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首页> 外文期刊>Biochemistry >AcpM, the Meromycolate Extension Acyl Carrier Protein of Mycobacterium tuberculosis, Is Activated by the 4 '-Phosphopantetheinyl Transferase PptT, a Potential Target of the Multistep Mycolic Acid Biosynthesis
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AcpM, the Meromycolate Extension Acyl Carrier Protein of Mycobacterium tuberculosis, Is Activated by the 4 '-Phosphopantetheinyl Transferase PptT, a Potential Target of the Multistep Mycolic Acid Biosynthesis

机译：AcpM，结核分枝杆菌的梅拉米考特延伸酰基载体蛋白，被4'-磷酸泛亚锡基转移酶PptT激活，这是多步霉菌酸生物合成的潜在目标

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摘要

Modification of acyl carrier proteins (ACP) or domains by the covalent binding of a 4'-phosphopantetheine (4'-PP) moiety is a fundamental condition for activation of fatty acid synthases (FASes) and polyketide synthases (PKSes). Binding of 4'-PP is mediated by 4' phosphopantetheinyl transfersases (PPTases). Mycobacterium tuberculosis (Mtb) possesses two essential PPTases: acyl carrier protein synthase (Mtb AcpS), which activates the multidomain fatty acid synthase I (FAS I), and Mtb PptT, an Sfp-type broad spectrum PPTase that activates PKSes. To date, it has not been determined which of the two Mtb PPTases, AcpS or PptT, activates the meromycolate extension ACP, Mtb AcpM, en route to the production of mycolic acids, the main components of the mycobacterial cell wall. In this study, we tested the enzymatic activation of a highly purified Mtb apo-AcpM to Mtb holo-AcpM by either Mtb PptT or Mtb AcpS. By using SDS-PAGE band shift assay and mass spectrometry analysis, we found that Mtb PptT is the PPTase that activates Mtb AcpM. We measured the catalytic activity of Mtb PptT toward CoA, using an activation assay of a blue pigment synthase, BpsA (a nonribosomal peptide synthase, NRPS). BpsA activation by Mtb PptT was inhibited by Mtb apo-AcpM through competition for CoA, in accord with Mtb AcpM activation. A structural model of the putative interaction between Mtb PptT and Mtb AcpM suggests that both hydrophobic and electrostatic interactions stabilize this complex. To conclude, activation of Mtb AcpM by Mtb PptT reveals a potential target of the multistep mycolic acid biosynthesis.
机译：通过共价结合4'-磷酸泛素（4'-PP）部分来修饰酰基载体蛋白（ACP）或域是激活脂肪酸合酶（FASes）和聚酮化合物合酶（PKSes）的基本条件。 4'-PP的结合是由4'磷酸泛肽基转移酶（PPTase）介导的。结核分枝杆菌（Mtb）具有两个必需的PPTase：激活多域脂肪酸合酶I（FAS I）的酰基载体蛋白合酶（Mtb AcpS），和激活PKSes的Sfp型广谱PPTase Mtb PptT。迄今为止，尚未确定两种Mtb PPTase，即AcpS或PptT中的哪一种在分支杆菌酸（分枝杆菌细胞壁的主要成分）的生产过程中激活了菌丝体延伸ACP，Mtb AcpM。在这项研究中，我们测试了由Mtb PptT或Mtb AcpS对高纯度Mtb apo-AcpM到Mtb holo-AcpM的酶促活化作用。通过使用SDS-PAGE带移分析和质谱分析，我们发现Mtb PptT是激活Mtb AcpM的PPTase。我们使用蓝色色素合酶BpsA（非核糖体肽合酶，NRPS）的活化试验测量了Mtb PptT对CoA的催化活性。与Mtb AcpM激活相一致，Mtb apo-AcpM通过竞争CoA抑制了Mtb PptT激活的BpsA。 Mtb PptT和Mtb AcpM之间推定相互作用的结构模型表明，疏水和静电相互作用均能稳定该复合物。总之，Mtb PptT对Mtb AcpM的激活揭示了多步霉菌酸生物合成的潜在目标。

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