigeon liver, catalyzes the formation of a number of compounds from acetyland malonylCoA when TPNH is omitted from the incubation mixture (12). Indeed, it appeared that some of these chromatographically separable compounds might be CoA esters. Later, one of these compounds was characterized as HMG-CoAl (13). The finding of HMG-CoA, a product related to both the 4 carbon intermediate and mevalonic acid, in the incubation mixture made it possible to study in greater detail the early reactions leading to the formation of fatty acids and sterols. Whether the 4 carbon intermediate in the formation of HMG-Coi), was free acetoacetyl-Cob or enzyme-bound acetoacetate was of particular concern. The present report describes the pathway of the biosynthesis of mevalonic acid from acetyl-CoA by a hitherto unsuspected route which utilizes malonyl-CoA as the initial condensing partner and involves no other CoA ester as an obligatory interme-