Differential inhibition of fungal oxidosqualene cyclase by 6E and 6Z isomers of 2,3-epoxy-10-aza-10,11-dihydrosqualene.
Inhibitory properties of 6E (compound 1) and 6Z (compound 2) isomers of 2,3-epoxy-10-aza-10,11-dihydrosqualene against oxidosqualene-lanosterol cyclase were assayed on microsomes and whole cells of Saccharomyces cerevisiae and Candida albicans. Only the 6E isomer (compound 1), bearing a correct substrate-like configuration, strongly inhibited the enzyme both in microsomes and cell cultures. The difference between compounds 1 and 2 (which had an unfavorable geometry) was especially evident when measuring [14C]acetate incorporation into non-saponifiable lipids extracted from treated cells. While isomer Z was totally ineffective at up to 30 microM, in cells treated with 5 microM isomer E, labelled oxidosqualene, the level of which was negligible in the control, rose to over 60% of the non-saponifiable lipids.
Balliano
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Istituto di Chimica Farmaceutica Applicata, Torino, Italy.
Milla
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P
Ceruti
M
M
Viola
F
F
Carrano
L
L
Cattel
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L
D002176:Candida albicans / Q000201:enzymology; D002455:Cell Division / Q000187:drug effects; D004852:Epoxy Compounds / Q000494:pharmacology*; D019751:Intramolecular Transferases; D007535:Isomerases / Q000037:antagonists & inhibitors*; D050356:Lipid Metabolism; D008861:Microsomes / Q000201:enzymology; D012441:Saccharomyces cerevisiae / Q000201:enzymology*; D013185:Squalene / Q000031:analogs & derivatives* / Q000494:pharmacology; D013237:Stereoisomerism
D004852:Epoxy Compounds; C076124:2,3-epoxy-10-aza-10,11-dihydrosqualene; D013185:Squalene; D007535:Isomerases; D019751:Intramolecular Transferases; C021924:lanosterol synthase