Sterol composition of Pneumocystis jirovecii with blocked 14alpha-demethylase activity.
Several drugs that interact with membrane sterols or inhibit their syntheses are effective in clearing a number of fungal infections. The AIDS-associated lung infection caused by Pneumocystis jirovecii is not cleared by many of these therapies. Pneumocystis normally synthesizes distinct C28 and C29 24-alkylsterols, but ergosterol, the major fungal sterol, is not among them. Two distinct sterol compositional phenotypes were previously observed in P. jirovecii. One was characterized by delta7 C28 and C29 24-alkylsterols with only low proportions of higher molecular mass components. In contrast, the other type was dominated by high C31 and C32 24-alkylsterols, especially pneumocysterol. In the present study, 28 molecular species were elucidated by nuclear magnetic resonance analysis of a human lung specimen containing P. jirovecii representing the latter sterol profile phenotype. Fifteen of the 28 had the methyl group at C-14 of the sterol nucleus and these represented 96% of the total sterol mass in the specimen (excluding cholesterol). These results strongly suggest that sterol 14alpha-demethylase was blocked in these organisms. Twenty-four of the 28 were 24-alkylsterols, indicating that methylation of the C-24 position of the sterol side chain by S-adenosyl-L-methionine:sterol C-24 methyl transferase was fully functional.
Giner
José-Luis
JL
Department of Chemistry, State University of New York-ESF, Syracuse, NY 13210, USA. jlginer@syr.edu
Zhao
Hui
H
Amit
Zunika
Z
Kaneshiro
Edna S
ES
D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006801:Humans; D008168:Lung / Q000382:microbiology; D008780:Methyltransferases / Q000378:metabolism; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D010088:Oxidoreductases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D045363:Pneumocystis carinii / Q000737:chemistry* / Q000201:enzymology / Q000302:isolation & purification; D058886:Sterol 14-Demethylase; D013261:Sterols / Q000032:analysis* / Q000737:chemistry
C548418:CYP51A1 protein, human; D065607:Cytochrome P-450 Enzyme Inhibitors; D013261:Sterols; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D058886:Sterol 14-Demethylase; D008780:Methyltransferases; C022670:delta 24-sterol methyltransferase