Bioinformatics Group.
Department of Plant Sciences Biometris, Wageningen University & Research, 6708 PB Wageningen, The Netherlands.
Bioinformatics. 2020 Dec 8;36(19):4846-4853. doi: 10.1093/bioinformatics/btaa595.
Polyketide synthases (PKSs) are enzymes that generate diverse molecules of great pharmaceutical importance, including a range of clinically used antimicrobials and antitumor agents. Many polyketides are synthesized by cis-AT modular PKSs, which are organized in assembly lines, in which multiple enzymes line up in a specific order. This order is defined by specific protein-protein interactions (PPIs). The unique modular structure and catalyzing mechanism of these assembly lines makes their products predictable and also spurred combinatorial biosynthesis studies to produce novel polyketides using synthetic biology. However, predicting the interactions of PKSs, and thereby inferring the order of their assembly line, is still challenging, especially for cases in which this order is not reflected by the ordering of the PKS-encoding genes in the genome.
Here, we introduce PKSpop, which uses a coevolution-based PPI algorithm to infer protein order in PKS assembly lines. Our method accurately predicts protein orders (93% accuracy). Additionally, we identify new residue pairs that are key in determining interaction specificity, and show that coevolution of N- and C-terminal docking domains of PKSs is significantly more predictive for PPIs than coevolution between ketosynthase and acyl carrier protein domains.
The code is available on http://www.bif.wur.nl/ (under 'Software').
Supplementary data are available at Bioinformatics online.
聚酮合酶（PKSs）是生成具有重要药物价值的各种分子的酶，包括一系列临床使用的抗菌剂和抗肿瘤剂。许多聚酮类化合物是由顺式 AT 模块化 PKS 合成的，这些 PKS 以装配线的形式组织在一起，其中多个酶按照特定的顺序排列。这种顺序由特定的蛋白质-蛋白质相互作用（PPIs）定义。这些装配线独特的模块化结构和催化机制使得它们的产物具有可预测性，并促使组合生物合成研究使用合成生物学来生产新型聚酮类化合物。然而，预测 PKS 之间的相互作用，从而推断它们的装配线顺序，仍然具有挑战性，特别是在这种顺序没有反映在基因组中 PKS 编码基因的排序中的情况下。
在这里，我们引入了 PKSpop，它使用基于共进化的 PPI 算法来推断 PKS 装配线中的蛋白质顺序。我们的方法可以准确地预测蛋白质的顺序（准确率为 93%）。此外，我们还确定了新的残基对，这些残基对决定相互作用的特异性至关重要，并表明 PKS 的 N 端和 C 端对接结构域的共进化对于 PPI 比酮合酶和酰基载体蛋白结构域之间的共进化更具预测性。
代码可在 http://www.bif.wur.nl/ 上获得（位于“软件”下）。
补充数据可在 Bioinformatics 在线获得。
