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Publication Abstract from PubMed

The first domain of modular polyketide synthases (PKSs) is most commonly a ketosynthase (KS)-like enzyme, KS(Q), that primes polyketide synthesis. Unlike downstream KSs that fuse alpha-carboxyacyl groups to growing polyketide chains, it performs an extension-decoupled decarboxylation of these groups to generate primer units. When Pik127, a model triketide synthase constructed from modules of the pikromycin synthase, was studied by cryoelectron microscopy (cryo-EM), the dimeric didomain comprised of KS(Q) and the neighboring methylmalonyl-selective acyltransferase (AT) dominated the class averages and yielded structures at 2.5- and 2.8-A resolution, respectively. Comparisons with ketosynthases complexed with their substrates revealed the conformation of the (2S)-methylmalonyl-S-phosphopantetheinyl portion of KS(Q) and KS substrates prior to decarboxylation. Point mutants of Pik127 probed the roles of residues in the KS(Q) active site, while an AT-swapped version of Pik127 demonstrated that KS(Q) can also decarboxylate malonyl groups. Mechanisms for how KS(Q) and KS domains catalyze carbon-carbon chemistry are proposed.

Priming enzymes from the pikromycin synthase reveal how assembly-line ketosynthases catalyze carbon-carbon chemistry.,Dickinson MS, Miyazawa T, McCool RS, Keatinge-Clay AT Structure. 2022 Sep 1;30(9):1331-1339.e3. doi: 10.1016/j.str.2022.05.021. Epub , 2022 Jun 22. PMID:35738283^[1]

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