Cholesterol

In animals, the triterpenoid alcohol lanosterol (Figure 5.55) is converted into cholesterol* (Figure 5.76), a process requiring, as well as the loss of three methyl groups, reduction of the side-chain double bond, and generation of a A5 6

estrane androstane

pregnane

cholane

androstane pregnane cholane

cholestane campestane

cholestane

ergostane

campestane

ergostane

Cholestane

stigmastane poriferastane

29 28

29 28

lanostane cycloartane

Figure 5.77

stigmastane poriferastane

29 28

29 28

lanostane cycloartane

Figure 5.77

double bond in place of the A8 9 double bond. The sequence of these steps is to some extent variable, and dependent on the organism involved. Accordingly, these individual transformations are considered rather than the overall pathway.

The methyl at C-14 is usually the one lost first, and this is removed as formic acid. The reaction is catalysed by a cytochrome P-450 mono-oxygenase, which achieves two oxidation reactions to give the 14a-formyl derivative (Figure 5.78), and loss of this formyl group giving the A814 diene, most probably via homolytic cleavage of the peroxy adduct as indicated (compare similar per-oxy adducts involved in side-chain cleavage from ring D, page 278, and in A ring aromatization, page 278). The 14-demethyl sterol is then obtained by an NADPH-dependent reduction step, the 15-proton being derived from water.

Loss of the C-4 methyls occurs sequentially, usually after removal of the 14a-methyl, with both carbons being cleaved off via a decarboxylation mechanism (Figure 5.79). This is facilitated by oxidizing the 3-hydroxyl to a ketone, thus generating intermediate P-keto acids. In this sequence, the enolate is restored to a ketone, in which the remaining C-4 methyl takes up the more favourable equatorial (4a) orientation.

The side-chain A24 double bond is reduced by an NADPH-dependent reductase, hydride from the coenzyme being added at C-25, with H-24 being derived from water (Figure 5.80). The A8 double bond is effectively migrated to A5 via A7 and the A5 7 diene (Figure 5.81). This sequence involves an allylic isomerization, a dehydrogenation, and a reduction. Newly introduced protons at C-9 and C-8 originate from water, and that at C-7 from NADPH.

The role of lanosterol in non-photosynthetic organisms (animals, fungi) is taken in photo-synthetic organisms (plants, algae) by the cyclopropane triterpenoid cycloartenol (Figure 5.55). This cyclopropane feature is found in a number of

estrane

O2 NADPH

sequential oxidation of 14-methyl group to aldehyde sequential oxidation of 14-methyl group to aldehyde

O2 NADPH

Enz-Fe-OOH

reduction of double bond

reduction of double bond

NADPH H2O

peroxy adduct formation via nucleophilic attack of peroxy-enzyme on to carbonyl

NADPH

Enz-Fe-OOH

homolytic cleavage of Co —Fe-Enz peroxy bond

HCO2H methyl group lost as formic acid

Figure 5.78

O2 NADPH

sequential oxidation of 4a-methyl group to carboxyl

HO2C

oxidation of 3ß-alcohol to ketone

O2 NADPH

rf repeat of whole process

NADPH

reduction of ketone back to 3ß-alcohol decarboxylation of P-keto acid

enol-keto tautomerism; methyl takes up more favoured equatorial configuration

enol-keto tautomerism; methyl takes up more favoured equatorial configuration

Figure 5.79

Figure 5.80

Figure 5.80

plant sterols, but the majority of plant steroids contain the normal methyl at C-10. This means that, in addition to the lanosterol ^ cholesterol modifications outlined above, a further mechanism to reopen the cyclopropane ring is necessary. This is shown in Figure 5.82. The stereochemistry at C-8 (HP) is unfavourable for a concerted mechanism involving loss of H-8 with cyclopropane ring opening. It is suggested therefore that a nucleophilic group from the enzyme attacks C-9, opening the cyclopropane ring and incorporating a proton from water. A trans elimination then generates the A8 double bond. The cyclopropane ring-opening process seems specific to 4a-monomethyl sterols. In plants, removal of the first 4-methyl group (4a;

reduction of double bond

Figure 5.81

reduction of double bond

Figure 5.81

cyclopropane ring opening initiated by attack of nucleophilic group on enzyme

1 4a-monomethyl cycloartanol derivative

trans elimination

Figure 5.82

1 4a-monomethyl cycloartanol derivative

Figure 5.82

trans elimination on

4a-monomethyl lanosterol derivative note the remaining 4^-methyl group then takes up the a-orientation) is also known to precede loss of the 14a-methyl. Accordingly, the substrate shown in Figure 5.82 has both 4a- and 14a-methyl groups. The specificity of the cyclopropane ring-opening enzyme means cycloartenol is not converted into lanosterol, and lanosterol is thus absent from virtually all plant tissues. Cholesterol is almost always present in plants, though often in only trace amounts, and is formed via cycloartenol.

Cholesterol

Cholesterol (Figure 5.76) is the principal animal sterol and since it is a constituent of cell membranes has been found in all animal tissues. Human gallstones are almost entirely composed of cholesterol precipitated from the bile. Cholesterol is currently available in quantity via the brains and spinal cords of cattle as a by-product of meat production, and these form one source for medicinal steroid semi-synthesis. Large quantities are also extractable from lanolin, the fatty material coating sheep's wool. This is a complex mixture of esters of long chain fatty acids (including straight-chain, branched-chain, and hydroxy acids) with long chain aliphatic alcohols and sterols. Cholesterol is a major sterol component. Saponification of crude lanolin gives an alcohol fraction (lanolin alcohols or wool alcohols) containing about 34% cholesterol and 38% lanosterol/dihydrolanosterol. Wool alcohols are also used as an ointment base.

Although the processes involved are quite complex, there appears to be a clear correlation between human blood cholesterol levels and heart disease. Atherosclerosis is a hardening of the arteries caused by deposition of cholesterol, cholesterol esters, and other lipids in the artery wall, causing a narrowing of the artery and thus an increased risk of forming blood clots (thrombosis). Normally, most of the cholesterol serves a structural element in cell walls, whilst the remainder is transported via the blood and is used for synthesis of steroid hormones, vitamin D (page 259), or bile acids (page 261). Transport of cholesterol is facilitated by formation of lipoprotein carriers, comprising protein and phospholipid shells surrounding a core of cholesterol, in both free and esterified forms. Risk of atherosclerosis increases with increasing levels of low density lipoprotein (LDL) cholesterol, and is reduced with increasing levels of high density lipoprotein (HDL) cholesterol. Blood LDL cholesterol levels are thus a good statistical indicator of the potential risk of a heart attack. The risks can be lessened by avoiding foods rich in cholesterol, e.g. eggs, reducing the intake of foods containing high amounts of saturated fatty acids such as animal fats, and replacing these with vegetable oils and fish that are rich in polyunsaturated fatty acids (see page 40). Blood LDL cholesterol levels may also be reduced by incorporating into the diet plant sterol esters or plant stanol esters, which reduce the absorption of cholesterol (see page 256). In humans, dietary cholesterol is actually a smaller contributor to LDL cholesterol levels than is dietary saturated fat. Cholesterol biosynthesis may also be inhibited by drug therapy using specific inhibitors of the mevalonate pathway, e.g. lovastatin and related compounds (see page 112).

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Responses

  • Vivian
    What is the configuration of cholesterol, E or Z of the double bond?
    7 years ago

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