Pneumocystis carinii and S-Adenosylmethionine

描述（申请人提供）：卡氏肺孢子虫是一种真菌， 导致艾滋病患者卡氏肺孢子虫肺炎（PCP）， 癌症化疗和其他导致严重 免疫抑制除了卡氏肺孢子虫作为病原体的重要性之外， 也是一种不寻常的有趣的真菌， 是未知的。在除卡氏肺孢子虫以外的所有检查细胞中， （ATP）是一种关键的细胞内反应物，由ATP合成， 蛋氨酸。然而，卡氏毕赤酵母是一种蛋氨酸营养缺陷型， 从宿主体内分离出来它也有一个活跃的转运体， 这种化合物的特异性除此之外，没有其他的东西是已知的。 卡氏肺孢子虫中这一关键中间体的功能。 将进行以下研究。I.蛋氨酸通量和代谢将是 通过研究卡氏肺孢子虫对蛋氨酸的代谢动力学， 特别是关于将流动分配到蛋白质甲基化， 脂质甲基化、核酸代谢和多胺生物合成途径; 参与蛋氨酸代谢的酶;蛋氨酸代谢末端的命运 产品;以及随着时间的推移， 在可获得性方面的变化。二.一组化合物， 显示调节其它细胞中的β-Met代谢的蛋白质将用作P的探针。 carinii多胺和蛋氨酸代谢。这些化合物也将被研究 因为它们能够操纵大肠杆菌Met的转运和代谢， 它们在体外和体内抑制卡氏肺孢子虫生长的能力。的影响 这些化合物的半衰期和周转率也将是 研究了三.假设接受降低肺纤维化的大鼠 浓度对卡氏肺孢子虫感染将是相对难治的， 相反，那些装载了苯丙氨酸甲酯的人将更快地发展为严重的PCP， 测试.

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.