3- hydroxy-3-methyl-glutaryl-CoA

Isoprenoids or terpenoids are a large class of naturally occurring organic compounds with tremendous chemical and structural diversity. They are organic materials produced in the HMG-CoA (3-hydroxy-3-methyl-glutaryl-CoA) reductase pathway... 

Bok, S.H., Lee, S.H., Park, Y.B., Bae, K.H., Son, K.H., Jeong, T.S., and Choi, M.S., Plasma and hepatic cholesterol and hepatic activities of 3-hydroxy-3-methyl-glutaryl-CoA reductase and acyl CoA cholesterol transferase are lower in rats fed citrus peel extract or a mixture of citrus bioflavonoids, J. Nutr., 129, 1182, 1999. 

Hydroxy 3-methyl glutaric aciduria 3-Hydroxy 3-methyl glutaryl-CoA lyase... 

The first two reactions in the cholesterol synthetic pathway are siri lar to those in the pathway that produces ketone bodies (see Figure 16.22, p. 194). They result in the production of 3-hydroxy-3-methyl-glutaryl CoA (HMG CoA, Figure 18.3). First, two acetyl CtA molecules condense to form acetoacetyl CoA. Next, a third molecule of acetyl CoA is added, producing HMG CoA, a six-carbon compound. [Note Liver parenchymal cells contain two isoenzymes of HMG CoA synthase. The cytosolic enzyme participates in cholesterol synthesis, whereas the mitochondrial enzyme Urc tions in the pathway for ketone body synthesis.]... 

Elaborate cascades initiate the clotting of blood (Chapter 12) and the action of the protective complement system (Chapter 31). Cascades considered later in the book are involved in controlling transcription (Fig. 11-13) and in the regulation of mammalian pyruvate dehydrogenase (Eq. 17-9), 3-hydroxy-3-methyl-glutaryl-CoA reductase and eicosanoids (Chapter 21), and glutamine synthetase (Chapter 24). 

D. A. Kleinsek, R. E. Dugan, T. A. Baker, and J. W. Porter, 3-Hydroxy-3-methyl-glutaryl-CoA reductase from rat liver, Methods Enzymol. 1981, 73, 462-479. 

Pravastatin, a 3-hydroxy-3-methyl glutaryl CoA reductase inhibitor applied as a therapeutic agent for hypercholesterolemia, can be synthesized by stereo- and regioselective hydroxylation of compactin by the soil microorganism Streptomyces sp. Y-110 (Fig. 22) [152]. The fermentative production of pravastatin has already been applied on an industrial scale by Sankyo Co. using different Streptomyces bacteria strains [153, 154]. 

FIG. 1 Schematic diagram of cholesterol transport in the tissues, with sites of action of the main drug affecting lipoprotein metabolism (C = cholesterol CE = cholesteryl ester TG = triglycerides MV A = mevalonate HMG-CoA reductase = 3-hydroxy-3-methyl-glutaryl-CoA reductase YLDL = very low density lipoproteins LDL = low density lipoproteins HDL = high density lipoproteins). (Reprinted from Rang et al (1999), with permission from Elsevier Science.)... 

Mice were fed diets containing either 6% HL-SAF (normal), 4 HL-SAF + 2% CLA (lipodystrophy control), or 3.5% HL-SAF + 2% CLA + 0.5% DHA (lipodystrophy + DHA) for 4 weeks. Values are expressed as mean + standard error for six mice. Different letters show significant differences at p < 0.05. HMG, 3-hydroxy-3-methyl-glutaryl-CoA reductase, ACAT1, acyl-CoA cholesterol acyltransferase-1. 

Whereas vitamin E (99) and vitamin A or its biosynthetic precursor, p-carotene, must be obtained by animals from dietary sources, many other isoprenoids, including the quinone type coenzyme Q family (where individual representatives differ by the length of their side chains), can be synthesized de novo by vertebrates. 3-Hydroxy-3-methylglutaryl-CoA reductase, the enzyme that catalyzes the conversion of (5 )-3-hydroxy-3-methyl-glutaryl-CoA (84) to mevalonate (85), is one of the most important drug targets for the prevention of cardiovascular disease (see below) (49, 50). 

The mevalonate pathway starts with a sequence of two Claisen condensations that afford (6 )-3-hydroxy-3-methyl-glutaryl-CoA (84) from three acetyl-CoA moieties. The pathway affords IPP that can be converted into DMAPP by isomerization. The first committed intermediate of the nonmevalonate pathway is 2C-methyl-D-erythritol 4-phosphate (90) obtained from 1-deoxy-D-xylulose 5-phosphate (43), which is a compound also involved in the biosynthesis of vitamins Bi (46, cf. Fig. 4) and Be (39, cf. Fig. 5), by rearrangement and subsequent reduction. Three enzyme-catalyzed steps are required to convert the compound into the cognate cyclic diphosphate 91 that is then converted reductively into a mixture of IPP and DMAPP by the consecutive action of two iron/sulfur proteins. 

Together with y-oryzanol, tocotrienols are responsible for the cholesterol-lowering effect of rice bran oil (250). Tocotrienol concentrates have been shown to have a hypocholesterolemic effect in animals and humans (251-257) possibly because of inhibition of hepatic 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoA reductase) (251, 258, 259). The presence of a-tocopherol at concentrations >20% in tocotrienol concentrates was, however, found to attenuate the inhibitory elfect of tocotrienols on HMG-COA reductase, thereby weakening their cholesterollowering activities (254). Tocotrienols were especially found to synergize the cholesterol-lowering effect of lovastatin (254). In addition, tocotrienols have been shown to influence certain hemostatic parameters and to reduce the occurrence of chemical-induced tumors in the rat (253). 

Abbreviations FASN, fatty acid synthase ACC, acetyl-CoA-carboxylase ACL, ATP-citrate lyase NADPH, nicotinamide adenine dinucleotide phosphate MAT, malonyl acetyl transferases KS, ketoacyl synthase KR, p-ketoacyl reductase DH, p-hydroxyacyl dehydratase ER, enoyl reductase TE, thioesterase ACP, acyl carrier protein VLCFA, very long chain fatty acids ELOVL, elongation of very long chain fatty acids SCDl, stearoyl-CoA desaturase-1 AMPK, AMP-activated kinase ME, malic enzyme FASKOL, liver-specific deletion of FAS PPARa, Peroxisome Proliferator-Activating Receptor alpha HMG-CoA, 3-hydroxy-3-methyl-glutaryl-CoA SREBP, sterol response element binding protein SIP, site-one protease S2P, site-two... 

This may be accounted for by the fact that the activity of the key regulatory enzyme of sterol biosynthesis, 3-hydroxy-3-methyl-glutaryl-CoA reductase, is reduced in this yeast by C-14 methyl sterols such as lanosterol that accumulate in response to treatment with these inhibitors (44,45). 

Hydroxy-3-methyl glutaryl-CoA + 2 reduced NADP mevalonate + CoA + 2NADP... 

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