3-Hydroxy-3-methyl-glutaryl coenzyme A

PARKER R A, PEARCE B 0, CLARK R w, GORDON D A, WRIGHT J J (1993) Tocotrienols regulate cholesterol production in mammalian cells by post-transcriptional suppression of 3-hydroxy 3-methyl-glutaryl-coenzyme A reductase. J Biol Chem, 268 11230-38. 

Fig. 8. Most important steps in the biosynthesis of cholesterol. The reduction of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) to yield mevalonic acid is an important rate-limiting step and also the site of attack of the HMG-CoA-reductase inhibitors (statins).

Fig. 5.1.1 Isoprenoid biosynthetic pathway. The enzyme mevalonate kinase (black solid bar) is deficient in patients affected with mevalonic aciduria and hyperimmunoglobulinemia D and periodic fever syndrome. -CoA -Coenzyme A, HMG-CoA 3-hydroxy-3-methyl-glutaryl-coenzyme A, -PP -pyrophosphate...

ACE angiotensin-converting enzyme HIV human immunodeficiency virus HMG-CoA reductase 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase. 

The structure, synthesis and biological activity of natural 2-oxetanones and their derivatives has been reviewed (95S729). The synthesis of some novel 3-(hydroxymethyl)-4-(2-substituted ethyl)-2-oxetanones and their biological activity as 3-hydroxy-3-methyl-glutaryl coenzyme-A inhibitors has been reported (94CPB1272, 94CPB2097). 

Romo et al. have used Lewis acids to catalyze the formation of a-silyl-/ -lactones in their synthesis of potential inhibitors of yeast 3-hydroxy-3-methyl glutaryl-coenzyme A (HMG-CoA) synthase <1998BMC1255>. In addition to various Lewis acid catalysts, a chiral promoter based on the chiral diol (l/ ,2R)-2-[(diphenyl)hydroxymethyl]cyclo-hexan-l-ol was introduced to the reaction in an attempt to improve the stereoselectivity. A variety of chiral 2-oxetanones were formed, with enantioselectivities ranging from 22% to 85%. Dichlorotitanium-TADDOL catalysts 113 and 114 have also been used in an attempt to encourage the stereoselective [2+2] cycloaddition of silyl ketenes and aldehydes (TADDOL = (—)-/ra r-4,5-bis(diphenyl-hydroxymethyl)-2,2-dimethyl-l,3-dioxolane), although this method only afforded 2-oxetanones in moderate yields and optical purity (Equation 41) <1998TL2877>. 

Fig. 3. Steroidogenic pathway in granulosa cells. A. Lipoprotein in receptors. B. 3-Hydroxy-3-methyl-glutaryl coenzyme A reductase (HMG-CoA reductase). C. Acyl-coenzyme A (cholesterol acyl transferase). D. Cholesterol esterase. E. Cholesterol transport to the mitochondria. F. Cholesterol side-chain cleavage enzymes (phospholipid membrane environment and enzyme levels). G. 3/3-Hydroxysteroid dehydrogenase (3/3-HSD). H. 20a-Hydroxysteroid dehydrogenase (20a-HSD). I. Aromatases.

HMG-CoA reductase catalyzes the rate-limiting conversion of 3-hydroxy-3-methyl-glutaryl coenzyme A to mevalonic acid which is a key intermediate in biosynthesis of cholesterol (Fig. 4.1)... 

Xu, L., and Simoni, R.D. (2003). The inhibition of degradation of 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase by sterol regulatory element binding protein cleavage-activating protein requires four phenylalanine residues in span 6 of HMG-CoA reductase transmembrane domain. Arch Biochem Biophys 414 232-243. 

Miziorko HM, Lane MD, Weidman SW. 3-Hydroxy-3-Methyl-glutaryl coenzyme-A synthase-use of a spin-labeled probe to study acyl coenzyme-A binding. Biochemistry 1979 18 399-403. 

Cerivastatin is a competitive inhibitor of HIVIG-CoA reductase, which is responsible for the conver sion of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) to mevalonate, a precursor of sterols, including cholesterol. The inhibition of cholesterol biosynthesis by cerivastatin reduces the level of cholesterol in hepatic cells, which stimulates the synthesis of LDL receptors. 

