HMG CoA

The product of this reaction 3 hydroxy 3 methylglutaryl coenzyme A (HMG CoA) has the carbon skeleton of mevalonic acid and is converted to it by enzymatic reduction... 

The primary transporter of cholesterol in the blood is low density Hpoprotein (LDL). Once transported intraceUularly, cholesterol homeostasis is controlled primarily by suppressing cholesterol synthesis through inhibition of P-hydroxy-P-methyl gluterate-coenzyme A (HMG—CoA) reductase, acyl CoA—acyl transferase (ACAT), and down-regulation of LDL receptors. An important dmg in the regulation of cholesterol metaboHsm is lovastatin, also known as mevinolin, MK-803, and Mevacor, which is an HMG—CoA reductase inhibitor (Table 5). 

Ketone body synthesis occurs only in the mitochondrial matrix. The reactions responsible for the formation of ketone bodies are shown in Figure 24.28. The first reaction—the condensation of two molecules of acetyl-CoA to form acetoacetyl-CoA—is catalyzed by thiolase, which is also known as acetoacetyl-CoA thiolase or acetyl-CoA acetyltransferase. This is the same enzyme that carries out the thiolase reaction in /3-oxidation, but here it runs in reverse. The second reaction adds another molecule of acetyl-CoA to give (i-hydroxy-(i-methyl-glutaryl-CoA, commonly abbreviated HMG-CoA. These two mitochondrial matrix reactions are analogous to the first two steps in cholesterol biosynthesis, a cytosolic process, as we shall see in Chapter 25. HMG-CoA is converted to acetoacetate and acetyl-CoA by the action of HMG-CoA lyase in a mixed aldol-Claisen ester cleavage reaction. This reaction is mechanistically similar to the reverse of the citrate synthase reaction in the TCA cycle. A membrane-bound enzyme, /3-hydroxybutyrate dehydrogenase, then can reduce acetoacetate to /3-hydroxybutyrate. 

Degradation of HMG-CoA reductase. This enzyme has a half-life of only three hours, and the half-life itself depends on cholesterol levels high [cholesterol] means a short half-life for HMG-CoA reductase. 

FIGURE 25.33 HMG-CoA reductase activity is modulated by a cycle of phosphorylation and dephosphorylation. 

Lovastatin is administered as an inactive lactone. After oral ingestion, it is hydrolyzed to the active mevinolinic acid, a competitive inhibitor of the reductase with a Ki of 0.6 nM. Mevinolinic acid is thought to behave as a transition-state analog (Chapter 16) of the tetrahedral intermediate formed in the HMG-CoA reductase reaction (see figure). 

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). 

In Scheme 10, HMG-CoA reductase inhibitor 92 was synthesized via a Suzuki coupling approach. Hiyama s group also carried out a Hiyama coupling to make the same compound (93TL8263). Vinylsilane 119 was prepared by platinum-catalyzed reaction from terminal alkyne 89. 

The search for inhibitors of this pathway began with the first key regulatory enzyme, HMG CoA reductase. Several clinically useful inhibitors of HMG CoA reductase are now known. One of the most successful, Mevacor, produced by Merck, is one of the pharmaceutical industry s best selling products. However, the problem with inhibiting a branched biosynthetic pathway at an early point is that the biosynthesis of other crucial biomolecules may also be inhibited. Indeed, there is some evidence that levels of ubiquinone and the dolichols are affected by some HMG CoA reductase inhibitors. Consequently, efforts have recently been directed towards finding inhibitors of squalene synthase, the enzyme controlling the first step on the route to cholesterol after the FPP branch point. 

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