Goldberg B, Yarlett N, Sufrin J, Lloyd D, Bacchi C J
Haskins Laboratories, Pace University, New York, New York 10038, USA.
FASEB J. 1997 Mar;11(4):256-60. doi: 10.1096/fasebj.11.4.9068614.
African trypanosomes are pathogens of humans and livestock in equatorial Africa. There is a great deal of resistance to present front line drugs for treating African trypanosomiasis such as melarsoprol (Arsobal) and pentamidine. In the search for new and novel drugs against this disease, we have found a unique transporter of S-adenosylmethionine (AdoMet), a metabolite used in transmethylation reactions and polyamine synthesis. This transporter is distinct from those for methionine and adenosine, since AdoMet uptake was not inhibited by trypanocidal drugs, which compete with adenosine for transport. AdoMet analogs competing with [methyl-3H]AdoMet for uptake required a positively charged sulfonium group on the 5' position of the ribose. Since transport of AdoMet does not normally occur to a significant extent in mammalian cells, the parasite transporter provides a selective and novel route to deliver new chemotherapeutic agents against these organisms.
非洲锥虫是赤道非洲地区人类和家畜的病原体。目前用于治疗非洲锥虫病的一线药物，如美拉胂醇（Arsobal）和喷他脒，存在很大的耐药性。在寻找治疗这种疾病的新型药物的过程中，我们发现了一种独特的S-腺苷甲硫氨酸（AdoMet）转运体，AdoMet是一种用于转甲基反应和多胺合成的代谢物。这种转运体与甲硫氨酸和腺苷的转运体不同，因为锥虫杀灭药物与腺苷竞争转运，却不会抑制AdoMet的摄取。与[甲基-3H]AdoMet竞争摄取的AdoMet类似物在核糖的5'位置需要一个带正电荷的锍基团。由于AdoMet在哺乳动物细胞中通常不会大量转运，寄生虫转运体为递送针对这些生物体的新型化疗药物提供了一条选择性的新途径。