The incorporation of malonate into mevalonic acid and steroids has been investigated further. Experiments with normal and tumorous rats have demonstrated the previously unsuspected fact that the S-methyl group of methionine is incorporated into cholesterol and cholest-7-en-3jS-ol. Some of the enzymes involved in mevalonate synthesis have been isolated. Yeast acetoacetyl coenzyme A thiolase (EC 2.3.1.9) has a molecular weight of about 190 000 and 3-hydroxy-3-methyl glutaryl coenzyme A synthetase (EC 4.1.3.5) a molecular weight of 130 000. Rat liver 3-hydroxy-3-methylglutaryl coenzyme A reductase (EC 1.1.1.34) used only [4/ - H]NADPH in the formation of mevalonic acid with incorporation of two tritium atoms (at Hp and Hp) (see Scheme 1). 

Arnadottir M, Eriksson LO, Thysell H, Karkas JD. Plasma concentration profiles of simvastatin 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitory activity in kidney transplant recipients with and without ciclosporin. Nephron 1993 65 410-113. 

Iharrea, P., Villareal, E Moya, I., Aguirre, P. Palacios,]. (1992). Development of hepatic activity of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase and cholesterol 7a-hy-droxylase in young chick. Comp. Biochem. Physiol, 103A, 417-20. 

Through-bond and through-space solid-state NMR correlation experiments including CP-INADEQUATE at natural isotope abundance have been applied by Brus and Jegorov to establish the structure and dynamic behaviour of simvastatin (C25H38O5), an active metabolite which inhibits 3-hydroxy-3-methyl-glutaryl coenzyme A, (HMG-CoA) reductase, the enzyme that is necessary in an early step of the cholesterol synthesis. 2D INADEQUATE spectroscopy has been applied by Meier et to establish the structures of a series of fullerene derivatives. 

Another explanation to palm oil hypocholesterolemic action would be the presence of tocotrienols. They are admittedly considered hypocholesterolemic once they regulate cholesterol synthesis through 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inactivation - enzyme that primarily synthesizes the cholesterol [147]. 

In order to increase the effectiveness of PS in the reduction of CHD-associated factors, PS can be used in combination with other drugs or bioactive substances [23], For instance, PS have been used in combined therapies with statins (3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) inhibitors) [36], with... 

Derivatives of cholesterol which inhibit the biosynthesis of cholesterol in aortic smooth muscle, presumably by suppressing the activity of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, also effect a corresponding decrease in the levels of glycosylated lipid intermediates with an apparent inhibition of the biosynthesis of glycoproteins. ... 

While statin drugs (drugs eurrently used to reduce blood cholestm) levels) inhibit 3-hydroxy-3-methyl glutaryl coenzyme A reductase in the cholestmrl synthesis pathway, policosanol inhibits the same pathway but a step earlier Pohcosanol could, therefore, prove to be a useful alternative to statin drugs. 

Of the cholesterol-lowering medications available to date, statins are currently the first choice for treating patients with hypercholesterolemia. They lower serum LDL cholesterol concentrations by 24-50% (Knopp, 1999) by blocking the synthesis of cholesterol through inhibition of the action of 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase in the fiver. 

Fluvastatin (28, Scheme 2.4) is a member of the 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG CoA) reductase inhibitor family and is prescribed to treat hypercholesterolemia. As part of their nonracemic synthesis of fluvastatin, researchers at Novartis used a monoacetyltri-phenylglycol chiral auxiliary 25 originally reported by Braun and Devant. A diastereoselective lithium aldol reaction between Braun and Devant s reagent 25 and the fluarophenylindolenal 24 afforded the allylic alcohol 26 as... 

The Mukaiyama-Michael reaction was further applied by Robichaud et al. at Merck (Whitehouse Station, NJ) for the synthesis of compactin, an 3-hydroxy-3-methyl-glutaryl-coenzyme A inhibitor (Scheme 11.9). The organocatalytic reaction created two of the four stereocenters in 82% ee and... 

Ligand 15a was also applied by Inoue and Nakada in the synthesis of the potent 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitor FR901512 52 (Scheme 12.38). MethaUyl chloride was coupled with aldehyde 53 to afford product 54 in excellent yield (93%) and an enantiomeric excess of 92%. " ... 

This mutant was also shown to accept 3-azidopropanal 39 as a new substrate in a sequential aldol reaction to form a novel azidopyranose 40, offering a new pathway for the synthesis of one of the building blocks 41 of atorvastatin (Scheme 28.19). Atorvastatin is the best-selling statin (marketed under the name of Lipitor by Pfizer, New York, NY), drug used to lower the cholesterol levels by inhibiting the HMG CoA (3-hydroxy-3-methyl-glutaryl coenzyme A) reductase, which plays a central role in the production of cholesterol in the fiver. ... 

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