Polyketides are a group of natural products with valuable pharmacological activities, biosynthesized by bacterial or fungal megaenzymes called polyketide synthases (PKSs). These are composed of multiple modules in an assembly line, each introducing a specific moiety of the final compound in a stepwise manner. Among them, trans-acyltransferase PKSs have evolved through the recombination of biosynthetic gene clusters. Now, Mabesoone et al. report in Science the identification, by coevolution analysis, of a common amino acid motif for hybrid PKS formation. This motif — LPTYPF(X₅)W — is found to be a boundary between the ketosynthase domain and a C-terminal region that yields functional PKSs upon trans-acyltransferase PKS recombination. The team used it as an artificial fusion site in the oocydin biosynthetic gene cluster: only LPTYPF(X₅)W-fused chimeras could produce the desired chlorinated compounds. Fusion of the motif to a range of different exchange units also enabled the biosynthesis in diverse bacterial hosts of elongated, varied substrates active against HeLa cells.

On a similar topic, Bozhüyük et al., also in Science, report the use of computational modelling and principal component analyses to understand the intragenomic recombination of nonribosomal peptide synthetases (NRPSs). They identified regions that do not share consistent phylogenetic histories as synthetic breakpoints for engineering NRPSs with high success rates. NRPSs are molecular assembly lines composed of several repeating modules of catalytic domains that biosynthesize complex peptides independently of ribosomes. The team’s approach, termed ‘exchange unit between T domains’ (XUT), allowed the identification of the conserved FFXXGGXS amino acid motif as a recombination site in the thiolation domain. Its application enabled the obtainment of recombinant NRPSs that produced biologically active peptides against the eukaryotic proteasome.

聚酮化合物是一组具有有价值的药理活性的天然产物，由称为聚酮化合物合酶（PKS）的细菌或真菌大酶生物合成。这些由装配线上的多个模块组成，每个模块以逐步的方式引入最终化合物的特定部分。其中，反式酰基转移酶PKS是通过生物合成基因簇的重组而进化而来的。现在，Mabesoone 等人。在《科学》杂志上报告了通过共同进化分析鉴定出杂种 PKS 形成的常见氨基酸基序。该基序——LPTYPF(X ₅ )W——被发现是酮合酶结构域和C末端区域之间的边界，该区域在反式酰基转移酶PKS重组时产生功能性PKS。研究小组将其用作卵胞素生物合成基因簇中的人工融合位点：只有LPTYPF(X ₅ )W融合嵌合体才能产生所需的氯化化合物。该基序与一系列不同交换单元的融合还使得能够在不同的细菌宿主中生物合成对HeLa细胞具有活性的细长的、不同的底物。

关于类似的主题，Bozhüyük 等人也在《科学》杂志上报道了使用计算模型和主成分分析来了解非核糖体肽合成酶 (NRPS) 的基因组内重组。他们确定了不具有一致系统发育历史的区域作为合成断点，以高成功率改造 NRPS。 NRPS 是由多个催化结构域重复模块组成的分子装配线，可独立于核糖体生物合成复杂的肽。该团队的方法被称为“T 结构域之间的交换单元”(XUT)，允许将保守的 FFXXGGXS 氨基酸基序鉴定为硫醇化结构域中的重组位点。它的应用使得获得重组 NRPS 能够产生针对真核蛋白酶体的生物活性肽。