Azasterol inhibitors in yeast. Inhibition of the Δ24-sterol methyltransferase and the 24-methylene sterol Δ24(28)-reductase in sterol mutants of Saccharomyces cerevisiae

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Abstract
The effects of several monoazasterol on sterol biosynthesis were examined in the ergosterol deficient mutants erg 2, erg 3 and erg 5 of S. cerevisiae. When the mutants were aerobically cultured in the presence of 1 .mu.M 23-azacholesterol, the 24-methylene sterol .DELTA.24(28)-reductase was essentially blocked and the immediate .DELTA.24(28)-unsaturated precursor of the final sterol metabolite in each respective erg strain accumulated. Total sterol production was enhanced in the cultures grown in the presence of 1 .mu.M 23-azacholesterol. In cultures which were grown in the presence of 1 .mu.M 25-azacholesterol which effectively blocked the .delta.24-sterol methyltransferase, all 3 erg strains accumulated zymosterol as the major sterol component with lesser quantities of predicted terminal sterols. Mutant erg 2 (block at .delta.8 .fwdarw. .DELTA.7 isomerase) grew poorly in the presence of 1 .mu.M 25-azacholesterol and produced low levels of cholesta-5,8,24-trienol and cholesta-5,8,22,24-tetraenol, which were isolated and characterized for the first time. Compared with controls, erg 2 treated with 1 .mu.M 23-azacholesterol produced increased amounts of ergosta-5,8,22,24(28)-tetraenol, which was previously unidentified as a yeast sterol. In erg 5 (block at .DELTA.22-dehydrogenase) treatment with 1 .mu.M 25-azacholestanol effectively blocked the .DELTA.24-sterol methyltransferase and resulted in increased total sterol production. Cholesta-5,7,24-trienol accounted for 27%29% of the sterol pool in 25-azasterol inhibited erg 5 cultures. The 25-azasterol inhibited erg 5 mutant thus provides a source of cholesta-5,7,24-trienol, a potential provitamin D3 substitute.