Cholesterol steroid biosynthesis from

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). 

From lanosterol, the pathway for steroid biosynthesis continues on to yield cholesterol. Cholesterol then becomes a branch point, serving as the common precursor from which all other steroids are derived. 

Cholesterol is a major constituent of the cell membranes of animal cells (see p. 216). It would be possible for the body to provide its full daily cholesterol requirement (ca. 1 g) by synthesizing it itself However, with a mixed diet, only about half of the cholesterol is derived from endogenous biosynthesis, which takes place in the intestine and skin, and mainly in the liver (about 50%). The rest is taken up from food. Most of the cholesterol is incorporated into the lipid layer of plasma membranes, or converted into bile acids (see p. 314). A very small amount of cholesterol is used for biosynthesis of the steroid hormones (see p. 376). In addition, up to 1 g cholesterol per day is released into the bile and thus excreted. 

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). 

The resolution of two high spin forms in adrenal mitochondria has been exploited in studies of the stimulation of steroid biosynthesis by ACTH and the effects of stress. Mitochondria from stressed rats showed increased amounts of high spin P-450, most notably in that corresponding to cholesterol side chain cleavage and similar but not identical effects were observed when hypophysectomised rats were treated with ACTH [118]. This supports the thesis that ACTH stimulation increases the availability of cholesterol for side chain cleavage. In adrenals, ESR can also be used to monitor the presence of reducing equivalents to P-450 as, in this case, the P-450 is linked to NADPH via an iron-sulphur protein, adrenal ferredoxin. This shows typical signals on reduction at g = 2.01, 1.94 [119]. A similar iron-sulphur protein (g = 2.03, 1.94) occurs in mammalian testes connected with a P-450 system [120]. 

Biosynthesis of steroid hormones from cholesterol. The different pathways occur to varying extent in adrenals, gonads, and placenta. The systematic names for cytochrome P-450 enzymes, namely CYP followed by a number, are given in parentheses. CYPI1B2 and CYP17 possess multiple enzyme activities. [Reproduced with permission from P. C. White and P. W. Speiser, Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Endocrine Reviews 21,245 (2000).]... 

All steroid hormones are synthesized from cholesterol, with the rate-limiting step in steroid biosynthesis being the cleavage of the cholesterol side chain. 

Arthropoda.—Steroid biosynthesis seems to be absent from all of this phylum. Examples of the class Arachnida, Diplopoda, Crustacea, and Insecta have been examined. Steroid metabolism in insects has been reviewed. " It should be borne in mind that insects can synthesise some terpenoids [e.g. (32) and (46)], but there is an absolute dietary requirement for steroids. Phytosterols such as -sitosterol are converted back into cholesterol derivatives apparently by the reverse of side chain alkylation (86 R = Et) (85 R = CHMe)—> (85 R = CHj)— (84)— (74). In addition a A -double bond is introduced. Parasites, and other organisms naturally present, may contribute to some of these reactions. ... 

The important insect hormone a-ecdysone (121) and related steroids are also present in plants (Section 9). Their biosynthesis from cholesterol probably proceeds via the A -diene to the triolone (119). The side chain is then hydroxylated to the (22/ )-hydroxy steroid (120), a-ecdysone (121), and ) -ecdysone (122) (crustecdysone). Finally, breakdown of )8-ecdysone gave... 

A variety of steroidal natural products have been isolated from insects, even though, as mentioned previously, insects are not able to carry out de novo steroid biosynthesis. The steroidal nucleus, as it occurs in insect primary and secondary metabolites thus must ultimately come from dietary or symbiotic microbial sources. For many phytophagus insects, C28 and C29 phytosterols are converted into cholesterol (C27) through a series of dealkylation pathways, with cholesterol subsequently serving as the starting point for further metabolic transformations, and resulting in a wide variety of steroid-based natural products. In other cases, dietary phytosterols are sequestered and deployed unmodified, and as with other compound classes, the relative importance of dietary sequestration versus modification is not always clear. 

Squalene is an intermediate in cholesterol and steroid biosynthesis. It is formed from presqualene pyrophosphate (Figure 19.21) in the walls of the endoplasmic reticulum using electrons from NADPH. In the reaction, the pyrophosphate is removed from the molecule. 

Animals accumulate cholesterol from their diet, but are also able to biosynthesize it from acetate. The pioneering work that identihed the key intermediates in the complicated pathway of cholesterol biosynthesis was carried out by Konrad Bloch (Harvard) and Feodor Lynen (Munich), corecipients of the 1964 Nobel Prize for physiology or medicine. An important discovery was that the triterpene squalene (see Figure 26.6) is an intermediate in the formation of cholesterol from acetate. Thus, the early stages of cholesterol biosynthesis are the same as those of terpene biosynthesis described in Sections 26.8-26.10. In fact, a signihcant fraction of our knowledge of terpene biosynthesis is a direct result of experiments carried out in the area of steroid biosynthesis. 

Why is HMG-CoA so important in cholesterol biosynthesis The starting material for steroid biosynthesis is acetyl-GoA. Isoprene units are formed from acetyl-GoA in the early stages of a lengthy process that leads ultimately to cholesterol. HMG-GoA is a key intermediate, and its formation is a target of cholesterol-lowering drugs. 

Free steroids are all biosynthesized from cholesterol following a well-established pathway (Dorfman and Sharma, 1965 Kahnt and Neher, 1965) (Fig. 1). Biosynthesis of steroid conjugates, however, can be divided into two categories (Fig. 2). (1) Steroids deriving from free pre-... 

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