Cholesterol oxides biosynthesis

The Opening of Squalene-2,3-Epoxide Steroids are tetracyclic compounds that serve a wide variety of biological functions, including hormones (sex hormones), emulsifiers (bile acids), and membrane components (cholesterol). The biosynthesis of steroids is believed to involve an acid-catalyzed opening of squalene-2,3-epoxide (Figure 14-6). Squalene is a member of the class of natural products called terpenes (see Section 25-8). The enzyme squalene epoxidase oxidizes squalene to the epoxide,... 

See also Fatty Acid Oxidation, Biosynthesis of Cholesterol (from Chapter 19), Ketogenesis, Figure 18.21... 

Squalene is also an intermediate in the synthesis of cholesterol. StmcturaHy, chemically, and biogeneticaHy, many of the triterpenes have much in common with steroids (203). It has been verified experimentally that squalene is the precursor in the biosynthesis of all triterpenes through a series of cyclization and rearrangement reactions (203,204). Squalene is not used much in cosmetics and perfumery formulations because of its light, heat, and oxidative instabiUty however, its hydrogenated derivative, squalane, has a wide use as a fixative, a skin lubricant, and a carrier of Hpid-soluble dmgs. 

Ascorbic acid is involved in carnitine biosynthesis. Carnitine (y-amino-P-hydroxybutyric acid, trimethylbetaine) (30) is a component of heart muscle, skeletal tissue, Uver and other tissues. It is involved in the transport of fatty acids into mitochondria, where they are oxidized to provide energy for the ceU and animal. It is synthesized in animals from lysine and methionine by two hydroxylases, both containing ferrous iron and L-ascorbic acid. Ascorbic acid donates electrons to the enzymes involved in the metabohsm of L-tyrosine, cholesterol, and histamine (128). 

The most important oxirane, from an anthropocentric viewpoint, is probably squalene oxide (72), a precursor of lanosterol (73) and thus of the maligned but essential cholesterol (74 Scheme 87) 78MI50501). The cyclization of (72) to (73) represents nucleophilic tr-attack on oxirane carbon cf. Section 5.05.3.4.3(t)()), and the process has also been extensively investigated in vitro (68ACR1). Oxiranes are even more ubiquitous in steroid biosynthesis than had been thought, for a cholesterol epoxide has been shown to be a product of mammalian steroid biosynthesis <81JA6974). 

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. 

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. 

CYP27A1 catalyzes the side chain oxidation (27-hydroxylation) in bile acid biosynthesis. Because bile acid synthesis is the only elimination pathway for cholesterol, mutations in the CYP27A1 gene lead to abnormal deposition of cholesterol and cholestanol in various tissues. This sterol storage disorder is known as cerebrotendinous xanthomatosis. CYP27B1 is the 1-alpha hydroxylase of vitamin D3 that converts it to the active vitamin form. The function of CYP27C1 is not yet known. 

Chloropentammine Ir (HI) complex, incomplete Ir (III) autoreduction, 39 151-152 Chloroplasts, quantum conversion in, 14 1 1 -Chloroprop-2-ene thermal decomposition, 41 80 Chlorpromazine, reactivity with EDA complexes, 20 333, 336 CH O, 32 374-375 CH3OH, oxidation, 38 21-23 Cholestenone, hydrogenation, 25 57, 58 Cholesterol, biosynthesis of, 25 382 Cholinesterases, stracture of active surface, 10 130... 

By far the most impressive example of electrophilic addition in natural prodnct formation is in the biosynthesis of steroids. The snbstrate sqnalene oxide is cyclized to lanosterol in a process catalysed by a single enzyme. Lanosterol is then converted into the primary animal-steroid cholesterol. Sqnalene oxide comes from sqnalene, which is itself formed throngh a combination of two molecules of farnesyl diphosphate. 

The cyclization of epoxyolefins has been the subject of intense study ever since the discovery that these reactions are involved in the biosynthesis of many terpenes, including cholesterol. An early example is the cyclization of geraniolene oxide 25 using BF3Et20 to give a mixture of acyclic and cyclic products (Scheme 6) [57,58]. 

Figure 9-4. Metabolism of the branched-chain amino acids. The first two reactions, transamination and oxidative decarboxylation, are catalyzed by the same enzyme in all cases. Details are provided only for isoleucine. Further metabolism of isoleucine and valine follows a common pathway to propionyl CoA. Subsequent steps in the leucine degradative pathway diverge to yield acetoacetate. An intermediate in the pathway is 3-hydroxy-3-methylglutaryl CoA (HMG-CoA), which is a precursor for cytosolic cholesterol biosynthesis.

For a synthesis of the anti-cancer drug taxol TPAP/NMO was used in three steps, two for oxidation of primary alcohols to aldehydes (by TPAP/NMO/PMS/ CHjClj) and one for a secondary alcohol to ketone (by TPAP/NMO/PMS/CHjClj-CHjCN) [66], cf. also [111] and for the SERCA inhibitor thapsigargin (two primary alcohol and one secondary alcohol oxidation steps) [112], This system was also used during synthesis of the cholesterol biosynthesis inhibitor 1233A [52], the antibiotic and anti-parasitic ionophore tetronasin [113, 114] and for the cytotoxic sponge alkaloids motopuramines A and B [115]. 

The potential role of the RIA technique in the analysis of BAs was investigated some time ago in a study about the development of a method for the detection of 3/I-hy-droxy-5-cholenoic acid [41]. This technique was considered by the authors to be important in the evaluation of oxidation of the cholesterol side chain, a minor pathway of BA biosynthesis. 3/THydroxy-5-cholenoic acid was found in human meconium [42] and in amniotic fluid [43], suggesting an important role in foetal life. In healthy subjects this compound was found in urine [44] but not in serum [45]. The kidney probably excretes it and its serum concentration is too low to be detected. The aim of this report was to provide a new method for the investigation of the role of 3/T hydroxy-5-cholenoic acid in cholestatic disease. 

The reducing equivalents temporarily stored in N AD(P)H are utilized in a number of ways, all of which lead to biosynthesis of essential molecules and/or oxidative degradation of metabolites. Examples range from the simple reduction of a substrate for biosynthetic purposes (e.g. the steroid reductase mediated hydrogenation of the isolated double bond of desmosterol to give cholesterol, Table 1) (71MI11000) to complex electron transport chains that are switched on by the transfer of the electrons of N AD(P)H to the next electron carrier of the chain. These multienzyme systems are used for a number of purposes (see below). 

Most animal steroids arise from cholesterol, which in turn is derived from squalene. This C30 triterpene, whose biosynthesis is described in Section B, is named after the dogfish Squalus in whose liver it accumulates as a result of blockage in oxidation to cholesterol. Squalene is also a prominent constituent of human skin lipids. Its conversion to cholesterol, which takes place in most animal tissues,117/154-156 is initiated by a microsomal enzyme system that utilized 02 and NAD-PH to form squalene 2,3-oxide (Fig. 22-6, step a). 

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