Department of Biochemistry, Faculty of Natural and Agricultural Science, University of Pretoria, Pretoria 0002, South Africa.
Amino Acids. 2010 Feb;38(2):633-44. doi: 10.1007/s00726-009-0424-7. Epub 2009 Dec 9.
Inhibition of polyamine biosynthesis and/or the perturbation of polyamine functionality have been exploited with success against parasitic diseases such as Trypanosoma infections. However, when the classical polyamine biosynthesis inhibitor, alpha-difluoromethylornithine, is used against the human malaria parasite, Plasmodium falciparum, it results in only a cytostatic growth arrest. Polyamine metabolism in this parasite has unique properties not shared by any other organism. These include the bifunctional arrangement of the catalytic decarboxylases and an apparent absence of the typical polyamine interconversion pathways implying different mechanisms for the regulation of polyamine homeostasis that includes the uptake of exogenous polyamines at least in vitro. These properties make polyamine metabolism an enticing drug target in P. falciparum provided that the physiological and functional consequences of polyamine metabolism perturbation are understood. This review highlights our current understanding of the biological consequences of inhibition of the biosynthetic enzymes in the polyamine pathway in P. falciparum as revealed by several global analytical approaches. Ultimately, the evidence suggests that polyamine metabolism in P. falciparum is a validated drug target worth exploiting.
抑制多胺生物合成和/或扰乱多胺功能已成功用于对抗寄生虫病，如锥虫感染。然而，当经典的多胺生物合成抑制剂α-二氟甲基鸟氨酸用于抗人类疟疾寄生虫疟原虫时，它只会导致细胞生长停滞。该寄生虫中的多胺代谢具有独特的性质，与任何其他生物体都不同。这些特性包括催化脱羧酶的双功能排列和典型的多胺相互转化途径的明显缺失，这意味着多胺动态平衡的调节机制不同，其中包括至少在体外摄取外源性多胺。这些特性使多胺代谢成为疟原虫中一个诱人的药物靶点，只要理解多胺代谢干扰的生理和功能后果。这篇综述强调了我们目前对多胺途径中生物合成酶抑制对疟原虫的生物学后果的理解，这是通过几种全局分析方法揭示的。最终，证据表明，疟原虫中的多胺代谢是一个值得开发的经过验证的药物靶点。
