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首页> 外文期刊>ACS Chemical Biology >Molecular Basis of Bacillus subtilis ATCC 6633 Self-Resistance to the Phosphono-oligopeptide Antibiotic Rhizocticin
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Molecular Basis of Bacillus subtilis ATCC 6633 Self-Resistance to the Phosphono-oligopeptide Antibiotic Rhizocticin

机译：枯草芽孢杆菌ATCC 6633的分子基础对膦寡肽抗生素Rhizocticin的自体抗性

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摘要

Rhizocticins are phosphono-oligopeptide antibiotics that contain a toxic C-terminal (Z)-L-2-amino-5-phosphono-3-pentenoic acid (APPA) moiety. APPA is an irreversible inhibitor of threonine synthase (ThrC), a pyridoxal 5'-phosphate (PLP)-dependent enzyme that catalyzes the conversion of O-phospho-L-homoserine to L-threonine. ThrCs are essential for the viability of bacteria, plants, and fungi and are a target for antibiotic development, as de novo threonine biosynthetic pathway is not dfound in humans. Given the ability of APPA to interfere in threonine metabolism, it is unclear how the producing strain B. subtilis ATCC 6633 circumvents APPA toxicity. Notably, in addition to the housekeeping APPA-sensitive ThrC (BsThrC), B. subtilis encodes a second threonine synthase (RhiB) encoded within the rhizocticin biosynthetic gene cluster. Kinetic and spectroscopic analyses show that PLP-dependent RhiB is an authentic threonine synthase, converting O-phospho-L-homoserine to threonine with a catalytic efficiency comparable to BsThrC. To understand the structural basis of inhibition, we determined the crystal structure of APPA bound to the housekeeping BsThrC, revealing a covalent complex between the inhibitor and PLP. Structure-based sequence analyses reveal structural determinants within the RhiB active site that contribute to rendering this ThrC homologue resistant to APPA. Together, this work establishes the self-resistance mechanism utilized by B. subtilis ATCC 6633 against APPA exemplifying one of many ways by which bacteria can overcome phosphonate toxicity.
机译：rhizocticins是含有毒性C-末端（Z）-L-2-氨基-5-膦-3-戊烯酸（APPA）部分的膦寡糖抗生素。 APPA是苏氨酸合成酶（THRC）的不可逆抑制剂，吡哆醛5'-磷酸（PLP）依赖性酶，其催化O-磷酸-1-纯于L-苏氨酸的转化物。 THRC对于细菌，植物和真菌的活力至关重要，并且是抗生素发育的靶标，因为De Novo苏氨酸生物合成途径没有在人体中被发现。鉴于Appa在苏氨酸代谢中干扰的能力，目前还不清楚生产菌株B.枯草芽孢杆菌ATCC 6633周围的毒性。值得注意的是，除了家务治疗APPA敏感的THRC（BSTHRC），B.枯草芽孢杆菌编码在rhizocticin生物合成基因簇内编码的第二个苏氨酸合酶（rhib）。动力学和光谱分析表明，PLP依赖性的rhib是一种正宗的苏氨酸合成酶，将O-磷酸-1-莫野碱转化为苏氨酸，催化效率与BSTHRC相当。要了解抑制的结构基础，我们确定了与管家BSTHRC结合的APPA的晶体结构，揭示了抑制剂和PLP之间的共价络合物。基于结构的序列分析揭示了罗布活性位点内的结构决定簇，其有助于使该基于APA的抗性。这项工作在一起建立了B.枯草芽孢杆菌ATCC 6633针对APPA使用的自抵抗机制，其中含有细菌可以克服膦酸毒性的许多方式之一。

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  • 来源
    《ACS Chemical Biology》 |2019年第4期|共9页
  • 作者

    Petronikolou Nektaria; Ortega Manuel A.; Borisova Svetlana A.; Nair Satish K.; Metcalf William W.;

  • 作者单位

    Univ Illinois Dept Biochem Roger Adams Lab 600 S Mathews Ave Urbana IL 61801 USA;

    Univ Illinois Carl R Woese Inst Genom Biol 1206 W Gregory Dr Urbana IL 61801 USA;

    Univ Illinois Carl R Woese Inst Genom Biol 1206 W Gregory Dr Urbana IL 61801 USA;

    Univ Illinois Dept Biochem Roger Adams Lab 600 S Mathews Ave Urbana IL 61801 USA;

    Univ Illinois Carl R Woese Inst Genom Biol 1206 W Gregory Dr Urbana IL 61801 USA;

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  • 正文语种 eng
  • 中图分类 生物化学;
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