Methylglutaryl-CoA

An example is provided by the reaetion of methyl-3-([( 1, l-dimethylethyl)diphe-nylsilyl]oxy)-4-(ehloromethoxyphosphinyl)butyrate with lithium pyrazolylalky-nide, whieh is used to prepare eompounds with strueture H0P(0)(PzC=C)CH2CH (0H)CH2C02H useful as 3-hydroxyl-3-methylglutaryl CoA (HMG CoA) redue-tase inhibitors (88GEP3817298) (Seheme 76). 

As summarized in Figure 27.7, the mevalonate pathway begins with the conversion of acetate to acetyl CoA, followed by Claisen condensation to yield acetoacety) CoA. A second carbonyl condensation reaction with a third molecule of acetyl CoA, this one an aldol-like process, then yields the six-carbon compound 3-hydroxy-3-methylglutaryl CoA, which is reduced to give mevalonate. Phosphorylation, followed by loss of C02 and phosphate ion, completes the process. 

Step 2 of Figure 27.7 Aldol Condensation Acetoacetyl CoA next undergoes an aldol-like addition (Section 23.1) of an acetyl CoA enolate ion in a reaction catalyzed by 3-hydroxy-3-methylglutaryl-CoA synthase. The reaction again occurs... 

Most of the acetyl-CoA formed by 3-oxidation in liver is converted to acetoacetate by the 3-hydroxy-3-methylglutaryl-CoA pathway (Guzman and Gelen, 1993). Acetoacetate is reversibly converted to D-3-hydroxybutyrate by D-3-hy-droxybutyrate dehydrogenase in the mitochondrial matrix in all tissues. 

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. 

P-Hydroxy-P-methylglutaryl-CoA is split by hydroxymethylglutaryl-CoA lyase into acetyl-CoA and acetoacetate ... 

The initial reactions in the first step, prior to the formation of P-hydroxy-p-methylglutaryl-CoA from acetyl-CoA, resemble those involved in ketogenesis with the only distinction that ketogenesis occurs in the mitochondria, while cho-lesterol biosynthesis is carried out extramitochondrially ... 

Further, p-hydroxy-(3-methylglutaryl-CoA is converted with hydroxymethylgluta-ryl-CoA reductase to mevalonic acid ... 

Starvation elicits mobilization of triglycerides from the adipose tissue and inhibits the endogenic cholesterol synthesis owing to the low activity of hydroxy-methylglutaryl-CoA reductase. The latter process provides the possibility for the active production of ketone bodies in the liver. 

Roberts, J.R. and Miziorko, H.M. 1997. Evidence supporting a role for histidine-235 in cation binding to human 3-hydroxy-3-methylglutaryl-CoA lyase. Biochemistry 36 7594—7600. 

It has been found that the 3-hydroxy-3-methylglutaryl-CoA (HMG CoA) inhibitors statins (atorvastatin, pravastatin, and cerivastatin), widely prescribed cholesterol-lowering agents, are able to inhibit phorbol ester-stimulated superoxide formation in endothelial-intact segments of the rat aorta [64] and suppress angiotensin II-mediated free radical production [65]. Delbose et al. [66] found that statins inhibited NADPH oxidase-catalyzed PMA-induced superoxide production by monocytes. It was suggested that statins can prevent or limit the involvement of superoxide in the development of atherosclerosis. It is important that statin... 

The therapeutic class that uniquely exemplifies lactone prodrugs are the statins, i.e., the cholesterol-lowering agents that act by inhibiting 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase (EC 1.1.1.34). This microsomal enzyme catalyzes conversion of HMG-CoA to mevalonate, an important rate-limiting step in cholesterol biosynthesis. Cholesterol synthesis occurs mainly... 

Hampton, R. Y., R. G. Gardner, and J. Rine, Role of 26S proteasome and HRD genes in the degradation of 3-hydroxy-3-methylglutaryl-CoA reductase, an integral endoplasmic reticulum membrane protein. Md Biol Cell, 1996, 7(12), 2029 4. 

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... 

Three molecules of acetyl-CoA are used to form MVA, a third molecule being incorporated via a stereospecific aldol addition to give the branched-chain ester P-hydroxy-P-methylglutaryl-CoA (HMG-CoA). This third acetyl-CoA molecule appears to be bound to the enzyme via a thiol group (see Section 13.4.3), and this linkage is subsequently hydrolysed to form the free acid group of HMG-CoA. 

Formation of mevalonate. The conversion of acetyl CoA to acetoacetyl CoA and then to 3-hydroxy-3-methylglutaryl CoA (3-HMG CoA) corresponds to the biosynthetic pathway for ketone bodies (details on p. 312). In this case, however, the synthesis occurs not in the mitochondria as in ketone body synthesis, but in the smooth endoplasmic reticulum. In the next step, the 3-HMG group is cleaved from the CoA and at the same time reduced to mevalonate with the help of NADPH+H 3-HMG CoA reductase is the key enzyme in cholesterol biosynthesis. It is regulated by repression of transcription (effectors oxysterols such as cholesterol) and by interconversion... 

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