9c3x

Publication Abstract from PubMed

Type III polyketide synthases (PKSs) have a much simpler three-dimensional architecture compared with their type I and type II counterparts, yet they catalyze iterative polyketide elongation to generate a myriad of products in plants, fungi, and eubacteria. Despite this mechanistic complexity occurring within a single active site, the mechanism by which type III PKSs stabilize and direct their highly reactive keto and enolate intermediates has yet to be fully understood. Here, we report the synthesis and deployment of stable polyketone CoA analogues for each putative intermediate involved in the biphenyl synthase (BIS) mechanism together with three high-resolution crystal structures of each in complex with BIS from Malus domestica. This set of structures reveals key mechanistic features that control the number of iterative elongation steps and that shape the static architectural features responsible for organization of a water-mediated hydrogen bonding network necessary for termination of the elongation reaction by an intramolecular aldol cyclization and production of the 3,5-dihydroxybiphenyl BIS product. Elucidating these protein-substrate interactions provides a foundation for using polyketone CoA analogues to further unravel the control mechanisms of PKS catalysis and gain the insight necessary for predictive engineering of these enzymes.

Elucidating the Iterative Elongation Mechanism in a Type III Polyketide Synthase.,Re RN, La Clair JJ, Noel JP, Burkart MD J Am Chem Soc. 2025 May 1. doi: 10.1021/jacs.5c05635. PMID:40312803^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.