S-3-Hydroxy-3-methylglutaryl-CoA

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]. 

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. 

Ohashi, K., Osuga, J., Tozawa, R., Kitamine, T., Yagyu, H., Sekiya, M., Tomita, S., Okazaki, H., Tamura, Y., Yahagi, N., lizuka, Y., Harada, K., et al. (2003). Early embryonic lethality caused by targeted disruption of the 3-hydroxy-3-methylglutaryl-CoA reductase gene. J Biol Chem 278 42936 2941. 

Dale, S., Arro, M., Becerra, B., Morrice, N.G., Boronat, A., Hardie, D.G. and Ferrer A. (1995) Bacterial expression of the catalytic domain of 3-hydroxy-3-methylglutaryl-CoA reductase (isoform hmgrl) from Arabidopsis thaliana and its inactivation by phosphorylation at ser577 by Brassica oleracea 3-hydroxy-3-methylglutaryl-CoA reductase kinase. Bur.. Biochem., 233,506-13. 

Denbow, C.J., Lang, S. and Cramer, C.L. (1996) The N terminal domain of tomato 3-hydroxy-3-methylglutaryl-CoA reductases sequence, microsomal targeting and glycosylation. /. Biol. Chem., 271, 9710-5. 

MacKintosh, R.W., Davies, S.P., Clarke, PR., Weekes, J., Gillespie, J.G., Gibb, B.J. and Hardie, D.G. (1992) Evidence for a protein kinase cascade in higher plants 3-hydroxy-3-methylglutaryl-CoA reductase kinase. Eur. ]. Biochem., 209,923-31. 

Wettstein, A., Caelles, C., Boronat, A., Jenke, H.-S. and Bach, T.J. (1989) Molecular cloning and characterization of a cDNA encoding radish 3-hydroxy-3-methylglutaryl-CoA reductase. Biol. Chem. Hoppe Seyler, 370,806-7. 

Simunovic V, Zapp J, Rachid S, Krug D, Meiser P, Muller R. Myxovirescin A biosynthesis is directed by hybrid polyketide synthases/nonribosomal peptide synthetase, 3-hydroxy-3-methylglutaryl-CoA synthases, and trans-acting acyltransferases. ChemBioChem. 2006 7 1206-1220. 

Theisen ML, Misra I, Saadat D, Campobasso N, Miziorko HM, Harrison DHT. 3-Hydroxy-3-methylglutaryl-CoA synthase intermediate complex observed in real-time . Proc. Natl. Acad. Sci. U.S.A. 2004 101 16442-16447. 

Dilaveris P, Giannopoulos G, Riga M, Synetos A, Stefanadis C (2007) Beneficial effects of statins on endothelial dysfunction and vascular stiffness. Curr Vase Pharmacol 5 227-237 Hernandez-Perera O, Perez-Sala D, Navarro-Antolin J, Sanchez-Pascuala R, Hernandez G, Diaz C, Lamas S (1998) Effects of the 3 -hydroxy- 3 -methylglutaryl-CoA reductase inhibitors, atorvastatin and simvastatin, on the expression of endothelin-1 and endothelial nitric oxide synthase in vascular endothelial cells. J Clin Invest 101 2711-2719... 

Sato R, Goldstein JL, Brown MS (1993) Replacement of serine-871 of hamster 3 -hydroxy-3 -methylglutaryl-CoA reductase prevents phosphorylation by AMP-activated kinase and blocks inhibition of sterol synthesis induced by ATP depletion. Proc Natl Acad Sci U S A 90(20) 9261-9265... 

Ketone body formation, which occurs within the matrix of liver mitochondria, begins with the condensation of two acetyl-CoAs to form acetoacetyl-CoA. Then acetoacetyl-CoA condenses with another acetyl-CoA to form /3-hydroxy-/3-methylglutaryl-CoA (HMG-CoA). In the next reaction, HMG-CoA is cleaved to form acetoacetate and acetyl-CoA. Acetoacetate is then reduced to form /3-hydroxybutyrate. Acetone is formed by the spontaneous decarboxylation of acetoacetate when the latter molecule s concentration is high. (This condition, referred to as ketosis, occurs in uncontrolled diabetes, a metabolic disease discussed in Special Interest Box 16.3, and during starvation. In both of these conditions there is a heavy reliance on fat stores and /3-oxidation of fatty acids to supply energy.)... 

Configurational analysis at C-4 of the (35)-[4- H. H]-3-hydroxy-3-methylglutaryl-CoA first involved chemical reduction to the corresponding mevalonates. The configuration at C-2 of the labeled mevalonates was established by conversion to androst-l,4-diene-3,l7-dione (using a preparation of rat liver and a strain of Mycobacterium phlei), independently determined to involve loss of the pro-(S) hydrogen at C2 of mevalonate (206). 

During the past decade, the most important development in the field of fungal natural products may have been the discovery and successful commercialization of HMG-CoA reductase (3-hydroxy-3-methylglutaryl CoA reductase) inhibitors. Their huge success in the pharmaceutical market reflects the fact that coronary heart disease has become one of the top killers in the industrialized nations (in the U.S. alone, more than 600,000 people die of heart disease each year) [25]. Hypercholesterolemia has been identified as an important cause for this disease. In the cholesterol biosynthetic pathway, HMG-CoA reductase is a rate-limiting... 

Ball, K.L. Dale, S. Weekes, J. Hardie, D.G. Biochemical characterization of two forms of 3-hydroxy-3-methylglutaryl-CoA reductase kinase from cauliflower (Brassica oleracia). Eur. J. Biochem., 219, 743-750 (1994)... 

Schmitt F, Ryan M, Cooper G (2007) A brief review of the pharmacologic and therapeutic aspects of memantine in Alzheimer s disease. Expert Opin Drug Metab Toxicol 3 135-141 Schuster S, Nadjar A, Guo JT, Li Q, Ittrich C, Hengerer B, Bezard E (2008) The 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor lovastatin reduces severity of L-DOPA-induced abnormal involuntary movements in experimental Parkinson s disease. J Neurosci 28 4311-4316... 

Koitabashi Y, Kumai T, Matsumoto N, Watanabe M, Sekine S, Yanagida Y, Kobaya i. Orange juice increased the bioavaUability of pravastatin, 3-hydroxy-3-methylglutaryl CoA reductase inhibitor, in rats and healthy human subjects. Life Sci (2006) 78,2852-9. 

Thumelin, S., Forestier, M, Girard, J. Pegorier, J-P. (1992) Biochem. J. 292,493-496. Developmental changes in mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase gene expression in rat liver, intestine and kidney. 

Note three features of this reaction. First, the creation of the new stereocenter is stereoselective Only the S enantiomer is formed. Although the acetyl group of each reactant is achiral, their condensation takes place in a chiral environment created by the enzyme 3-hydroxy-3-methylglutaryl-CoA synthetase. Second, hydrolysis of the thioester group of... 

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