Comprehensive and definitive structural identities of Pneumocystis carinii sterols

Pneumocystis causes a type of pneumonia in im- munodeficient mammals, such as AIDS patients. Mammals cannot alkylate the C-24 position of the sterol side chain, nor can they desaturate C-22. Thus, the reactions leading to these sterol modifications are particularly attractive targets for the development of drugs against fungal and protozoan pathogens that make them. In the present study, the defini- tive structures of 43 sterol molecular species in rat-derived Pneumocystis carinii were elucidated by nuclear magnetic res- onance spectroscopy. Ergosterol, � 5,7 sterols, trienes, and tetraenes were not among them. Most (32 of the 43) were 24-alkylsterols, products of S -adenosyl- L -methionine:C-24 sterol methyl transferase (SAM:SMT) enzyme activity. Their abundance is consistent with the suggestion that SAM:SMT is highly active in this organism and that the enzyme is an excellent anti- Pneumocystis drug target. In contrast, the com- prehensive analysis strongly suggest that P. carinii does not form � 22 sterols, thus C-22 desaturation does not appear to be a drug target in this pathogen. The lanosterol deriva- tives, 24-methylenelanost-8-en-3 � -ol and ( Z )-24-ethylidene- lanost-8-en-3 � -ol (pneumocysterol), previously identified in human-derived Pneumocystis jiroveci , were also detected among the sterols of the rat-derived P. carinii organisms. — Giner, J-L., H. Zhao, D. H. Beach, E. J. Parish, K. Jayasim- hulu, and E. S. Kaneshiro. Comprehensive and definitive structural identities of Pneumocystis carinii sterols. J. Lipid Res. 2002. 43: 1114-1124.