MECHANISM AND CONTROL OF FOLATE POLYGLUTAMATON

将抗代谢物活化为保留在细胞和线粒体中的代谢物是由酶叶酰聚谷氨酸合成酶（FPGS）催化的。 小鼠组织中FPGS基因的转录仅在分化组织中由上游启动子的组织特异性激活调节，所述分化组织用作叶酸代谢的专门器官，并且在所有正常和恶性分裂细胞群体中由下游启动子调节。 将研究这两个启动子的相互调控以及从上游启动子转录的FPGS同种型的功能。 FPGS的细胞内运输通过上游或下游启动子的转录来进行，其方式为产生运输到胞质溶胶的FPGS转录物和运输到线粒体区室的第二种形式。 将研究这种交通的动力学和功能。最后，将确定特定肽在酶机制中的作用。

Activation of antimetabolites to metabolites which are retained in cells and mitochondria is catalyzed by the enzyme folylpolyglutamate synthetase (FPGS). Transcription of the FPGS gene in mouse tissues is regulated by the tissue-specific activation of an upstream promoter only in differentiated tissues which serve as specialized organs of folate metabolism, and in all normal and malignant dividing cell populations from a downstream promoter. The recriprical regulation of these two promoters will be studied as will the function of the isoform of FPGS transcribed from the upstream promoter. The intracellular trafficing of FPGS is gaurenteed by the transcription of either upstream or downstream promoter in a manner which produces both a transcript for FPGS which traffices to the cytosol and a second form which traffices to the mitochondrial compartment. The dynamics and functions of this trafficing will be studied. Finally, the role of specific peptides in the enzyme mechanism will be determined.