HMG-CoA reductase,

The biosynthesis of sterols takes place via the protracted sterol/isoprenoid biosynthetic pathway (Chapter 1). Although the major portion of the carbon flux through this pathway is normally directed into sterols, several branches exist leading to the production of other isoprenoid compounds needed by the cell, such as ubiquinone, dolichol and isopentenyl adenine. Total carbon flux is regulated through the enzymes of the early, or common, portion of the pathway of which the most important is HMG-CoA reductase. Distribution of carbon between the various end products is regulated at later stages of the pathway. 

Because of its predominant role in the regulation of sterol biosynthesis, the first portion of this section will be devoted to the regulation of HMG-CoA reductase. The second portion will review current knowledge of other control points whose importance and roles have been less extensively studied and are less well understood. 

The enzyme HMG-CoA reductase catalyzes the reductive deacylation of HMG-CoA to mevalonate by two molecules of NADPH (Chapter 1). In most tissues this can be considered the first committed step in sterol/isoprenoid biosynthesis. Under most of the physiological conditions studied, this reaction is the rate-limiting step for sterol biosynthesis [81-83]. Evidence for this includes  

HMG-CoA reductase activity has been detected in mammals, birds, insects, reptiles, fish, higher plants, moulds, yeast and bacteria [112]. HMG-CoA reductase probably is present in any life form capable of synthesizing isoprenoids. In mammals, HMG-CoA reductase activity has been detected in many tissues (Table 3). The highest quantities are present in liver and intestine, which together provide 2/3-3/4 

Manunalian tissues in which HMG-CoA reductase activity has been detected 

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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). 

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). 

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. 

HMG-CoA-Reductase-Inhibitors Peroxisome Proliferator-Activated Recqrtors (PPARs) ACE Inhibitors Antiplatelet Drugs... 

Statins lower plasma cholesterol levels by inhibiting HMG-CoA reductase in the mevalonate pathway (Fig. 4). Some research has shown that certain statins (but not all) stimulate BMP-2 expression in osteoblasts, increase bone formation and mimic N-BP in that they inhibit bone resorption. The use of statins in osteoporosis is presently being investigated. 

HMG-CoA reductase inhibitors (statins). This effect has been suggested to account for some of the side effects of statins like myositis or rhabdomyolysis. 

Peroxisome Proliferator-Activated Receptor (PPARs) HMG-CoA Reductase Inhibitors... 

HMG-CoA-Reductase Inhibitors. Figure 1 Mechanism of action of statins - cholesterol synthesis pathway. The conversion of acetyl CoA to cholesterol in the liver. The step of cholesterol biosynthesis inhibited by HMG-CoA reductase inhibitors (statins) is shown. 

HMG-COA-Reductase Inhibitors Low-Density Lipoprotein Receptor Gene Family... 

HMG-CoA-Reductase-Inhibitors Lipoprotein Metabolism Lipid Transfer Proteins... 

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