Sterol metabolism in the opportunistic pathogen Pneumocystis: advances and new insights.

Pneumocystis can transiently colonize healthy individuals without causing adverse symptoms, and most people test positive for exposure to this organism early in life. However, it can cause Pneumocystis pneumonia (PcP) in people with impaired immune systems and is a major cause of death in HIV/AIDS. Although it has close affinities to the Ascomycetes, Pneumocystis has features unlike those of any single group of fungi. For example, Pneumocystis does not synthesize ergosterol, which is consistent with the inefficacy of amphotericin B and some triazoles in clearing PcP. Pneumocystis sterols include distinct delta7 24-alkylsterols. Metabolic radiolabeling experiments demonstrated that P. carinii synthesizes sterols de novo. Cholesterol is the most abundant sterol in Pneumocystis; most, if not all, is scavenged from the mammalian host lung by the pathogen. The P. carinii erg7, erg6, and erg11 genes have been cloned, sequenced, and expressed in heterologous systems. The recombinant P. carinii S-adenosyl-L-methionine:C-24 sterol methyl transferase (SAM:SMT) has a preference for lanosterol over zymosterol as substrate, and the enzyme can catalyze the transfer of either one or two methyl groups to the C-24 position of the sterol side chain. Two different sterol compositions were detected among human-derived P. jirovecii; one was dominated by C28 and C29 sterols, and the other had high proportions of higher molecular mass components, notably the C32 sterol pneumocysterol. The latter phenotype apparently represents organisms blocked at 14alpha-demethylation of the sterol nucleus. These studies suggest that SAM:SMT is an attractive drug target for developing new chemotherapy for PcP.