Enzyme HMG-CoA reductase

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. 

This cholesterol formation reaction is catalyzed by the enzyme HMG-CoA reductase. One means to stop or reduce the production of cholesterol is to interfere with the supply of mevalonate. This is the function of Lipitor, which acts as an inhibitor of HMG-CoA reductase. 

Competitive blocker of a-adrenergic receptors in heart and blood vessels Inhibits the enzyme HMG-CoA reductase and reduces the biosynthesis of cholesterol Acts as an angiotensin II receptor antagonist Inhibits the synthesis of prostaglandins via the selective inhibition of the enzyme cyclooxygenase-2... 

The protein p21 can be induced by p53-independent factors, including drugs known as statins. These drugs are used to lower blood cholesterol by inhibition of its synthesis, via the enzyme HMG-CoA reductase. It is not known how statins affect the p21 protein. 

The subsequent conversion of HMG-CoA into MVA involves a two-step reduction of the thioester group to a primary alcohol (see Section 7.11), and provides an essentially irreversible and rate-limiting transformation. Drug-mediated inhibition of this enzyme, HMG-CoA reductase (HMGR), can be used to regulate the biosynthesis of the steroid cholesterol. High levels of blood cholesterol are known to contribute to the incidence of coronary heart disease and heart attacks. 

Conversion of HMG CoA to mevalonic acid is catalyzed by the key regulatory enzyme, HMG CoA reductase. 

The introduction of the fungal metabolite lovastatin (26-9) has led to a sizeable class of clinically effective cholesterol lowering drugs. These agents, known familiarly as the statins, block an enzyme, HMG-CoA reductase, that is involved in the synthesis of mevalonate, an early precursor of cholesterol. Extensive work has... 

Research on the pathway of cholesterol biosynthesis led to the development of a new class of drugs called statins. All statins, including atorvastatin (Lipitor, 2.22) and rosuvastatin (Crestor, 2.23), are inhibitors of the enzyme HMG-CoA reductase (Figure 2.6). Structurally, the acid side chain found on statin drugs closely resembles mevalonic acid (2.18). The side chain plays an important role in the binding of statins to HMG-CoA reductase. 

The first two steps in cholesterol biosynthesis from acetyl-CoA are identical to those of ketone body formation (Figure 19.10). The difference is that ketone bodies are formed in the mitochondria, whereas cholesterol synthesis initially takes place in the ER. A thiolase catalyzes the condensation of two acetyl-CoA molecules to acetoacetyl-CoA, and the combination of a third acetyl-CoA with acetoacetyl-CoA to form /8-hydroxymethylglutaryl-CoA (HMG-CoA) is catalyzed by HMG-CoA synthase. Although HMG-CoA is split into acetoacetate and acetyl-CoA in the mitochondria, in cholesterol biosynthesis, HMG-CoA is reduced by a microsomal enzyme, HMG-CoA reductase, to mevalonate (see Figure 19.17). The reducing agent is NADPH. 

The other system controlling cholesterol biosynthesis involves both the cytosolic HMG-CoA synthase and the ER enzyme HMG-CoA reductase and is based on the cellular levels of respective mRNAs. Increasing free cholesterol decreases both enzyme activities by decreasing the levels of their mRNAs and increasing enzyme degradation processes. The half-life of HMG-CoA reductase may be as short as 1.7 h. Cellular uptake of LDL maintains cholesterol biosynthesis at a relatively low level, and this is achieved through an LDL degradation product-free cholesterol. Some authorities have maintained that hydroxylated... 

The rate-limiting step for cholesterol synthesis is the production of mevalonate from 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) by the enzyme HMG-CoA reductase. Cholesterol synthesised in the hep-atocyte can be further metabolised by lecithin cholesterol acyl transferase (LCAT) to cholesterol ester, which is packaged into lipoproteins and secreted into the bloodstream. Alternatively, it can be excreted via the biliary system either as a neutral lipid or following conversion to bile acids. 

The IBP and its products are displayed in Figure 12.1. HMG-CoA, ultimately derived from acetyl-CoA is converted to mevalonate via the enzyme HMG-CoA reductase (HMGR) [8]. This reaction is the rate-limiting step in the pathway. Mevalonate is then phosphorylated via mevalonate kinase (MK) to yield 5-phosphomevalonate [9]. IPP is formed following additional phosphorylation and decarboxylation steps [10]. Isomerization of IPP via the enzyme IPP isomerase yields DMAPP [11]. In mammals, the enzyme farnesyl pyrophosphate synthase (FDPS) catalyzes the synthesis of both GPP and FPP [12]. In plants, a separate GPP synthase has been identified [13]. GPP is a key intermediate in plants as it serves as the precursor for all monoterpenes. In animals, however, GPP appears to serve only as an intermediate in the synthesis of FPP. Very low basal levels of GPP have been measured in cell culture, although cellular GPP levels can become markedly increased in the setting of FDPS inhibition [14]. 

Qureshi (168) first isolated tocotrienols from barley and proved that they could suppress the hepatic production of cholesterol through their ability to suppress the activity of the enzyme HMG-CoA reductase, which regulates cholesterol synthesis in the liver. 

