Mevaldic acid

This is another example of the generalization that enzyme reactions of the same type have the same stereospecificity for the pyridine nucleotide, no matter what their cellular origin. There is another mevaldic reductase in the cytosol of liver, which catalyzes the reduction of mevaldic acid to mevalonic acid by NAD or NADP, and this enzyme also has A (or pro R) stereospecificity for the pyridine nucleotide but the hydrogen transfer occurs to the pro R position on C—5. This latter enzyme can use either 3R or 3S mevaldic acid that is, it is indifferent to... 

Beedle, A. S., Munday, K. A., Wilton, D. C. The stereochemistry of the reduction of mevaldic acid-coenzyme A hemithioacetal by rat liver 3-hydroxy-3-methylglutaryl coenzyme A-reductase. FEBS Letters 28, 13—15 (1972). 

Mevaldic Acid. 3 Hydroxy-3-methyl S-oxopenta-tioic acid 3 -hydroxy -3 -methyIglutaraldehvdic acid, C6H 1 -04 mol wt 146.14. C 49.31%, H 6.90%, O 43.79%. Prepn by acid hydrolysis of 3-hydroxy -3 -methyl -5.5 -dimethoxy-pentanoic acid Shunk ei al.. J. Am. Chem, Soc. 79, 3294 (1957). Exists in equilibrium with i ,o-dihydiuxy-IS-rnclhyl-S -valcrolactone. 

In an effort to mimic the transition state of the enzymatic reduction of mevaldic acid by NADPH, nicotinamide derivative 1008 was considered a likely candidate as an HMG-CoA reductase inhibitor. 

Methymycin, M-10079 Methynolide, in M-10079 Mevaldic acid, see H-20185 Mexicanic acid, in H-30147 Mexicanolt, see T-30107 M-factor mating hormone, M-30117 MG 299A, in 1-10059 MG 299B, in 1-10059... 

The major pathway for the formation of MVA in yeast and mammalian systems is shown in Fig. 2. Acetyl-CoA and acetoacetyl-CoA are condensed by the enzyme hydroxymethylglutaryl-CoA (HMG-CoA) synthase (HMG-CoA acetoacetyl-CoA lyase, E.C. 4.1.3.5) to form 3-hydroxy-3-methylglu-taryl-CoA (HMG-CoA). In a two-step reduction, HMG-CoA is then reduced to MVA in a reaction catalyzed by the enzyme HMG-CoA reductase. In the first step of this reaction, the CoA hemithioacetal of mevaldic acid is formed. In the second step, this compound is reduced to MVA both steps require NADPH. Hydroxymethylglutaryl-CoA reductase is an important control point in the regulation of cholesterol biosynthesis in mammalian systems. The HMG-CoA reductase enzymes from yeast and mammalian liver have been purified to homogeneity, and some of their properties have been determined. This work is covered in detail in several reviews (Beytia and Porter, 1976 Rodwell et al., 1976 Kandutsch et al., 1978). 

There exists unequivocal evidence of the biosynthesis of mevalonic acid (MVA) from acetate in yeast and rat liver enzyme systems. The first step appears to be the S5mthesis of 3-hydroxy-3-methylglutarate. This initial step involves the condensation of acetoacetyl-coenzyme A and acetylcoenzyme A [295]. Yeast enzymes reduce the asymmetric monocoenz5nne A ester of hydroxy-methyl-glutaric acid in two steps, (a) to mevaldic acid and (b) to mevalonic acid [296]. The next step is the oxidative generation of the five-carbon biological building... 

The main biochemical source of mevalonate is acetyl coenzyme A. Lynen and co-workers suggest that it is the hemithioacetal of mevaldate and coenzyme A (or the enzyme) which is reduced to mevalonic acid. 

Both reductive steps in the conversion of HMG-CoA (3) into mevalonic acid (5) catalysed by microsomal rat liver HMG-CoA reductase occur by direct hydrogen transfer from the 4R position of NADPH this stereochemistry agrees with that previously reported for the corresponding yeast enzyme. The hemithioacetal addition compound (13) of 3R mevaldic add and coenzyme A... 

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