J. Lipid Res. Neurobiology of Lipids (ISSN1683-5506)
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Journal of Lipid Research, Vol. 43, 1114-1124, July 2002
Copyright © 2002 by Lipid Research, Inc.

Comprehensive and definitive structural identities of Pneumocystis carinii sterols

José-Luis Giner*, Hui Zhao*, David H. Beach{dagger}, Edward J. Parish§, Koka Jayasimhulu** and Edna S. Kaneshiro1,{ddagger}

* Department of Chemistry, State University of New York, ESF, Syracuse, NY 13210
{dagger} Department of Microbiology & Immunology, SUNY Upstate Medical University, Syracuse, NY 13210
§ Department of Chemistry, Auburn University, Auburn, AL 36849
** Department of Chemistry, University of Cincinnati, Cincinnati, OH 45221
{ddagger} Department of Biological Sciences, University of Cincinnati, Cincinnati, OH 45221

1 To whom correspondence should be addressed. e-mail: edna.kaneshiro{at}uc.edu

Pneumocystis causes a type of pneumonia in immunodeficient 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 definitive structures of 43 sterol molecular species in rat-derived Pneumocystis carinii were elucidated by nuclear magnetic resonance spectroscopy. Ergosterol, {Delta}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 comprehensive analysis strongly suggest that P. carinii does not form {Delta}22 sterols, thus C-22 desaturation does not appear to be a drug target in this pathogen.

The lanosterol derivatives, 24-methylenelanost-8-en-3ß-ol and (Z)-24-ethylidenelanost-8-en-3ß-ol (pneumocysterol), previously identified in human-derived Pneumocystis jiroveci, were also detected among the sterols of the rat-derived P. carinii organisms.

Abbreviations: GLC, gas-liquid chromatography; MS, mass spectrometry; PcP, Pneumocystis pneumonia; RRT, relative retention time; SAM:SMT, S-adenosyl-L-methionine:C-24 sterol methyl transferase

Supplementary key words AIDS • 24-alkylsterols • drug targets • gas-liquid chromatography • mass spectrometry • opportunistic infections • nuclear magnetic resonance spectroscopy • pneumocysterol • S-adenosyl-L-methionine:C-24 sterol methyl transferase


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