Editing function of type II thioesterases in the biosynthesis of fungal polyketides

Polyketide synthases (PKSs) are megasynthases with multiple autonomously folding domains, which operate cooperatively in the PKS assemblies to synthesize specific polyketide scaffolds. Any nonreactive intermediates tethered to acyl carrier protein (ACP) domain in the PKS will block the elongation process of polyketide chains. In this study, we systematically elucidate the editing function of fungal type II thioesterases (TEIIs) to hydrolyze ACP domain-bounded nonreactive acyl groups, which are uploaded by substrate promiscuous fungal phosphopantetheinyl transferase. Thereof, the TEIIs encoded in gene clusters of nonreducing PKS with reductase domain exhibit universal editing function. Besides, editing function was also found for TEIIs encoded in gene clusters of highly-reducing PKS with condensation domain. Hence, the editing TEIIs with function of recovery PKS are applied to improve the yield of the fungal polyketides in vivo . Our study provides valuable insights into the editing process of fungal PKSs, highlights the crucial role of TEIIs in enhancing polyketide production and introduces a novel metabolic engineering strategy for fungal polyketide biosynthesis by leveraging the editing function of TEIIs. (c) 2024 Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.