Biosynthesis of ergosterol

Clotrimazole and other azole derivatives have a different mode of action than the polyenes, eg, amphotericin B. The latter biad to the ergosterol present ia the membranes of yeasts and fungi, but azole derivatives inhibit the cytochrome P-450 dependent biosynthesis of ergosterol (8—11). This inhibition not only results in a reduction of ergosterol, but also in an accumulation of C-14 methyl sterols. They disturb membrane permeabiUty, inhibit cell rephcation, and are basically responsible, in combination with the reduction of ergosterol levels, for the antifungal action. 

Like the a2ole derivatives, it inhibits the biosynthesis of ergosterol. However, naftifine [65472-88-0] does not inhibit the cytochrome P-450 dependent C-14-demethylase, but the epoxidation of squalene. Squalene epoxidase cataly2es the first step in the conversion of squalene via lanosterol to ergosterol in yeasts and fungi or to cholesterol in mammalian cells. The squalene epoxidase in C. albicans is 150 times more sensitive to naftifine, C2 H2 N, than the en2yme in rat fiver (15). Naftifine is available as a 1% cream. 

Plasma levels of 3—5 p.g/mL are obtained two hours after adraiinistration of 200 mg ketoconazole. No accumulation in the bloodstream was noted after a 30-wk treatment with this dose. The half-life is approximately eight hours. When ketoconazole is taken with meals, higher plasma levels are obtained. Distribution studies using radioactive ketoconazole in rats show radioactivity mainly in the Hver and the connective tissue. Radioactivity is also present in the subcutaneous tissue and the sebaceous glands. After one dose of 200 mg in humans, ketoconazole is found in urine, saUva, sebum, and cenimen. Like miconazole, the mode of action is based on inhibition of the cytochrome P-450 dependent biosynthesis of ergosterol. This results in disturbed membrane permeabiUty and membrane-bound enzymes (8,10,23,25). 

Bammert GF et al. Genome-wide expression patterns in Saccharomyces cerevisiae comparison of drug treatments and genetic alterations affecting biosynthesis of ergosterol. Antimicrob Agents Che-mother 2000 44 1255-1265. 

The 5-fluorocytosine (flucytosine) is an inhibitor of sterol C-14 demethylase, an enzyme involved in the biosynthesis of ergosterol, an element of fungal wall. It is marketed as an anti-fungal agent, whereas nucleoside derivatives of the... 

Mecfianism of Action An antifungal agent that locks biosynthesis of ergosterol, essential for fungal cell membrane. Fungicidal. Therapeutic Effect Relieves athlete s... 

Fluconazole was designed following much earlier work on imidazole derivatives, which had been shown to inhibit a crucial step in biosynthesis of ergosterol, the essential sterol of the fungal membrane. Imidazoles were shown to be poorly effective in vivo because of rapid and extensive metabolism. Note the design features ... 

Triarimol almost completely suppressed the biosynthesis of ergosterol by Ustilago maydis,162 although total sterol production was unaltered, and (88), obtusifoliol (93), and 14a-methylergosta-8,24(28)-dien-3j8-ol accumulated. These three sterols may be the first intermediates in ergosterol biosynthesis in this organism, although alternative interpretations of the inhibition effects are possible. 

Clotrimazole, as a 1% solution, is the most effective topical fungicide for the treatment of otomycosis. It is active against Aspergillus and Candida species, the most common pathogens responsible for these infections. It acts by interfering with the biosynthesis of ergosterol and is very effective for refractory or chronic cases caused by the dermatophytes or Candida species. ... 

They act by inhibiting the biosynthesis of ergosterol, a constituent of the fungal cell membrane, resulting in disruption of the cell. 

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),... 

The past decade has shown that hydrocarbon desaturation is not uncommon but, except in cases such as the biosynthesis of ergosterol, it generally accounts for a minor proportion of the metabolic products. The earliest reported example of P450-mediated hydrocarbon desaturation appears to be the conversion of lindane (1,2,3,4,5,6-hexachloro-cyclohexane) to 1,2,3,4,5,6-hexachlorocyclohex-ene, but the known hydrocarbon desaturation reactions now include the A -desaturation of androstenedione and deoxycorticosterone by adrenal mitochondria, the oxidation of dihydronaphthalene to naphthalene and 7,8-dihydrobenzo[a] pyrene to benzo[a]pyrene the conversion of warfarin to dehydrowarfarin ", the desaturation of lovostatin and simvastatin to the 6-exo-methylene... 

Semisynthetic y0-lactam antibiotics with a 1,2,4-triazolyl substituent have been prepared and are in clinical use. However, the most important application of 1,2,4-triazoles is as biocides. 3-Amino-1,2,4-triazole (amitrole, amizol) is an unselective herbicide. Triadimenol 4 is one of the most effective fungicides. Its configuration IS, 2R) is essential for its action [162]. The 1,2,4-triazole fungicides inhibit the biosynthesis of ergosterol in fungi. 

Formation of a A -Double Bond.—The biosynthesis of ergosterol from... 

The limited uptake of the precinsor cholesterol into the cells in general and the need for sustainable steroid production based on renewable resources fuelled the development of the industrially relevant de novo artificial biosynthesis of hydrocortisone starting from endogenous ergosterol in recombinant Saccharomyces cerevi-siae [339, 340]. The biosynthesis of ergosterol,... 

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