3-Hydroxy-3-methylglutaryl-coenzyme A reductase

The statins lower cholesterol by inhibiting the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase, which is required for the biosynthesis of mevalonic acid (see Section 26.10). Mevalonic acid is an obligatory precursor to cholesterol, so less mevalonic acid translates into less cholesterol. 

Statins (3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors)... 

ACE-I, angiotensin-converting enzyme inhibitors ARB, angiotensin-receptor blockers AZA, azathioprine CMV, cytomegalovirus CPK, creatinine phos-phokinase CSA, cyclosporine HMG-CoA, 3-hydroxy 3-methylglutaryl coenzyme A reductase K+, potassium LFTs, liver function tests Rl, renal insufficiency SCr, serum creatinine SRL, sirolimus TAC, tacrolimus TMP-SMX, trimethoprim-sulfamethoxazole. 

During the preparation of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, the benzyl ester protecting group was removed by catalytic hydrogenolysis (Scheme 4.42). 

There is interest in the use of lipid-lowering agents, especially the 3-hydroxy-3-methylglutaryl coenzyme A-reductase inhibitors, to prevent AD. Pravastatin and lovastatin, but not simvastatin, were associated with a lower prevalence of AD. Further study is needed before these agents can be recommended for this use. 

Beedle, A. S., Munday, K. A., Wilton, D. C. The stereochemistry of hydrogen transfer from NADPH catalyzed by 3-hydroxy-3-methylglutaryl-coenzyme A reductase from rat liver. European J. Biochem. 28, 151—155 (1972). 

Fischer, V., Johanson, L., Heitz, F., Tullmann, R., Graham, E., Baldeck, J.P. and Robinson, W.T., The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor fluvastatin effect on human cytochrome P-450 and implications for metabolic drug interactions. Drug Metab. Dispos., 1999, 27, 410 16. 

The statin family of six closely related hypocholesterolemic drugs are all potent competitive inhibitors of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG CoA reductase), the rate-limiting enzyme in cholesterol biosynthesis. The liver is their target organ, and decreased hepatic cholesterol synthesis ultimately leads to increased removal of LDL particles from the circulation. As a consequence, all other hypocholesterolemic drugs have been relegated to secondary status. 

Hydroxy-3-methylglutaryl coenzyme A reductase inhibition. Seed oil, administered intragastrically to rats at a dose of 2 mL/kg, was active "". 

Li S., C.A. Wagner, J.A. Freisen, and D.W. Borst (2003). 3-Hydroxy-3-methylglutaryl-coenzyme A reductase in the lobster mandibular organ Regulation by the eyestalk. General and Comparative Endocrinology 134 147-155. 

Thieno[2,3-. ]pyridine derivatives, 155, can be successfully used as replacements for the hexahydronaphthalene ring found in naturally occurring 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors <2001BML1285>. These compounds also display significant inhibition of cholesterol biosynthesis in vivo. 

Polonsky TS, Davidson MH Reducing the residual risk of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor therapy with combination therapy. Am 3 Cardiol 2008 101(Suppl) 27B. 

LeHoux and Grondin (1993) investigated the effects of chitosan on plasma and liver cholesterol levels, liver weight, and 3-hydroxy-3-methylglutaryl coenzyme A reductase in rats fed on a sterol diet (1% cholesterol and 0.2% cholic acid). Chitosan at a level of 5% lowered plasma and liver cholesterol levels by 54% and 64%, respectively. High MW chitosan (>750 kDa) had less hypocholesterolemic potential than that of 70 kDa. 

McNamara, D. J., Quackenbush, F. W. and Rodwell, V. W. 1972. Regulation of hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase. Developmental pattern. J. Biol. Chem. 247, 5805-5810. 

Proposed structure of HMG-CoA reductase derived from studies of recombinant DNA that codes for the enzyme. The enzyme is attached to the endoplasmic reticulum membrane and consists of two domains the hydrophobic domain, embedded in the membrane, and the catalytic domain, which protrudes into the cytosol. (Source Adapted from L. Liscum, J. Finer-Moore, R. M. Stroud, K. L. Luskey, M. S. Brown, and J. L. Goldstein, Domain structure of 3-hydroxy-3-methylglutaryl coenzyme A reductase, a glycoprotein of the endoplasmic reticulum, J. Biol. Chem. 260 522-530, 1985.)... 

Rajkovic, A., Simonsen, J.N., Davis, R.E. and Rottman, F.M. (1989) Molecular cloning and sequence analysis of 3-hydroxy-3-methylglutaryl-coenzyme A reductase from the human parasite Schistosoma mansoni. Proceedings of the National Academy of Sciences USA 86, 8217-8221. 

Some of the most exciting natural products discovered in recent years are the cholesterollowering agents derived from fungi. These drugs inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-COA reductase), an enzyme critical in the biosynthesis of cholesterol. The first HMG-COA reductase inhibitors were isolated from Pencillium sp. 

Dideoxy-D-eryt/zro-hexopyranose (172) has been obtained from 3-deoxy-D-eryt/zro-pentose (171, Scheme 51)248 as an intermediate for the synthesis of the lactone moiety of inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, that lowers cholesterol levels. 

SY Sit, RA Parker, I Motoe, HW Balsubramanian, CD Cott, PJ Brown, WE Harte, MD Thompson, J Wright. Synthesis, biological profile, and quantitative structure-activity relationship of a series of novel 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. J Med Chem 33 2982-2999, 1990. 

T Matsuoka, S Miyakoshi, K Tanzawa, K Nakahara, M Hosobuchi, N Serizawa. Purification and characterization of cytochrome P-450sca from Streptomyces car-bophilus. ML-236B (compactin) induces a cytochrome-P450sca in Streptomyces carbophilus that hydroxylates ML-236 B to pravastatin sodium (CS-514), a tissue-selective inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase. Eur J Bio-chem 184 707-713, 1989. 

Endo A, Tsujita Y Kuroda M, Tanzawa K. Inhibition of cholesterol synthesis in vitro and in vivo by ML-236A and ML-236B, competitive inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, EurJ Biochem I 977 77 31-36,... 

Blanco-Colio LM, Munoz-Garcia B, Martin-Ventura JL, et al. 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors decrease Fas ligand expression and cytotoxicity in... 

Chin D. J., Luskey K. L., Anderson R. G. W., Faust J. R., Goldstein J. L. and Brown M. S. (1982) Appearance of crystalloid endoplasmic reticulum in compactin-resistant Chinese hamster cells with a 500-fold increase in 3-hydroxy-3-methylglutaryl coenzyme A reductase. Proc. Natl. Acad. Sci. USA 79, 1185-1189. 

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