Three drugs, lovastatin. simvastatin, and pravastatin, cont-pn.se the list of approved HMG-CoA reductase inhihi(o l ol the treatment of hyperlipidemia in patients. The three dnipr have structures similar to the substrate. HMG-CoA. of ihr enzyme HMG-CoA reductase. Lovastatin and simvastatin arc lactones and pnxlrugs. activated by hydrnlysis in lb liver lo their respective )8-hydroxy acids. Pniva.slalin. in coti-irasl. is administered as the. stxlium salt of (he jS-hydroxv acid. 

Cytosolic HMG CoA is a key intermediate in cholesterol biosynthesis. In the endoplasmic reticulum, it is reduced to mevalonic acid by the regulatory enzyme HMG CoA reductase. 

D. In the synthesis of cholesterol, but not of ketone bodies, HMG CoA is reduced by NADPH + H+ to mevalonic add. The enzyme, HMG CoA reductase, is highly regulated (it is inhibited by cholesterol and bile salts and induced by insulin). Mevalonic acid is converted to isopentenyl pyrophosphate, which provides isoprenoid units for the synthesis of cholesterol and its derivatives and for many other compounds. 

Liver enzymes HMG-CoA reductase inhibitors have been associated with biochemical abnormalities of liver function. These abnormalities usually occurred within the first six months of treatment, usually resolved after discontinuation of the drug, and were not associated with cholestasis. 

Various experiments on animals and humans had shown that cholesterol could either be absorbed from the diet, or if the diet was lacking sufficient cholesterol to meet the body s needs, then it could be synthesized. Cholesterol production within the body is controlled by a feedback mechanism in which cholesterol inhibited the enzyme HMG CoA reductase, an enzyme discovered in 1959 by Feodor Lynen et al. (Figure 1.36) at the Max Planck Institute (Munich).24 ... 

The search for a suitable compound took 2 years and involved more than 6,000 microbes. The second mould shown to inhibit Upid synthesis was Penicillium citrinum. The active compound from P. citrinum was ML-236B (Mevastatin) capable of inhibiting Upid synthesis from either C-HMG CoA, or " C-acetate. However, there was no inhibitory effect on Upid production from H-labeled mevalonate. From this, it was possible to deduce that mevastatin did, in fact, inhibit the enzyme HMG CoA reductase. Two moulds were found to meet the requirements. Firstly Pythium ulti-mum was found to produce a substance caUed citrinin that was shown to irreversibly inhibit HMG CoA reductase. 

FIGURE 6.7 The natural compounds compactin (mevastatin) and lovastatin block the cholesterol biosynthesis in inhibiting the enzyme HMG-CoA reductase. The later developed compounds simvastatin and pravastatin are semi-synthetic analogs. The open-ring derivative pravastatin is less lipophilic and therefore presents less central side effects. For all these compounds the ring-opened form is the actual active form in vivo. 

Lovastatin is a member of a class of drugs (atorvastatin and simvastatin are others in this class) called statins that are used to treat hypercholesterolemia. The statins act as competitive inhibitors of the enzyme HMG-CoA reductase. These molecules mimic the structure of the normal substrate of the enzyme (HMG-CoA) and act as transition state analogues. While the statins are bound to the enzyme, HMG-CoA cannot be converted to mevalonic acid, thus inhibiting the whole cholesterol biosynthetic process. Recent studies indicate that there may be important secondary effects of statin therapy because some of the medical benefits of statins are too rapid to be a result of decreasing atherosclerotic lesions. Statin therapy has been associated with reduced risks of dementia, Alzheimer disease, ischemic cerebral stroke, and other diseases that are not correlated with high cholesterol levels. Although this is still an active area of research, it appears that the pleiotropic effects of statins may be a result of a reduction in the synthesis of isoprenoid intermediates that are formed in the pathway of cholesterol biosynthesis. 

Figure 2. The mevalonic acid biosynthetic pathway. The transformation of hy-droxymethyl-coenzyme A (HMG-CoA) to mevalonic acid is the first committed step of the pathway. The enzyme, HMG-CoA reductase, catalyzes this step and is inhibited by the compounds, mevinolin and compactin. Note that farnesyl-pyrophosphate (Farnesyl-PP), the substrate of the protein, farnesyltransferase, can be used to make cholesterol or elongated to make geranylgeranyl-pyrophosphate (Geranylgeranyl-PP). The later compound is the substrate for the protein, geranylgeranyltransferase, or is further elongated to make the long-chain isoprenoids, dolichols, ubiquinones, and isoprenoic acids.

A class of pharmaceuticals called the statins inhibit the enzyme HMG-CoA reductase. What is the primary effect of this drug on patients ... 

Atorvastatin (Lipitor) Antilipidemic agent Inhibits the enzyme HMG-CoA reductase and reduces the biosynthesis of cholesterol... 

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 ... 

Statins work by reducing the endogenous synthesis of cholesterol in the liver through the inhibition of an enzyme, HMG-CoA reductase (3-hydroxy-3-methylglutaryl-CoA, if you must know). As a result, more DDLs are taken up from the circulation by the liver to provide the cholesterol needed to synthesize bile acids. An example of a statin is atorvastatin and others have similar names. 

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