Lanosterol, ergosterol from

The supply of the authentic sample is important in the study of biosynthesis. We synthesized the intermediates of biosynthesis of ergosterol from lanosterol in yeast [66]. Treatment of methyl phenyl sulfone (79) with epoxy alcohol (80) afforded phenyl sulfone derivative (83) [67]. Coupling of 83 with C-22-iodide derivative (47),... 

Cholesterol is the most common steroid of mammalian membranes. It is formed biologically from lanosterol, as shown. Ergosterol is the most common steroid of fungal membranes. It differs from cholesterol by the presence of two additional double bonds that affect its three dimensional structure. Also shown are three so-called steroid hormones, andros-terone, estradiol, and testosterone. Note the presence of an aromatic A-ring in estradiol. 

There are approximately 20 enzymatic steps from lanosterol to cholesterol or ergosterol, and probably as many from 24-methylenedihydrolanosterol to ergosterol. 

Ergosterol also arises from lanosterol by a one-carbon addition to C-24 followed by a shift of the A24 double bond to the exo position, forming a A24 methylene function. There follows oxidative removal of the three methyls at C-14 and C-4 with concomitant shift of the A24 double bond to A22 position isomerization of A8 position to A7 and formation of an additional A5 double bond yielding ergosterol. 

In ergosterol biosynthesis, side chain alkylation of lanosterol normally takes place to build 24-methylenedihydrolanosterol, which itself is then the substrate for demethylation reactions at and C. The C -demethylation has been studied in detail. It is an oxidative demethylation catalyzed by a cytochrome P -system. The first step involved in this reaction is the hydroxylation of the Cj -methy1-group to form the C -hydroxymethyl derivative. A second hydroxylation and loss of water lead to the C -formyl intermediate, which is hydroxylized a third time to form the corresponding carboxylic acid. Decarboxylation does not directly take place, but proceeds instead by abstraction of a proton from C, followed by elimination and formation of a A 4-double bond. The NADPH-dependent reduction of the A14 -double bond finishes the demethylation reaction. Subsequently, demethylation at has to take place twice, followed by a dehydrogenation reaction in A" -position and isomerization from A8 to A7 and A24(28) to A22. respectively. 

Fig. 34. 3. Structures of selected sterols. Sources animal - lanosterol, cholesterol and ergosterol (also microbial) plant - all others. (From Warner, K., Su, C, and White, P.J. "Role of Antioxidants and Polymerization Inhibitors in Protecting Frying Oils" in Frying Technology and Practices, M.K. Gupta, K. Warner, and P.J. White (Eds.), pp. 37-49, AOCS Press, Champaign, IL 2004. With permission.)...

Holotoxin Ai inhibits the RNA biosynthesis in Candida albicans and Saccharomyces carlsbergensis, as indicated by the decrease in incorporation of C-uridine to the acid-insoluble fraction of the cells. Similar results were obtained for glycoside fractions of 14 species of Pacific sea cucumbers [132]. Apparently the inhibition of RNA biosynthesis in Saccharomyces carlsbergensis is related to nucleotide loss from yeast cells after treatment with glycosides. Holotoxin Ai also inhibits biosyntheses of squalene, lanosterol and ergosterol in S. carlsbergensis [133]. Mitosis is arrested and DNA synthesis inhibited in onion root bulbs by crude holothurin [134]. 

In our laboratory, the major sterol biosynthesised in untreated extracts was the triene (VIII) (1J), rather than ergosterol Itself which is, of course, the end product of the pathway in intact cells. It should be noted that VIII arises directly from 14-demethylation of lanosterol. In the presence of 0.1 yM prochloraz (or even 0.01 pM prochloraz in some experiments) the concentration of VIII was significantly reduced, while the level of lanosterol Increased (4) indicating clearly that prochloraz inhibited 14-demethylation. At higher fungicide concentrations both the triene and ergosterol were totally absent and only lanosterol was present. 

A schematic of fungal ergosterol biosynthesis starting from squalene is shown in Figure 40.1. The biosynthetic pathway has been simplified to emphasize steps important to the action of currently employed antifungal drugs. The last nonsteroidal precursor to both ergosterol and cholesterol is the hydrocarbon squalene. Squalene is converted to squalene epoxide by the enzyme squalene epoxidase. Squalene epoxide is then cyclized to lanosterol, the first steroid in the biosynthetic pathway. The... 

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