The Landscape of Recombination Events That Create Nonribosomal Peptide Diversity.
The Landscape of Recombination Events That Create Nonribosomal Peptide Diversity.
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DOI：
10.1093/molbev/msab015
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发表时间：
2021-05-04
影响因子：
10.7
通讯作者：
Dittmann E
中科院分区：
文献类型：
--
作者：
Baunach M;Chowdhury S;Stallforth P;Dittmann E
非核糖体肽（NRP）是微生物生态中重要的分子介质，提供了不可缺少的药物。然而，与NRPs惊人的结构多样性相关的灵活的生物合成机制的进化却知之甚少。在这里，我们发现重组是细菌NRP合成酶（NRPS）基因跨遥远细菌门进化的关键驱动因素，它通过生物合成基因的广泛混合和匹配指导了大量NRP家族的结构多样化。对大量单个重组事件的系统剖析不仅揭示了交换单元的性质和起源的惊人多样性，而且还允许推导出能够在保持动态多酶复合物功能的同时有效交换腺苷化(a)结构域底物的总体原则。在大多数情况下，重组事件针对Acore域的可变部分，但域接口和灵活的亚博域仍然未开发。我们的研究结果强烈反驳了普遍的假设，即腺苷化和缩合(C)结构域共同进化，并显著挑战了C结构域在NRP合成过程中作为严格选择性过滤器的作用。此外，它们还为NRPS多样性进化过程中自然交换单元的选择提供了宝贵的经验，可以指导未来的工程方法。
Nonribosomal peptides (NRP) are crucial molecular mediators in microbial ecology and provide indispensable drugs. Nevertheless, the evolution of the flexible biosynthetic machineries that correlates with the stunning structural diversity of NRPs is poorly understood. Here, we show that recombination is a key driver in the evolution of bacterial NRP synthetase (NRPS) genes across distant bacterial phyla, which has guided structural diversification in a plethora of NRP families by extensive mixing and matching of biosynthesis genes. The systematic dissection of a large number of individual recombination events did not only unveil a striking plurality in the nature and origin of the exchange units but allowed the deduction of overarching principles that enable the efficient exchange of adenylation (A) domain substrates while keeping the functionality of the dynamic multienzyme complexes. In the majority of cases, recombination events have targeted variable portions of the Acore domains, yet domain interfaces and the flexible Asub domain remained untapped. Our results strongly contradict the widespread assumption that adenylation and condensation (C) domains coevolve and significantly challenge the attributed role of C domains as stringent selectivity filter during NRP synthesis. Moreover, they teach valuable lessons on the choice of natural exchange units in the evolution of NRPS diversity, which may guide future engineering approaches.
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影响因子：
21.8
作者：
Bozhueyuek, Kenan A. J.;Linck, Annabell;Bode, Helge B.
通讯作者：
Bode, Helge B.
影响因子：
16.6
作者：
Calcott, Mark J.;Owen, Jeremy G.;Ackerley, David F.
通讯作者：
Ackerley, David F.
影响因子：
10.7
作者：
Holmes, EC;Worobey, M;Rambaut, A
通讯作者：
Rambaut, A
影响因子：
7.3
作者：
de Veer, Simon J.;Wang, Conan K.;Swedberg, Joakim E.
通讯作者：
Swedberg, Joakim E.
DOI：
10.1073/pnas.1934677100
发表时间：
2003-11-25
影响因子：
11.1
作者：
Challis, GL;Hopwood, DA
通讯作者：
Hopwood, DA