3-Hydroxy-3-methyl-glutaryl

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. 

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... 

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).

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... 

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...

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). 

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

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]. 

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. 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.)... 

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.

Figure 20-5. Biochemical pathway for ketogene-sis. Condensation of three molecules of acetyl-CoA results in synthesis of 3-hydroxy-3-methyl-glutaryl (HMG)-CoA and release of free CoA-SH, which is then available for continued P-oxidation. Deficiency of HMG-CoA lyase results in the inability to cleave the HMG-CoA to form acetoacetate (the initial ketone body ) and its reduction product P-hydroxybutyrate.

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)... 

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. 

HMG-CoA 3 -Hydroxy-3 -methyl-glutaryl-Co A kobs Observed rate constant... 

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. 

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). 

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