Denton Helen, McGregor Joanne C, Coombs Graham H
Division of Infection and Immunity, Institute of Biomedical and Life Sciences, University of Glasgow, Joseph Black Building, Glasgow G12 8QQ, UK.
Biochem J. 2004 Jul 15;381(Pt 2):405-12. doi: 10.1042/BJ20040283.
The reason why Leishmania parasites are susceptible to organic antimonial drugs, the standard chemotherapeutic agents for over 50 years, apparently lies in the fact that the mammalian stage of the parasite reduces the pentavalent form of the administered drug to a trivalent form that causes parasite death. We have identified and characterized a parasite-specific enzyme that can catalyse the reduction of pentavalent antimonials and may therefore be central to the anti-parasite activity of the drug. The unusual protein, a trimer of two-domain monomers in which each domain has some similarity to the Omega class glutathione S-transferases, is a thiol-dependent reductase (designated TDR1) that converts pentavalent antimonials into trivalent antimonials using glutathione as the reductant. The higher abundance of the enzyme in the mammalian stage of the parasite could explain why this parasite form is more susceptible to the drug.
利什曼原虫对有机锑药物敏感，而有机锑药物作为标准化疗药物已应用超过50年，其原因显然在于该寄生虫的哺乳动物阶段会将所给药的五价形式药物还原为三价形式，从而导致寄生虫死亡。我们已经鉴定并表征了一种寄生虫特异性酶，它能够催化五价锑的还原，因此可能是该药物抗寄生虫活性的关键所在。这种不同寻常的蛋白质是由两个结构域单体组成的三聚体，其中每个结构域与欧米伽类谷胱甘肽S-转移酶有一定相似性，它是一种硫醇依赖性还原酶（命名为TDR1），利用谷胱甘肽作为还原剂将五价锑转化为三价锑。该酶在寄生虫的哺乳动物阶段丰度较高，这可以解释为什么这种寄生虫形式对该药物更敏感。
