Bond C S, Zhang Y, Berriman M, Cunningham M L, Fairlamb A H, Hunter W N
Department of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, UK Department of Biochemistry University of Sydney Sydney NSW 2006 Australia.
Structure. 1999 Jan 15;7(1):81-9. doi: 10.1016/s0969-2126(99)80011-2.
Trypanothione reductase (TR) helps to maintain an intracellular reducing environment in trypanosomatids, a group of protozoan parasites that afflict humans and livestock in tropical areas. This protective function is achieved via reduction of polyamine-glutathione conjugates, in particular trypanothione. TR has been validated as a chemotherapeutic target by molecular genetics methods. To assist the development of new therapeutics, we have characterised the structure of TR from the pathogen Trypanosoma cruzi complexed with the substrate trypanothione and have used the structure to guide database searches and molecular modelling studies.
The TR-trypanothione-disulfide structure has been determined to 2.4 A resolution. The chemical interactions involved in enzyme recognition and binding of substrate can be inferred from this structure. Comparisons with the related mammalian enzyme, glutathione reductase, explain why each enzyme is so specific for its own substrate. A CH***O hydrogen bond can occur between the active-site histidine and a carbonyl of the substrate. This interaction contributes to enzyme specificity and mechanism by producing an electronic induced fit when substrate binds. Database searches and molecular modelling using the substrate as a template and the active site as receptor have identified a class of cyclic-polyamine natural products that are novel TR inhibitors.
The structure of the TR-trypanothione enzyme-substrate complex provides details of a potentially valuable drug target. This information has helped to identify a new class of enzyme inhibitors as novel lead compounds worthy of further development in the search for improved medicines to treat a range of parasitic infections.
锥虫硫醇还原酶（TR）有助于在锥虫体内维持细胞内的还原环境，锥虫是一类原生动物寄生虫，在热带地区感染人类和牲畜。这种保护功能是通过还原多胺 - 谷胱甘肽共轭物，特别是锥虫硫醇来实现的。TR已通过分子遗传学方法被确认为化疗靶点。为了协助开发新的治疗方法，我们已对病原体克氏锥虫的TR与底物锥虫硫醇复合后的结构进行了表征，并利用该结构指导数据库搜索和分子建模研究。
TR - 锥虫硫醇 - 二硫化物结构已确定至2.4埃分辨率。可以从该结构推断出参与酶对底物识别和结合的化学相互作用。与相关的哺乳动物酶谷胱甘肽还原酶的比较解释了为什么每种酶对其自身的底物具有如此高的特异性。活性位点组氨酸与底物的羰基之间可形成一个CH***O氢键。当底物结合时，这种相互作用通过产生电子诱导契合来促进酶的特异性和作用机制。以底物为模板、活性位点为受体进行数据库搜索和分子建模，已鉴定出一类环状多胺天然产物，它们是新型的TR抑制剂。
TR - 锥虫硫醇酶 - 底物复合物的结构提供了一个潜在有价值的药物靶点的详细信息。这些信息有助于鉴定一类新的酶抑制剂作为新型先导化合物，在寻找治疗一系列寄生虫感染的改进药物方面值得进一步开发。
