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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Bisubstrate specificity in histidine/tryptophan biosynthesis isomerase from Mycobacterium tuberculosis by active site metamorphosis
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Bisubstrate specificity in histidine/tryptophan biosynthesis isomerase from Mycobacterium tuberculosis by active site metamorphosis

机译：结核分枝杆菌通过活动位点变态在组氨酸/色氨酸生物合成异构酶中的双底物特异性

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摘要

In histidine and tryptophan biosynthesis, two related isomeriza-tion reactions are generally catalyzed by two specific single-substrate enzymes (HisA and TrpF), sharing a similar (β/α)_8-barrel scaffold. However, in some actinobacteria, one of the two encoding genes (trpF) is missing and the two reactions are instead catalyzed by one bisubstrate enzyme (PriA). To unravel the unknown mechanism of bisubstrate specificity, we used the Mycobacterium tuberculosis PriA enzyme as a model. Comparative structural analysis of the active site of the enzyme showed that PriA undergoes a reaction-specific and substrate-induced metamorphosis of the active site architecture, demonstrating its unique ability to essentially form two different substrate-specific actives sites. Furthermore, we found that one of the two catalytic residues in PriA, which are identical in both isomerization reactions, is recruited by a substrate-dependent mechanism into the active site to allow its involvement in catalysis. Comparison of the structural data from PriA with one of the two single-substrate enzymes (TrpF) revealed substantial differences in the active site architecture, suggesting independent evolution. To support these observations, we identified six small molecule compounds that inhibited both PriA-catalyzed isomerization reactions but had no effect on TrpF activity. Our data demonstrate an opportunity for organism-specific inhibition of enzymatic catalysis by taking advantage of the distinct ability for bisubstrate catalysis in the M. tuberculosis enzyme.
机译：在组氨酸和色氨酸的生物合成中，两个相关的异构化反应通常由两种特定的单底物酶（HisA和TrpF）催化，它们共享相似的（β/α）_8桶形支架。但是，在某些放线菌中，缺少两个编码基因（trpF）之一，而是通过一种双底物酶（PriA）催化了两个反应。为了揭示双底物特异性的未知机制，我们使用结核分枝杆菌PriA酶作为模型。酶的活性位点的比较结构分析表明，PriA经历了反应特异性和底物诱导的活性位点构型的变态，证明了其基本形成两个不同底物特异性活性位点的独特能力。此外，我们发现PriA中两个异构化反应中相同的两个催化残基之一是通过底物依赖性机制募集到活性位点的，以使其参与催化。来自PriA的结构数据与两种单底物酶（TrpF）之一的比较表明，活性位点结构存在实质性差异，表明独立进化。为了支持这些观察，我们鉴定了六个小分子化合物，它们均抑制了PriA催化的异构化反应，但对TrpF活性没有影响。我们的数据证明了通过利用结核分枝杆菌酶中双底物催化的独特能力，有机体特异性抑制酶催化的机会。

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    Anne V. Due; Jochen Kuper; Arie Geerlof; Jens Peter von Kries; Matthias Wilmanns;

  • 作者单位

    European Molecular Biology Laboratory, Hamburg Unit, Notkestrasse 85, D-22603 Hamburg, Germany The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037;

    European Molecular Biology Laboratory, Hamburg Unit, Notkestrasse 85, D-22603 Hamburg, Germany Rudolf Virchow Center for Biomedical Research, Versbacher Strasse 9, D-97078 Wurzburg, Germany;

    European Molecular Biology Laboratory, Hamburg Unit, Notkestrasse 85, D-22603 Hamburg, Germany Helmholtz Center Munich, Institute of Structural Biology, Ingolstadter Landstrasse 1, D-85764 Neuherberg, Germany;

    Leibniz-Institute for Molecular Pharmacology (FMP), Robert-Roessle-Strasse 10, D-13125 Berlin, Germany;

    European Molecular Biology Laboratory, Hamburg Unit, Notkestrasse 85, D-22603 Hamburg, Germany;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
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  • 关键词

    amino acid biosynthesis; enzyme evolution; mycobacteria; active site substrate adaptability; protein structure symmetry;

    机译：氨基酸生物合成酶进化分枝杆菌;活性部位底物适应性;蛋白质结构对称;

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