Cholesterol, biosynthesis

The ultimate precursor of all the carbon atoms in cholesterol and in the other steroids that are derived from cholesterol is the acetyl group of acetyl-GoA. There are many steps in the biosynthesis of steroids. The condensation of three acetyl groups produces mevalonate, which contains six carbons. Decarboxylation of mevalonate produces the five-carbon isoprene unit frequently encountered in the structure of lipids. The involvement of isoprene imits is a key point in the biosynthesis of steroids and of many other compounds that have the generic name terpenes. Vitamins A, E, and K come from reactions involving terpenes that humans cannot carry out. That is why we must consume these vitamins in our diets vitamin D, the remaining lipid-soluble vitamin, is derived from cholesterol (Section 8.8). Isoprene units are involved in the biosynthesis of ubiquinone (coenzyme Q) and of derivatives of proteins and tRNA with specific five-carbon units attached. Isoprene units are often added to proteins to act as anchors when the protein is attached to a membrane. 

Condensation of isoprenoid units then leads to the production of squalene and, ultimately, cholesterol. Both of the isoprenoid derivatives we have met so far are required. Two further condensation reactions take place. As a result, famesyl pyrophosphate, a 15-carbon compound, is produced. Two molecules of famesyl pyrophosphate condense to form squalene, a 30-carbon compound. The reaction is catalyzed by squalene synthase, and NADPH is required for the reaction. 

How does cholesterol serve as a precursor of other steroids  

FIGURE 21.30 The synthesis of bile acids from cholesterol. 

Atherosclerosis is a condition in which arteries are blocked to a greater or lesser extent hy the deposition of cholesterol plaques, which can lead to heart attacks. The process by which the clogging of arteries occurs is complex. Both 

Two types of regulations are important. The diurnal variations in reductase activity are brought about by alterations in the amounts of the enzyme protein and, also, the reductase-specific mRNA. An increase in HMG-CoA reductase appears to be due to an increase in its synthesis while decreases are caused by a cessation of its formation. Several compounds such as oxygenated sterols (but not cholesterol itself) seem to prevent transcription of the reductase gene. Mevalonate (or products of its metabolism), in addition to inhibiting synthesis of the reductase, also appears to enhance its degradation. 

Because of the involvement of cholesterol in the aetiology of arterio-vascular disease (section 5.5.3) considerable efforts have been made to develop suitable pharmaceutical agents which could reduce its formation. Two interesting compounds which inhibit HMG-CoA reductase are natural antibiotics isolated from the moulds Penicillium spp. and Aspergillus terreus 

Isopentenyl pyrophosphate is potentially a bifunctional molecule. Its terminal vinyl group gives a nucleophilic character whereas when it isomerizes to 3,3-dimethylallyl diphosphate, the latter is electrophilic. Thus, longer-chain polyprenyls are formed by a favourable condensation of isopentenyl pyrophosphate first with dimethylallyl pyrophosphate and later with other allylic diphosphates. The initial interconversion of isopentenyl diphosphate and dimethylallyl diphosphate is promoted by an isomerase. The successive condensations yield the Cio compound geranyl diphosphate and then the C15 farnesyl diphosphate. The two molecules of famesyl diphosphate condense to form presqualene pyrophosphate which is reduced by NADPH to give the C30 open chain terpenoid squalene. The condensation reactions with IPP are a rather novel method of C-C bond formation since in the formation of other types of natural products (peptides, sugars, fatty acids, etc.) the reactions involve Claisen- or aldol-type condensations. 

The conversion of lanosterol to cholesterol involves a 19-step reaction sequence catalysed by microsomal enzymes. The exact order of the reactions has not been delineated and, indeed, there may be more than one pathway. The main features of the transformation are the removal of three methyl groups, reduction of the 24(25)-double bond and isomerization of the 8(9)-double bond to position 5 in cholesterol. 

Cholesterol balance in cells is maintained by a number of factors (Table 7.6). In fact, it has been found that uptake of lipoproteins may influence cholesterol synthesis itself via the LDL receptor mechanism described in section 5.3.5(g). 

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Animals accumulate cholesterol from then diet but are also able to biosynthesize It from acetate The pioneering work that identified the key intermediates m the com plicated pathway of cholesterol biosynthesis was carried out by Konrad Bloch (Harvard) and Feodor Lynen (Munich) corecipients of the 1964 Nobel Prize for physiology or... 

The conversion of lanosterol to cholesterol involves 19 steps and is described in the article Cholesterol Biosynthesis Lanosterol to Cholesterol on pp 377-384 in the March 2002 issue of the Journal of Chemical Education... 

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. 

Konrad Emil Bloch (1912-20001 was born in Neisse, Germany, and began his study at the Technische Hochschule in Munich. He then immigrated to the United States in 1936 and obtained his Ph.D. from Columbia University College of Physicians and Surgeons in 1938. After first serving as professor at the University of Chicago, he moved to Harvard University in 1954. He is best known for his work on cholesterol biosynthesis, for which he shared the 1964 Mobel Prize in medicine. 

Scheme 1. Sites of inhibition of cholesterol biosynthesis by Mevacor and zaragozic acid A.

Vinyloxiranes can also be converted into P-lactones (Scheme 9.30) [133, 134], Opening of 66 with Fe2(CO)9 resulted in the (7t-allyl)tricarbonyliron derivative 67 in good yield, together with a minor diastereomer (not shown). Oxidative cleavage of 67 then gave 3-lactone 68, which was used as a key intermediate in the preparation of the cholesterol biosynthesis inhibitor 1233A. 

Rate-limiting enzyme in cholesterol biosynthesis inhibition by statins results in reduction of plasma LDL-cholesterol levels. 

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. 

CYP 51 51P1 51P2 51P3 Lanosterol 14-alpha demethylase (cholesterol biosynthesis)... 

A class of cholesterol lowering drugs that inhibit 3-hydroxy-3-methylglutary 1-CoA reductase, the rate-limiting enzyme step in cholesterol biosynthesis. 

Russell DW Cholesterol biosynthesis and metabolism. Cardiovascular Drugs Therap 1992 6 103. 

A series of hypocholesteremic agents were isolated from Monascus and named monacolin J, K, and L. These polyketides were first isolated from cultures of Penicillium citrinum and they can inhibit specifically the enzyme controlling the rate of cholesterol biosynthesis. They are currently used in China in traditional and modem medicine. 

Cholesterol biosynthesis is a multistage process in general, it may be divided into three steps ... 

This reaction is irreversible and is a rate-limiting stage of the overall cholesterol biosynthesis. 

The Chemistry of Cholesterol Biosynthesis Elegant and Familiar Reactions in Nature... 

The last acyclic precursor of cholesterol biosynthesis is squalene, consisting of a linear polyalkene chain of 30 carbons. 

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... 

This potent inhibitor of cholesterol biosynthesis has been synthesized178 by one-pot esterification of the alcohol 210 with the acid chloride of 2,2-dimethylbutanoic[l-14C] acid, obtained by carbonation of the Grignard reagent prepared from 2-chloro-2-methylbutane (equation 74). Desilylation of 211 afforded [14C]simvastatin 209 in 29% radiochemical yield from 14C-labelled C02. This 14C-labelled drug was needed for elucidation of its metabolic fate in experimental animals. 

The primary action of BARs is to bind bile acids in the intestinal lumen, with a concurrent interruption of enterohepatic circulation of bile acids, which decreases the bile acid pool size and stimulates hepatic synthesis of bile acids from cholesterol. Depletion of the hepatic pool of cholesterol results in an increase in cholesterol biosynthesis and an increase in the... 

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