Path to Actinorhodin: Regio- and Stereoselective Ketone Reduction by a Type II Polyketide Ketoreductase Revealed in Atomistic Detail.
In: JACS Au, Jg. 2 (2022-04-07), Heft 4, S. 972
Online
academicJournal
Zugriff:
In type II polyketide synthases (PKSs), which typically biosynthesize several antibiotic and antitumor compounds, the substrate is a growing polyketide chain, shuttled between individual PKS enzymes, while covalently tethered to an acyl carrier protein (ACP): this requires the ACP interacting with a series of different enzymes in succession. During biosynthesis of the antibiotic actinorhodin, produced by Streptomyces coelicolor , one such key binding event is between an ACP carrying a 16-carbon octaketide chain ( act ACP) and a ketoreductase ( act KR). Once the octaketide is bound inside act KR, it is likely cyclized between C7 and C12 and regioselective reduction of the ketone at C9 occurs: how these elegant chemical and conformational changes are controlled is not yet known. Here, we perform protein-protein docking, protein NMR, and extensive molecular dynamics simulations to reveal a probable mode of association between act ACP and act KR; we obtain and analyze a detailed model of the C7-C12-cyclized octaketide within the act KR active site; and we confirm this model through multiscale (QM/MM) reaction simulations of the key ketoreduction step. Molecular dynamics simulations show that the most thermodynamically stable cyclized octaketide isomer (7 R ,12 R ) also gives rise to the most reaction competent conformations for ketoreduction. Subsequent reaction simulations show that ketoreduction is stereoselective as well as regioselective, resulting in an S -alcohol. Our simulations further indicate several conserved residues that may be involved in selectivity of C7-12 cyclization and C9 ketoreduction. Detailed insights obtained on ACP-based substrate presentation in type II PKSs can help design ACP-ketoreductase systems with altered regio- or stereoselectivity.
Competing Interests: The authors declare no competing financial interest.
(© 2022 The Authors. Published by American Chemical Society.)
Titel: |
Path to Actinorhodin: Regio- and Stereoselective Ketone Reduction by a Type II Polyketide Ketoreductase Revealed in Atomistic Detail.
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Autor/in / Beteiligte Person: | Serapian, SA ; Crosby, J ; Crump, MP ; van der Kamp MW |
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Zeitschrift: | JACS Au, Jg. 2 (2022-04-07), Heft 4, S. 972 |
Veröffentlichung: | Washington, DC : American Chemical Society, [2021]-, 2022 |
Medientyp: | academicJournal |
ISSN: | 2691-3704 (electronic) |
DOI: | 10.1021/jacsau.2c00086 |
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