S-3-Hydroxy-3-methylglutaryl

In our example, EC book and Empath find an exact match to HMG-CoA reductase. The Empath link shows the metabolic step that the enzyme catalyzes (Figure 10.5 [50]). The reaction is between S-3-hydroxy-3-methylglutaryl-CoA and Mevalonate. The step summary on the right side of the chart image shows activation and regulation of the enzyme, its biological scope, direction, reversibility and stoichiometry. A pathway search... 

Figure 11 Biosynthesis of isoprenoid type cofactors. 18, Heme a 39, pyridoxal 5 -phosphate 43, 1-deoxy-D-xylulose 5-phosphate 46, thiamine pyrophosphate 83, acetyl-CoA 84, (S)-3-hydroxy-3-methylglutaryl-CoA 85, mevalonate 86, isopentenyl diphosphate (IPP) 87, dimethylallyl diphosphate (DMAPP) 88, pyruvate 89, D-glyceraldehyde 3-phosphate 90, 2C-methyl-D-erythritol 4-phosphate 91, 2C-methyl-erythritol 2,4-cyclodiphosphate 92, 1-hydroxy-2-methyl-2-( )-butenyl 4-diphosphate 93, polyprenyl diphosphate 94, cholecalciferol 95, fS-carotene 96, retinol 97, ubiquinone 98, menaquinone 99, a-tocopherol.

Terpenic compounds are resorbed from the digestive tract and sue situated in the hepatie tissues. Thanks to their ability to dissolve fats, they prevent the formation of cholesterol gathering inside the liver and they also recover proper colloidal state to the bile. Terpenes also enhance the bile content in the hepatic cells and in the liver tracts. Terpenic hydrocarbons dilating the smooth muscles [78, 79] make the hepatic tracts more distended both inside and outside. It has been pointed out that the terpenes contained in Rowachol dissolve bile stones [87-89]. The meehanism of terpenes activity has not as yet been completely explained. It was explained that menthol and other monoterpenes inhibit the activity of the lecithin-cholesterol acyltransferase in the human serum [90]. They also lower the activity of the hepatic S-3-hydroxy-3-methylglutaryl-CoA reductase, which is responsible for the physiological inhibition of cholesterol synthesis in the liver [82, 91, 92]. 

Triterpenes originate from squalene via mevalonic acid, which is formed from sequential condensation of three acetyl-coenzyme A units and subsequent reduction with NADPH to generate (3.S )-3-hydroxy-3-methylglutaryl-coenzyme A. The next ATP/Mg2+-dependent steps... 

Clegg, R. J., Middleton, B., Bell, G. D., White, D. A. 1980. Inhibition of hepatic cholesterol synthesis and S-3-hydroxy-3-methylglutaryl-CoA reductase by mono and bicyclic monoterpenes administered in vivo. 

Enzyme-catalyzed aldol reaction with a third molecule of acetyl-CoA on the ketone carbonyl of acetoacetyl-CoA gives (S)-3-hydroxy-3-methylglutaryl-CoA. 

Coronary artery disease is the leading cause of death in the United States and other Western countries, where about one-half of all deaths can be attributed to atherosclerosis. Atherosclerosis results from the buildup of fatty deposits called plaque on the inner walls of arteries. A major component of plaque is cholesterol derived from low-density lipoproteins (LDLs), which circulate in blood plasma. Because more than one-half of total body cholesterol in humans is synthesized in the liver from acetyl-CoA, intensive efforts have been directed toward finding ways to inhibit this synthesis. The rate-determining step in cholesterol biosynthesis is reduction of (S)-3-hydroxy-3-methylglutaryl CoAto (R)-mevalonic acid. This reduction is catalyzed by the enzyme HMG-CoA reductase and requires two moles of NADPH per mole of HMG-CoA. 

Shefer, S., Tint, G. S., Jean-Guillaume, D. etal. Is there a relationship between 3-hydroxy- 3-methylglutaryl coenzyme a reductaseactivity and forebrain pathology in the PKU mouse /. Neurosci. Res. 61 549-563,2000. 

S. Erturk, A. Onal and S.M. Cetin, Analytical methods for the quantitative determination of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors in biological samples. J. Chromatogr.B 793 (2003) 195-203. 

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). 

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. 

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.)... 

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. 

S Omura, H Tomoda, H Kumagai, MD Greenspan, JB Yodkovitz, JS Chen, AW Albert, I Martin, S Mochales, RL Monaghan, JC Chabala, RE Schwartz, AA Pat-chett. Potent inhibitory effect of antibiotic 1233A on cholesterol biosynthesis which specifically blocks 3-hydroxy-3-methylglutaryl coenzyme A synthase. J Antibiot 40 1356-1357, 1987. 

H Tomoda, H Kumagai, H Tanaka, S Omura. F-244 specifically inhibits 3-hydroxy-3-methylglutaryl coenzyme A synthase. Biochim Biophys Acta 922 351-356, 1987. 

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. 

Gil G., Brown M. S. and Goldstein J. L. (1986) Cytoplsamic 3-hydroxy-3-methylglutaryl coenzyme A synthase from the hamster. J. Biol. Chem. 261, 3717-3724. 

Keller G. A., Pazirandeh M. and Krisans S. (1986) 3-Hydroxy-3-methylglutaryl coenzyme A reductase localization in rat liver peroxisomes and microsomes of control and cholestyramine-treated animals quantitative biochemical and immunoelectron microscopical analyses. J. Cell Biol. 103, 875-886. 

Sit, S., Parker, R., Motoe, I., Balsubramanian, H., Cott, C., Brown, P., Harte, W.,Thompson, M., and Wright, J. 1990. Synthesis, biological profile, and quantitative structure-activity relationship of a series of novel 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors./. Med. Chem., 33,2982-2999. 

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