Critical importance of the de novo pyrimidine biosynthesis pathway for Trypanosoma cruzi growth in the mammalian host cell cytoplasm

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• 作者：Muneaki Hashimoto^a ; ^{muneaki@juntendo.ac.jp} ; Jorge Morales^a ; Yoshihisa Fukai^a ; Shigeo Suzuki^a ; Shinzaburo Takamiya^a ; Akiko Tsubouchi^a ; Syou Inoue^a ; Masayuki Inoue^b ; Kiyoshi Kita^c ; Shigeharu Harada^d ; Akiko Tanaka^e ; Takashi Aoki^a ; Takeshi Nara^a ; ^{tnara@juntendo.ac.jp}
• 关键词：CPSII ; carbamoyl-phosphate synthetase II ; LIT ; liver infusion tryptose ; DHOD ; dihydroorotate dehydrogenase ; MOI ; a multiplicity of infection
• 刊名：Biochemical and Biophysical Research Communications
• 出版年：2012
• 出版时间：20 January 2012
• 年：2012
• 卷：417
• 期：3
• 页码：1002-1006
• 全文大小：293 K

文摘

The intracellular parasitic protist Trypanosoma cruzi is the causative agent of Chagas disease in Latin America. In general, pyrimidine nucleotides are supplied by both de novo biosynthesis and salvage pathways. While epimastigotes¡ªan insect form¡ªpossess both activities, amastigotes¡ªan intracellular replicating form of T. cruzi¡ªare unable to mediate the uptake of pyrimidine. However, the requirement of de novo pyrimidine biosynthesis for parasite growth and survival has not yet been elucidated. Carbamoyl-phosphate synthetase II (CPSII) is the first and rate-limiting enzyme of the de novo biosynthetic pathway, and increased CPSII activity is associated with the rapid proliferation of tumor cells. In the present study, we showed that disruption of the T. cruzi cpsII gene significantly reduced parasite growth. In particular, the growth of amastigotes lacking the cpsII gene was severely suppressed. Thus, the de novo pyrimidine pathway is important for proliferation of T. cruzi in the host cell cytoplasm and represents a promising target for chemotherapy against Chagas disease.