3-Hydroxy-3-methylglutaryl-CoA synthase HMG

The terpenes, carotenoids, steroids, and many other compounds arise in a direct way from the prenyl group of isopentenyl diphosphate (Fig. 22-1).16a Biosynthesis of this five-carbon branched unit from mevalonate has been discussed previously (Chapter 17, Fig. 17-19) and is briefly recapitulated in Fig. 22-1. Distinct isoenzymes of 3-hydroxy-3-methylglutaryl-CoA synthase (HMG-CoA synthase) in the liver produce HMG-CoA destined for formation of ketone bodies (Eq. 17-5) or mevalonate.7 8 A similar cytosolic enzyme is active in plants which, collectively, make more than 30,000 different isoprenoid compounds.910 However, many of these are formed by an alternative pathway that does not utilize mevalonate but starts with a thiamin diphosphate-dependent condensation of glyceraldehyde 3-phosphate with pyruvate (Figs. 22-1,22-2). 

Finally, the enzyme 3-hydroxy-3-methylglutaryl-CoA synthase (HMG-CoA synthase) adds a third acetyl-CoA. 

Such a condensation is mediated by the enzyme 3-hydroxy-3-methylglutaryl-CoA synthase (HMGS). The mechanism of this catalysis is outlined in Figure 1.21. An initial frani-thioesterase step transfers the acetyl group of the first acetyl-CoA to an enzymatic cysteine. In the Claisen condensation phase of the reaction, the a-carbon of a second acetyl-CoA is deprotonated, forming an enolate. The enolate carbon attacks the electrophilic thioester carbon, forming a tetrahedral intermediate which quickly collapses to expel the cysteine thiol [22]. 

Cytosolic 3-hydroxy-3-methylglutaryl-CoA synthase produces the 3-hydroxy-3-methylglutaryl-CoA for cholesterol synthesis, and mitochondrial HMG-CoA synthase produces the HMG-CoA, which is converted to acetoacetate. 

Ipl3-pl2 20.94 HMGCS2 3 -Hydroxy- 3 -methylglutaryl-CoA synthase 2 (mitochondrial) 600234 HMG-CoA synthase-2 deficiency... 

Step B of Figure 27.7 Aldol Condensation Acetoacetyl CoA next undergoes an aldol-like addition of an acetyl CoA enolate ion in a reaction catalyzed by 3-hydroxy-3-methylglutaryl-CoA synthase. The reaction occurs by initial binding of the substrate to a cysteine SH group in the enzyme, followed by enolate-ion addition and subsequent hydrolysis to give (3S)-3-hydroxy-3-methylglutaryl CoA (HMG-CoA). 

The ketone bodies (acetoacetate, 3-hydroxybutyrate, and acetone) are formed in hepatic mitochondria when there is a high rate of fatty acid oxidation. The pathway of ketogenesis involves synthesis and breakdown of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) by two key enzymes, HMG-CoA synthase and HMG-GoA lyase. 

Other Claisen condensations are involved in synthesis of fatty acids and polyketides217 (Chapter 21) and in formation of 3-hydroxy-3-methylglutaryl-CoA, the precursor to the polyprenyl family of compounds (Chapter 22). In these cases the acetyl group of acetyl-CoA is transferred by a simple displacement mechanism onto an -SH group at the active site of the synthase to form an acetyl-enzyme.218 219 The acetyl-enzyme is the actual reactant in step b of Eq. 17-5 where this reaction, as well as that of HMG-CoA lyase, is illustrated. 

The sequence of cholesterol biosynthesis begins with a condensation in the cytosol of two molecules of acetyl-CoA in a reaction catalyzed by thiolase (fig. 20.3). The next step requires the enzyme /3-hydroxy-/3-methylglutaryl-CoA (HMG-CoA) synthase. This enzyme catalyzes the condensation of a third acetyl-CoA with /3-ketobutyryl-CoA to yield HMG-CoA. HMG-CoA is then reduced to mevalonate by HMG-CoA reductase. The activity of this reductase is primarily responsible for control of the rate of cholesterol biosynthesis. 

In the initial reactions of the biosynthetic pathway, 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) is formed from acetyl-CoA by the action of thiolase and HMG-CoA synthase in the cytosol of the liver cell. 

Acetoacetate is formed from acetyl CoA in three steps (Figure 22.19). Two molecules of acetyl CoA condense to form acetoacetyl CoA. This reaction, which is catalyzed hy thiolase, is the reverse of the thiolysis step in the oxidation of fatty acids. Acetoacetyl CoA then reacts with acetyl CoA and water to give 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) and CoA. This condensation resembles the one catalyzed by citrate synthase (Section 17.13). This reaction, which has a favorable equilibrium owing to the hydrolysis of a thioester linkage, compensates for the unfavorable equilibrium in the formation of acetoacetyl CoA. 3-Hydroxy-3-methylglutaryl CoA is then cleaved to acetyl CoA and acetoacetate. The sum of these reactions is... 

Fig. 117.9 An overview of the cytosolic mevalonate pathway and plastidial mevalonate-independent pathway for the biosynthesis of terpenoids (isoprenoids) in plant cells [99] (DMAPP, dimethylallyl diphosphate DXP, l-deoxy-D-xylulose-5-phosphate DXS, DXP synthase DXR, DXP reductoisomerase MEP, 2-C-methyl-D-erythritol 4-phosphate GASP, gfyc-eraldehyde-3-phosphate HMG-CoA, 3-hydroxy-3-methylglutaryl-CoA HMGR, HMGR-CoA reductase IPP, isopentenyl diphosphate. Mevinolin and fosmidomycin are inhibitors of HMGR and DXR, respectively)...

We have identified the mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase gene as a PPAR target, and we have found that this reeeptor, which mediates the induction of the gene by fatty acids, binds as a PPAR-RXR heterodimer to a... 

Laufs U, Fata VL, Liao JK. 1997. Inhibition of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase blocks hypoxia-mediated down-regulation of endothelial nitric oxide synthase. J. Biol. Chem. 272 31725-29... 

Endres M, Laufs U, Huang ZH, Nakamura T, Huang P, et al. 1998. Stroke protection by 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors mediated by endothelial nitric oxide synthase. Proc. Natl. Acad. Sci. USA 95 8880-85... 

In the next reaction, /J-ketobutyryl-CoA condenses with another acetyl-CoA to form )3-hydroxy-/J-methylglutaryl-CoA (HMG-CoA). This reaction is catalyzed by /J-hydroxy-/J-methylglutaryl-CoA synthase (HMG-CoA synthase). 

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