Structural highlights
Function
[PIKA1_STRVZ] Involved in the biosynthesis of 12- and 14-membered ring macrolactone antibiotics such as methymycin and neomethymycin, and pikromycin and narbomycin, respectively. Component of the pikromycin PKS which catalyzes the biosynthesis of both precursors 10-deoxymethynolide (12-membered ring macrolactone) and narbonolide (14-membered ring macrolactone) (PubMed:18512859, PubMed:19437523). Chain elongation through PikAI, PikAII and PikAIII followed by thioesterase catalyzed termination results in the production of 10-deoxymethynolide, while continued elongation through PikAIV, followed by thioesterase (TE) catalyzed cyclization results in the biosynthesis of the narbonolide.[1] [2] [3] [4]
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 Jun 13. pii: S0969-2126(22)00230-1. doi:, 10.1016/j.str.2022.05.021. PMID:35738283[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Tang L, Fu H, Betlach MC, McDaniel R. Elucidating the mechanism of chain termination switching in the picromycin/methymycin polyketide synthase. Chem Biol. 1999 Aug;6(8):553-8. doi: 10.1016/S1074-5521(99)80087-8. PMID:10421766 doi:http://dx.doi.org/10.1016/S1074-5521(99)80087-8
- ↑ Gupta S, Lakshmanan V, Kim BS, Fecik R, Reynolds KA. Generation of novel pikromycin antibiotic products through mutasynthesis. Chembiochem. 2008 Jul 2;9(10):1609-16. doi: 10.1002/cbic.200700635. PMID:18512859 doi:http://dx.doi.org/10.1002/cbic.200700635
- ↑ Yan J, Gupta S, Sherman DH, Reynolds KA. Functional dissection of a multimodular polypeptide of the pikromycin polyketide synthase into monomodules by using a matched pair of heterologous docking domains. Chembiochem. 2009 Jun 15;10(9):1537-43. doi: 10.1002/cbic.200900098. PMID:19437523 doi:http://dx.doi.org/10.1002/cbic.200900098
- ↑ Kittendorf JD, Sherman DH. The methymycin/pikromycin pathway: a model for metabolic diversity in natural product biosynthesis. Bioorg Med Chem. 2009 Mar 15;17(6):2137-46. doi: 10.1016/j.bmc.2008.10.082. Epub , 2008 Nov 5. PMID:19027305 doi:http://dx.doi.org/10.1016/j.bmc.2008.10.082
- ↑ Dickinson MS, Miyazawa T, McCool RS, Keatinge-Clay AT. Priming enzymes from the pikromycin synthase reveal how assembly-line ketosynthases catalyze carbon-carbon chemistry. Structure. 2022 Jun 13. pii: S0969-2126(22)00230-1. doi:, 10.1016/j.str.2022.05.021. PMID:35738283 doi:http://dx.doi.org/10.1016/j.str.2022.05.021
