揭示泰国伯克霍尔德氏菌抗菌甲基不饱和 2-烷基-4-喹啉酮生物合成的关键步骤

IF 7.9 2区 综合性期刊 Q1 CHEMISTRY, MULTIDISCIPLINARY Cell Reports Physical Science Pub Date : 2024-07-10 DOI:10.1016/j.xcrp.2024.102100
Viktoriia Savchenko, Miriam Jaegers, René Rasche, Eric Herrmann, Simone König, Daniel Kümmel, Thomas Böttcher, Susanne Fetzner, Simon Ernst
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引用次数: 0

摘要

天然产物中的 2-烷基-4(1H)-喹啉酮家族包括多种可作为信号和抗生素的化合物。泰国伯克霍尔德氏菌(Burkholderia thailandensis)的 2-烷基-4(1H)-喹啉酮生物合成途径强烈倾向于生产具有反式-Δ2-不饱和烷基链的 3-甲基化喹啉酮。在这里,我们完成了对该途径的描述,并破译了这种偏好的生化原理。我们的数据表明,中间产物 2-氨基苯甲酰基乙酸酯到 2-(2′-氨基苯甲酰基)丙酸酯(2-ABP)的高效甲基化,加上最终缩合酶 HmqBC 对 2-ABP 和 3-烯酰基供体的底物偏好,是决定产物模式的主要因素。令人惊讶的是,2-ABP 似乎主要分解为 4-羟基-3-甲基-2(1H)-喹啉酮,这表明 HmqBC 造成了酶的瓶颈。虽然喹诺酮类产品的多样性作为一种多靶点抗生素鸡尾酒可能是有利的,但该途径的关键酶还是朝着促进产生对革兰氏阳性细菌和真菌具有特别活性的同系物的方向进化,此外,这些同系物还能抵御 C3 靶向解毒作用。
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Unraveling key steps in the biosynthesis of antimicrobial methylated unsaturated 2-alkyl-4-quinolones of Burkholderia thailandensis

The 2-alkyl-4(1H)-quinolone family of natural products comprises a diverse set of compounds acting as signals and antibiotics. The 2-alkyl-4(1H)-quinolone biosynthetic pathway of Burkholderia thailandensis exhibits a strong preference for the production of 3-methylated quinolones with trans2-unsaturated alkyl chains. Here, we complete the description of the pathway and decipher the biochemical rationale for this preference. Our data suggest that highly efficient methylation of the intermediate 2-aminobenzoylacetate to 2-(2′-aminobenzoyl)propionate (2-ABP), combined with substrate preference of the final condensing enzyme HmqBC for 2-ABP and a 3-alkenoyl donor, is the major factor determining the product pattern. Surprisingly, 2-ABP appears to largely decompose to 4-hydroxy-3-methyl-2(1H)-quinolone, indicating an enzymatic bottleneck created by HmqBC. While the diversity of quinolone products acting as a multitarget antibiotic cocktail may be advantageous, key enzymes of the pathway nevertheless have evolved toward promoting the production of congeners that are active especially toward gram-positive bacteria and fungi and, moreover, resist C3-targeted detoxification.

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来源期刊
Cell Reports Physical Science
Cell Reports Physical Science Energy-Energy (all)
CiteScore
11.40
自引率
2.20%
发文量
388
审稿时长
62 days
期刊介绍: Cell Reports Physical Science, a premium open-access journal from Cell Press, features high-quality, cutting-edge research spanning the physical sciences. It serves as an open forum fostering collaboration among physical scientists while championing open science principles. Published works must signify significant advancements in fundamental insight or technological applications within fields such as chemistry, physics, materials science, energy science, engineering, and related interdisciplinary studies. In addition to longer articles, the journal considers impactful short-form reports and short reviews covering recent literature in emerging fields. Continually adapting to the evolving open science landscape, the journal reviews its policies to align with community consensus and best practices.
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