The Diiron Monooxygenase CmlA from Chloramphenicol Biosynthesis Allows Reconstitution of β-Hydroxylation during Glycopeptide Antibiotic Biosynthesis.,ACS Chemical Biology

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The Diiron Monooxygenase CmlA from Chloramphenicol Biosynthesis Allows Reconstitution of β-Hydroxylation during Glycopeptide Antibiotic Biosynthesis.
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2019-12-10 , DOI: 10.1021/acschembio.9b00862
Milda Kaniusaite _{1,

2} , Robert J A Goode _{1,

3} , Ralf B Schittenhelm _{1,

3} , Thomas M Makris ₄ , Max J Cryle _{1,

2}

Affiliation

β-Hydroxylation plays an important role in the nonribosomal peptide biosynthesis of many important natural products, including bleomycin, chloramphenicol, and the glycopeptide antibiotics (GPAs). Various oxidative enzymes have been implicated in such a process, with the mechanism of incorporation varying from installation of hydroxyl groups in amino acid precursors prior to adenylation to direct amino acid oxidation during peptide assembly. In this work, we demonstrate the in vitro utility and scope of the unusual nonheme diiron monooxygenase CmlA from chloramphenicol biosynthesis for the β-hydroxylation of a diverse range of carrier protein bound substrates by adapting this enzyme as a non-native trans-acting enzyme within NRPS-mediated GPA biosynthesis. The results from our study show that CmlA has a broad substrate specificity for modified phenylalanine/tyrosine residues as substrates and can be used in a practical strategy to functionally cross complement compatible NRPS biosynthesis pathways in vitro.

中文翻译：

来自氯霉素生物合成的二铁单加氧酶 CmlA 可以在糖肽抗生素生物合成过程中重建 β-羟基化。

β-羟基化在许多重要天然产物的非核糖体肽生物合成中发挥着重要作用，包括博莱霉素、氯霉素和糖肽抗生素 (GPA)。各种氧化酶都参与了这样的过程，其掺入机制从腺苷酸化之前在氨基酸前体中安装羟基到肽组装过程中直接氨基酸氧化不等。在这项工作中，我们通过将这种酶作为非天然反式作用酶，展示了来自氯霉素生物合成的罕见非血红素二铁单加氧酶 CmlA 用于多种载体蛋白结合底物 β-羟基化的体外效用和范围。 NRPS 介导的 GPA 生物合成。我们的研究结果表明，CmlA 对修饰的苯丙氨酸/酪氨酸残基作为底物具有广泛的底物特异性，并且可用于在体外功能性交叉互补兼容的 NRPS 生物合成途径的实际策略中。

更新日期：2019-12-11

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