Cholesterol biosynthesis function

Ajoene has antitumor activity, inhibits cholesterol biosynthesis, modulates membrane-dependent functions of immune cells, inhibits protein prenylation83 and is an anti-leukaemia agent for acute myeloid leukaemia.85 In antithrombotic assays, the Z isomer is more active than the E isomer.84... 

As indicated in Table 1, statins, which block cholesterol biosynthesis by inhibition of hepatic HMGCoA reductase, have been used extensively to reduce LDL-C levels. At most therapeutic doses, statins marginally increase HDL levels by 5-10% [3,16]. The HDL elevation observed with statins has been highly variable and not easily extrapolated from the effects on LDL. A recent study (STELLAR) demonstrated increased HDL elevation with the use of rosuvastatin compared to simvastatin, pravastatin or atorvastatin (10% vs. 2-6%) [16,24], Although the mechanism of HDL elevation by statins is not clearly understood, it is proposed that statins enhance hepatic apoA-I synthesis [25] and decrease apoB-containing lipoproteins [26]. A number of clinical trials have demonstrated that statins reduce the risk of major coronary events. However, it is not clear if the statin-induced rise in HDL levels is an independent contributor to the reduced risk of coronary events. The observed small increase in HDL and adverse side effect profile related to liver function abnormalities and muscle toxicity limits the use of statins as monotherapy for HDL elevation [27],... 

Both the heat-stable SCP protein of Ritter and Dempsey (R2) and the heat-labile SCP protein of Scallen et al. (S2) bind other lipids (e.g., phospholipids and fatty acids) in addition to water-insoluble cholesterol and its precursors (R2, R3, R5, S2). In view of this apparent lack of specificity, Ritter and Dempsey (R5) have suggested that the carrier protein may be more generally called lipid carrier protein (LCP), although its binding to squalene and sterol carrier protein may more directly refiect its functional role in cholesterol biosynthesis. Obviously, more work is needed to clearly define both structural role and functional properties of this protein or proteins. 

R5. Ritter, M. C., and Dempsey, M, E., Squalene and sterol carrier protein. III. Structural properties, lipid binding, and functional role in cholesterol biosynthesis. Proc. Nat. Acad. Sd. U.S. 70, 265-269 (1973). 

The answer is D. This patient s tests indicate that he has severe hypercholesterolemia and high blood pressure in conjunction with atherosclerosis. The deaths of several of his family members due to heart disease before age 60 suggest a genetic component, ie, familial hypercholesterolemia. This disease results from mutations that reduce production or interfere with functions of the LDL receptor, which is responsible for uptake of LDL-cholesterol by liver cells. The LDL receptor binds and internalizes LDL-choles-terol, delivers it to early endosomes and then recycles back to the plasma membrane to pick up more ligand. Reduced synthesis of apoproteins needed for LDL assembly would tend to decrease LDL levels in the bloodstream, as would impairment of HMG CoA reductase levels, the rate-limiting step of cholesterol biosynthesis. Reduced uptake of bile salts will also decrease cholesterol levels in the blood. 

In addition to their plasma membrane eukaryotic cells also contain internal membranes that define a variety of organelles (fig. 17.2). Each of these organelles is specialized for particular functions The nucleus synthesizes nucleic acids, mitochondria oxidize carbohydrates and lipids and make ATP, chloroplasts carry out photosynthesis, the endoplasmic reticulum and the Golgi apparatus synthesize and secrete proteins, and lysosomes digest proteins. Additional membranes divide mitochondria and chloroplasts into even finer, more specialized subcompartments. Like the plasma membrane, organellar membranes act as barriers to the leakage of proteins, metabolites, and ions they contain transport systems for import and export of materials, and they are the sites of enzymatic activities as diverse as cholesterol biosynthesis and oxidative phosphorylation. 

The first "statin" was discovered by Endo and coworkers at Sankyo in Tokyo in 1976. After testing over 8,000 microbial extracts, they found a compound, named mevastatin (ML-236B) (Figure 9), from Penicillium citrinum which showed specific inhibition of HMG CoA reductase and functioned in vivo, lowering serum cholesterol levels. Further development of mevastatin was curtailed because inhibition of cholesterol biosynthesis was not restricted to the liver. The compound enters the lens and adrenals, where it blocks the essential biosynthesis of cholesterol. The same compound was also isolated by a team at the Beecham Research Laboratories in Brockham Park, Surrey. Whilst screening for antifungal activity, they isolated the compound, which they named compactin, from Pencillium brevicompactum, but apparently failed to recognise it as a potent inhibitor of HMG CoA reductase. 

