Triterpenes And Steroids

The linking of two farnesyl groups head-to-head leads to the C30 terpene hydrocarbon squalene, a compound first found in the liver oil of sharks (Squalus species), but is now known to be a widely distributed compound (Figure 7.5). It is found, for example, in the oil of human skin. The coupling reaction to give squalene occurs in plants and vertebrates, but is not available to insects. The head-to-head joining of the two farnesyl groups is a complex reaction with cyclopropyl and cyclobutyl intermediates, and requires one molecule of NADPH. The essential steps of the coupling are shown in Figure 7.4. Squalene is most important as the compound from which all the plant triterpenoids and the steroids are biosynthesized. From mevalonate to squalene there are no less than 14 stereospecific steps, all well described.

The triterpenes derived from squalene are generally polycyclic compounds. Plants and animals (excluding insects) make them by folding squalene, oxidizing one double bond to give squalene epoxide which is then cyclized into a four-ring triterpenoid (Figure 7.6). The squalene epoxide is held on the active site of the enzyme in the correctly folded form for the first concerted cyclization, which leaves a carbocation at C-20. By a series of 1,2-shifts of two hydrogen atoms and enzyme^


farnesyl pyrophosphate r = c10h17

Hb presqualene pyrophosphi enzyme^

farnesyl pyrophosphate r = c10h17

Hb presqualene pyrophosphi

farnesyl pyrophosphate farnesyl pyrophosphate nadph

farnesyl pyrophosphate farnesyl pyrophosphate nadph squalene

Figure 7.5 The formation of squalene from two farnesyl pyrophosphate molecules joined head-to-head requires the elimination of the pyrophosphate groups and the use of one molecule of NADPH. The hydrogen transferred from NADPH is labelled with a dot for identification

Figure 7.6 Outline of the biosynthesis of the triterpenoid lanosterol from acetate and mevalonate via squalene

Figure 7.7 A summary of the steps by which the triterpene lanosterol is converted to the sterol cholesterol two methyl groups, and loss of one hydrogen atom a stable structure is reached.

In animals the triterpenoid is lanosterol (Figure 7.6), first identified in wool wax. Lanosterol does not normally accumulate but is converted by quite a large number of further reactions (summarized in Figure 7.7) to cholesterol, the characteristic animal sterol. While triterpenes are C30 compounds, in sterols, three methyl groups of the triterpenes have been lost. By the action of a cytochrome P450, the methyl group on C-14 is oxidized to a formyl group and then removed by folic acid. The pair of methyls on C-4 are sequentially oxidized to carboxylic acids and lost by decarboxylation (Figure 7.6). The side chain double bond of lanosterol is reduced in cholesterol and the A8 double bond is isomerized to a A5 double bond in cholestrol. The essential features of sterols are three cyclohexane rings and one cyclopentane ring fused together in the way shown. They always have an oxygen function at C-3, the position of the hydroxy 1 in cholesterol.

Animals make and use cholesterol. It is a constituent of all vertebrate cell walls, of blood lipoproteins and is the precursor of the bile acids and a number of mammalian hormones. Plants make sterols through cycloartenol, another triterpenoid, made by folding squalene differently and further alkylate the sterol formed (see Mann, Secondary Metabolism, 2nd edit. Oxford University Press, 1987, p. 138). The typical higher plant sterol is sitosterol, with campesterol and stigmasterol less widely found (Figure 7.8). Micro-organisms make a still greater variety of sterols. The extra side-chain methyl groups in plant sterols come from S-adenosyl methionine. Insects that feed on vertebrates have a ready supply of cholesterol. Those feeding on leaves or phloem of plants tend to convert the plant sterols to cholesterol. Feeders on fungi and bacteria have an even wider variety of sterols to assimilate. The de-alkylation of plant sterols in insects takes place in the gut (Figure 7.8). Cholesterol or some equivalent sterol is therefore an essential nutrient for insects. It has been found recently that rice planthoppers and some anobiid beetles harbour yeastlike symbionts that make sterols which the insect can use, making those insects less dependant upon food sources.

Figure 7.8 The de-alkylation of plant sterols in insect gut to cholesterol
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