Pneumocystis carinii and S-Adenosylmethionine

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DESCRIPTION (Provided by the applicant): Pneumocystis carinii is a fungus which causes P. carinii pneumonia (PCP) in people with AIDS, patients undergoing cancer chemotherapy and others with conditions causing severe immunosuppression. Beyond the importance of P. carinii as a pathogen, it is also an unusual and interesting fungus for which most basic metabolic processes are unknown. In all cells examined other than P. carinii, S-adenosylmethionine (AdoMet), a pivotal intracellular reactant, is synthesized from ATP and methionine. P. carinii, however is an AdoMet auxotroph and must acquire this compound from the host. It also has an active transporter which is completely specific for this compound. Other than this, nothing else is known about the function of this critical intermediate in P. carinii. The following studies will be performed. I. AdoMet flux and metabolism will be investigated bystudying: the dynamics of P. carinii AdoMet metabolism especially with respect to the partition of flow into protein methylation, lipid methylation, nucleic acid metabolism and polyamine biosynthesis pathways; the enzymes involved in AdoMet metabolism; the fate of AdoMet metabolic end products; and the changes in the concentrations of AdoMet metabolites with changes in the availability of AdoMet. II. A panel of compounds which have been shown to modulate AdoMet metabolism in other cells will be used as probes of P. carinii polyamine and AdoMet metabolism. These compounds will also be studied for their ability to manipulate AdoMet transport and metabolism as well as for their ability to inhibit P. carinii growth in vitro and in vivo. The effect of these compounds on AdoMet half life and turnover rate will also be investigated. III. The hypothesis that rats treated to lower lung AdoMet concentrations will be relatively refractory to P. carinii infection and, conversely, those loaded with AdoMet will develop severe PCP faster will be tested.