Haimeur A, Guimond C, Pilote S, Mukhopadhyay R, Rosen B P, Poulin R, Ouellette M
Centre de Recherche en Infectiologie, Université Laval, Québec, Canada.
Mol Microbiol. 1999 Nov;34(4):726-35. doi: 10.1046/j.1365-2958.1999.01634.x.
The levels of trypanothione, a glutathione-spermidine conjugate, are increased in the protozoan parasite Leishmania selected for resistance to the heavy metal arsenite. The levels of putrescine and spermidine were increased in resistant mutants. This increase is mediated by overexpression of ornithine decarboxylase (ODC), the rate-limiting enzyme in polyamine biosynthesis. Gene overexpression is generally mediated by gene amplification in Leishmania but, here, the mRNA and the enzymatic activity of ODC are increased without gene amplification. This RNA overexpression is stable when cells are grown in the absence of the drug and does not result from gene rearrangements or from an increased rate of RNA synthesis. Transient transfections suggest that mutations in the revertant cells contribute to these elevated levels of RNA. Stable transfection of the ODC gene increases the level of trypanothione, which can contribute to arsenite resistance. In addition to ODC overexpression, the gene for the ABC transporter PGPA is amplified in the mutants. The co-transfection of the ODC and PGPA genes confers resistance in a synergistic fashion in partial revertants, also suggesting that PGPA recognizes metals conjugated to trypanothione.
对于选择出的对重金属亚砷酸盐具有抗性的原生动物寄生虫利什曼原虫，谷胱甘肽 - 亚精胺共轭物曲古硫因的水平会升高。在抗性突变体中，腐胺和亚精胺的水平升高。这种升高是由多胺生物合成中的限速酶鸟氨酸脱羧酶（ODC）的过表达介导的。在利什曼原虫中，基因过表达通常由基因扩增介导，但在此处，ODC的mRNA和酶活性在没有基因扩增的情况下增加。当细胞在无药物条件下生长时，这种RNA过表达是稳定的，并且不是由基因重排或RNA合成速率增加导致的。瞬时转染表明回复细胞中的突变导致了这些升高的RNA水平。ODC基因的稳定转染增加了曲古硫因的水平，这可能有助于亚砷酸盐抗性。除了ODC过表达外，ABC转运蛋白PGPA的基因在突变体中也发生了扩增。ODC和PGPA基因的共转染以协同方式赋予部分回复体抗性，这也表明PGPA识别与曲古硫因结合的金属。
