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Conservation of the structure and function of bacterial tryptophan synthases

机译：细菌色氨酸合酶的结构和功能的保守性

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Tryptophan biosynthesis is one of the most characterized processes in bacteria, in which the enzymes from Salmonella typhimurium and Escherichia coli serve as model systems. Tryptophan synthase (TrpAB) catalyzes the final two steps of tryptophan biosynthesis in plants, fungi and bacteria. This pyridoxal 5′-phosphate (PLP)-dependent enzyme consists of two protein chains, α (TrpA) and β (TrpB), functioning as a linear αββα heterotetrameric complex containing two TrpAB units. The reaction has a complicated, multistep mechanism resulting in the β-replacement of the hydroxyl group of l-serine with an indole moiety. Recent studies have shown that functional TrpAB is required for the survival of pathogenic bacteria in macrophages and for evading host defense. Therefore, TrpAB is a promising target for drug discovery, as its orthologs include enzymes from the important human pathogens Streptococcus pneumoniae, Legionella pneumophila and Francisella tularensis, the causative agents of pneumonia, legionnaires' disease and tularemia, respectively. However, specific biochemical and structural properties of the TrpABs from these organisms have not been investigated. To fill the important phylogenetic gaps in the understanding of TrpABs and to uncover unique features of TrpAB orthologs to spearhead future drug-discovery efforts, the TrpABs from L. pneumophila, F. tularensis and S. pneumoniae have been characterized. In addition to kinetic properties and inhibitor-sensitivity data, structural information gathered using X-ray crystallo­graphy is presented. The enzymes show remarkable structural conservation, but at the same time display local differences in both their catalytic and allosteric sites that may be responsible for the observed differences in catalysis and inhibitor binding. This functional dissimilarity may be exploited in the design of species-specific enzyme inhibitors.
机译：色氨酸的生物合成是细菌中最具特征的过程之一，其中鼠伤寒沙门氏菌和大肠杆菌的酶充当模型系统。色氨酸合酶（TrpAB）催化植物，真菌和细菌中色氨酸生物合成的最后两个步骤。这种吡ido醛5'-磷酸（PLP）依赖性酶由两条蛋白链，即α（TrpA）和β（TrpB）组成，起包含两个TrpAB单元的线性αββα异四聚体复合物的作用。该反应具有复杂的多步机理，导致β-丝氨酸的羟基被吲哚部分取代。最近的研究表明，功能性TrpAB是巨噬细胞中病原细菌生存和逃避宿主防御所必需的。因此，TrpAB是一种有前途的药物发现靶标，因为其直系同源物包括来自重要人类病原体的酶，分别来自肺炎链球菌，肺炎军团菌和土拉弗朗西斯菌，肺炎的病原体，退伍军人病和吐拉血病。但是，尚未研究来自这些生物的TrpAB的特定生化和结构特性。为了填补对TrpAB的认识上的重要系统发育空白，并揭示TrpAB直系同源物的独特特征，以带头开展未来的药物发现工作，已鉴定了嗜肺乳杆菌，图拉菌和肺炎链球菌的TrpAB。除了动力学性质和抑制剂敏感性数据外，还介绍了使用X射线晶体学收集的结构信息。这些酶显示出显着的结构保守性，但同时在其催化位点和变构位点上均显示出局部差异，这可能是所观察到的催化和抑制剂结合差异的原因。在设计物种特异性酶抑制剂时可以利用这种功能上的差异。

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