Polyketides found in nature originate from backbones synthesized through iterative decarboxylative Claisen condensations catalysed by polyketide synthases (PKSs). However, PKSs suffer from complicated architecture, energy inefficiencies, complex regulation, and competition with essential metabolic pathways for extender unit malonyl-CoA, all combining to limit the flux of polyketide biosynthesis. Here we show that certain thiolases, which we term polyketoacyl-CoA thiolases (PKTs), catalyse polyketide backbone formation via iterative non-decarboxylative Claisen condensations, hence offering a synthetic and efficient alternative to PKSs. We show that PKTs can synthesize polyketide backbones for representative lactone, alkylresorcinolic acid, alkylresorcinol, hydroxybenzoic acid and alkylphenol polyketide families, and elucidate the basic catalytic mechanism and structural features enabling this previously unknown activity. PKT-catalysed reactions offer a route to polyketide formation that leverages the simple architecture of thiolases to achieve higher ATP efficiencies and reduced competition with essential metabolic pathways, all of which circumvent intrinsic inefficiencies of PKSs for polyketide product synthesis.

自然界中发现的聚酮化合物源于通过聚酮化合物合酶（PKS）催化的迭代脱羧克莱森缩合反应合成的主链。然而，PKS遭受复杂的结构，能量效率低下，复杂的调节以及与扩展单元丙二酰-CoA的基本代谢途径的竞争，所有这些结合限制了聚酮化合物生物合成的通量。在这里，我们显示某些硫醇，我们称之为聚酮酰基-CoA硫醇（PKT），通过迭代的非脱羧性克莱森缩合反应催化聚酮骨架的形成，从而为PKS提供了一种合成而有效的替代方法。我们显示PKT可以合成具有代表性的内酯，烷基间苯二酚酸，烷基间苯二酚，羟基苯甲酸和烷基酚聚酮化合物家族的聚酮骨架，并阐明使这种以前未知的活性的基本催化机理和结构特征。PKT催化的反应为聚酮化合物的形成提供了一条途径，该途径利用硫醇的简单结构来实现更高的ATP效率并减少与基本代谢途径的竞争，所有这些都避免了PKS固有的对聚酮化合物产品合成的低效率。