Squalene and phytosterols are components present in the unsaponifiable lipid fraction of foods (as tocopherols). Squalene is an intermediary in cholesterol biosynthesis, and 33.9-58.4 mg/100 g of it was found in the lipid fraction of quinoa (Jahaniaval et al., 2000 Ryan et ah, 2007) squalene is the biochemical precursor of the whole family of steroids, and besides their effective antioxidant activity, tocotrienols have other important functions, in particular in maintaining a healthy cardiovascular system and a possible role in protection against cancer (Nesaretnam, 2008). Squalene is used as a bactericide and as an intermediate in many pharmaceuticals, organic coloring materials, rubber chemicals, and surface-active agents (Ahamed et ah, 1998). 

Cholesterol biosynthesis proceeds via the isoprenoids in a multistep pathway. The end product, cholesterol, and the intermediates of the pathway participate in diverse cellular functions. The isoprenoid units give rise to dolichol, CoQ, heme A, isopentenyl-tRNA, famesylated proteins, and vitamin D (in the presence of sunlight and 7-dehydrocholesterol). Dolichol is used in the synthesis of glycoproteins, CoQ in the mitochondrial electron transport chain, famesylation and geranylgeranylation by posttrans-lational lipid modification that is required for membrane association and function of proteins such as p2V and G-protein subunits. 

Cholesterol has several functions including involvement in membrane structure, by modulation of membrane fluidity and permeability, serving as a precursor for steroid hormone and bile acid synthesis, in the covalent modification of proteins, and formation of the central nervous system in embryonic development. The latter role of cholesterol was discovered through mutations and pharmacological agents that block cholesterol biosynthesis that occurs in six steps ... 

It is not possible to write a comprehensive review of cholesterol biosynthesis in the space allotted nor is it our desire to do so. Consequently, we have been selective as to what has been included and the list of references is far from exhaustive. We hope that no one will be offended by our choices. In addition, where appropriate, the stress has been on enzymes from Uver. There are several recent and comprehensive reviews on cholesterol biosynthesis. Two books, one by Nes and McKean [1] and another by Gibbons, Mitropoulos and Myant [2] provide excellent and current reviews on the biosynthesis and function of cholesterol. In addition, about half of the chapters in a book edited by Porter and Spurgeon [3] deal with selected aspects of the biochemistry of sterologenesis and, taken as an aggregate, provide a comprehensive review of the subject. Also Schroepfer has published recently two reviews on cholesterol biosynthesis in Annual Reviews of Biochemistry [4,5]. 

Cholesterol is primarily restricted to eukaryotic cells where it plays a number of roles. Undoubtedly, the most primitive function is as a structural component of membranes. Its metabolism to bile acids and the steroid hormones is relatively recent in the evolutionary sense. In this chapter, the pathway of cholesterol biosynthesis will be divided into segments which correspond to the chemical and biochemical divisions of this biosynthetic route. The initial part of the pathway is the 3-step conversion of acetyl-CoA to 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA). The next is the reduction of this molecule to mevalonate, considered to be the rate-controlling step in the biosynthesis of polyisoprenoids. From thence, a series of phosphorylation reactions both activate and decarboxylate mevalonate to isopen tenyl pyrophosphate, the true isoprenoid precursor. After a rearrangement to the allylic pyrophosphate, dimethylallyl pyrophosphate, a sequence of l -4 con-... 

The major rate-limiting enzyme in cholesterol biosynthesis, 3-hydroxy-3-methylglutaryl Coenzyme A reductase (HMG-CoA reductase), has been a therapeutic target for many research groups. A synthesis of the functionalized thiophene 172, prepared for its biological activity, illustrates the utility of 162 for the introduction of one of the hydroxy chiral centers present in the molecule. This chiral center is then exploited for the introduction of the second chiral hydroxy center. Treatment of aldehyde 169 with the double anion of 162 at —95 °C in THF affords as the major product 170 (98.8 1.2). Treatment of the adduct with excess tert-butylacetate enolate at — 78 °C followed by acidic work-up furnishes the jS-hydroxyketone 171 in 86% isolated yield. Chelation-controlled reduction of the ketone, accomplished by initial complexation of the ketone and the hydroxy group with triethylborane followed by sodium borohydride addition, provides the desired dihydroxyester 172 (Scheme 39) [47]. 

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