1 Laboratory Redox Biology of Trypanosomes, Institut Pasteur de Montevideo , Montevideo, Uruguay .
2 Laboratorio de Fisicoquímica Biológica, Instituto de Química Biológica , Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay .
Antioxid Redox Signal. 2018 Feb 20;28(6):463-486. doi: 10.1089/ars.2017.7133. Epub 2017 Nov 27.
Major pathogenic enterobacteria and protozoan parasites from the phylum Euglenozoa, such as trypanosomatids, are endowed with glutathione (GSH)-spermidine (Sp) derivatives that play important roles in signaling and metal and thiol-redox homeostasis. For some Euglenozoa lineages, the GSH-Sp conjugates represent the main redox cosubstrates around which entire new redox systems have evolved. Several proteins underwent molecular adaptations to synthesize and utilize the new polyamine-based thiols. Recent Advances: The genomes of closely related organisms have recently been sequenced, which allows mining and analysis of gene sequences that belong to these peculiar redox systems. Similarly, the three-dimensional structures of several of these proteins have been solved, which allows for comparison with their counterparts in classical redox systems that rely on GSH/glutaredoxin and thioredoxin.
The evolutionary and structural aspects related to the emergence and use of GSH-Sp conjugates in Euglenozoa are reviewed focusing on unique structural specializations that proteins developed to use N,N-bisglutathionylspermidine (trypanothione) as redox cosubstrate. An updated overview on the biochemical and biological significance of the major enzymatic activities is also provided.
A thiol-redox system strictly dependent on trypanothione is a feature unique to trypanosomatids. The physicochemical properties of the polyamine-GSH conjugates were a major driving force for structural adaptation of proteins that use these thiols as ligand and redox cofactor. In fact, the structural differences of indispensable components of this system can be exploited toward selective drug development. Future research should clarify whether additional cellular processes are regulated by the trypanothione system. Antioxid. Redox Signal. 28, 463-486.
主要的致病性肠杆菌和原生动物寄生虫属于 Euglenozoa 门，例如鞭毛虫，它们具有谷胱甘肽 (GSH)-亚精胺 (Sp) 衍生物，在信号转导以及金属和硫醇-氧化还原稳态中发挥重要作用。对于一些 Euglenozoa 谱系，GSH-Sp 缀合物代表了整个新氧化还原系统进化围绕的主要氧化还原共底物。几种蛋白质经历了分子适应，以合成和利用新的多胺基硫醇。最新进展：最近测序了密切相关的生物体的基因组，这允许对属于这些特殊氧化还原系统的基因序列进行挖掘和分析。同样，这些蛋白质的几个三维结构已经被解决，这允许与依赖 GSH/谷胱甘肽还原酶和硫氧还蛋白的经典氧化还原系统的对应物进行比较。
本文重点介绍了 Euglenozoa 中 GSH-Sp 缀合物出现和使用的进化和结构方面，特别强调了蛋白质为使用 N,N-双谷胱甘肽亚精胺（三肽）作为氧化还原共底物而发展的独特结构专业化。还提供了主要酶活性的生化和生物学意义的最新概述。
严格依赖三肽的硫醇-氧化还原系统是鞭毛虫的一个独特特征。多胺-GSH 缀合物的物理化学性质是使用这些硫醇作为配体和氧化还原辅因子的蛋白质结构适应的主要驱动力。事实上，该系统不可缺少成分的结构差异可以被利用来进行有选择性的药物开发。未来的研究应该阐明是否有其他细胞过程受到三肽系统的调节。抗氧化。氧化还原信号。28, 463-486。
