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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Identification of the biosynthetic gene cluster for the pacidamycin group of peptidyl nucleoside antibiotics
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Identification of the biosynthetic gene cluster for the pacidamycin group of peptidyl nucleoside antibiotics

机译：pacidamycin组肽基核苷抗生素的生物合成基因簇的鉴定

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摘要

Pacidamycins are a family of uridyl tetra/pentapeptide antibiotics that act on the translocase MraY to block bacterial cell wall assembly. To elucidate the biosynthetic logic of pacidamcyins, a putative gene cluster was identified by 454 shotgun genome sequencing of the producer Streptomyces coeruleorubidus NRRL18370. The 31-kb gene cluster encodes 22 proteins (PacA-V), including highly dissociated nonribosomal peptide synthetase (NRPS) modules and a variety of tailoring enzymes. Gene deletions confirmed that two NRPSs, PacP and PacO, are required for the biosynthesis of pacidamycins. Heterologous expression and in vitro assays of PacL., PacO, and PacP established reversible formation of m-Tyr-AMP, L-Ala-AMP, and diaminopropionyl-AMP, respectively, consistent with the ami-no acids found in pacidamycin scaffolds. The unusual Ala4-Phe5 dipeptidyl ureido linkage was formed during in vitro assays containing purified PacL, Pad, PacN, and PacO. Both the genetic and enzymatic studies validate identification of the biosynthetic genes for this subclass of uridyl peptide antibiotics and provide the basis for future mechanistic study of their biosynthesis.
机译：泛酸霉素是一类尿嘧啶四/五肽抗生素，可作用于转位酶MraY上，以阻止细菌细胞壁的组装。为了阐明帕西霉素的生物合成逻辑，通过生产者蓝藻链霉菌NRRL18370的454 gun弹子基因组测序鉴定了一个推定的基因簇。 31kb的基因簇编码22种蛋白质（PacA-V），包括高度解离的非核糖体肽合成酶（NRPS）模块和多种定制酶。基因缺失证实，pacidamycins的生物合成需要两个NRPS PacP和PacO。 PacL。，PacO和PacP的异源表达和体外测定分别建立了m-Tyr-AMP，L-Ala-AMP和二氨基丙酰-AMP的可逆形成，这与在pacidamycin支架中发现的氨基酸一致。在包含纯化的PacL，Pad，PacN和PacO的体外分析过程中，形成了异常的Ala4-Phe5二肽基脲基键。遗传学和酶学研究均证实了该亚基尿嘧啶肽抗生素亚类的生物合成基因的鉴定，并为未来对其生物合成的机理研究提供了基础。

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  • 作者

    Wenjun Zhang; Bohdan Ostash; Christopher T. Walsh;

  • 作者单位

    Department of Biological Chemistry and Molecular Pharmacology Harvard Medical School,Boston, MA 02115 Department of Chemical and Biomolecular Engineering, University of California, Berkeley, CA 94720;

    rnDepartment of Microbiology and Moledular Genetics, Harvard Medical School,Boston, MA 02115 Department of Genetics and Biotechnology, Ivan Franko National University of L'viv, L'viv 79005, Ukraine;

    rnDepartment of Biological Chemistry and Molecular Pharmacology Harvard Medical School,Boston, MA 02115;

  • 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
  • 中图分类
  • 关键词

    adenylation; ureido-bond; uridine;

    机译：腺苷酸化脲基键;尿苷;

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