Chemoenzymatic Synthesis of C6-Modified Sugar Nucleotides to Probe the GDP- d -Mannose Dehydrogenase from Pseudomonas aeruginosa

Ahmadipour, Sanaz, Pergolizzi, Giulia, Rejzek, Martin, Field, Robert A. ORCID: https://orcid.org/0000-0001-8574-0275 and Miller, Gavin J. (2019) Chemoenzymatic Synthesis of C6-Modified Sugar Nucleotides to Probe the GDP- d -Mannose Dehydrogenase from Pseudomonas aeruginosa. Organic Letters, 21 (12). pp. 4415-4419. ISSN 1523-7060

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Abstract

The chemoenzymatic synthesis of a series of C6-modified GDP-d-Man sugar nucleotides is described. This provides the first structure-function tools for the GDP-d-ManA producing GDP-d-mannose dehydrogenase (GMD) from Pseudomonas aeruginosa. Using a common C6 aldehyde functionalization strategy, chemical synthesis introduces deuterium enrichment, alongside one-carbon homologation at C6 for a series of mannose 1-phosphates. These materials are shown to be substrates for the GDP-mannose pyrophosphorylase from Salmonella enterica, delivering the required toolbox of modified GDP-d-Mans. C6-CH3 modified sugar-nucleotides are capable of reversibly preventing GDP-ManA production by GMD. The ketone product from oxidation of a C6-CH3 modified analogue is identified by high-resolution mass spectrometry.

Item Type:	Article
Additional Information:	Funding Information: The Engineering and Physical Research Council (EPSRC) are thanked for project grant funding (No. EP/P000762/1) to G.J.M. at Keele. We also thank the EPSRC UK National Mass Spectrometry Facility (NMSF) at Swansea University, Dr. Richard Darton (Keele) for running nOe spectra, Prof. Peter Tipton (University of Missouri) for providing the GMD plasmid, and Professor Todd Lowary (University of Alberta) for providing the GDP-mannose pyrophosphorylase clone. Work at the JIC is supported by the Biotechnology and Biological Science Research Council (BBSRC) Institute Strategic Program on Molecules from NatureProducts and Pathways (No. BBS/E/J/000PR9790) and the InnovateUK IBCatalyst [Nos. BB/M02903411 and EP/N033167/10]. Funding Information: The Engineering and Physical Research Council (EPSRC) are thanked for project grant funding (No. EP/P000762/1) to G.J.M. at Keele. We also thank the EPSRC UK National Mass Spectrometry Facility (NMSF) at Swansea University, Dr. Richard Darton (Keele) for running nOe spectra, Prof. Peter Tipton (University of Missouri) for providing the GMD plasmid, and Professor Todd Lowary (University of Alberta) for providing the GDP-mannose pyrophosphorylase clone. Work at the JIC is supported by the Biotechnology and Biological Science Research Council (BBSRC) Institute Strategic Program on Molecules from Nature??"Products and Pathways (No. BBS/E/J/000PR9790) and the InnovateUK IBCatalyst [Nos. BB/M02903411 and EP/N033167/10]. Publisher Copyright: © 2019 American Chemical Society.
Uncontrolled Keywords:	biochemistry,physical and theoretical chemistry,organic chemistry ,/dk/atira/pure/subjectarea/asjc/1300/1303
Faculty \ School:	Faculty of Science > School of Chemistry, Pharmacy and Pharmacology
Related URLs:	http://www.scopus.com/inward/record.url?...
Depositing User:	LivePure Connector
Date Deposited:	02 Sep 2024 15:30
Last Modified:	25 Sep 2024 18:05
URI:	https://ueaeprints.uea.ac.uk/id/eprint/96446
DOI:	10.1021/acs.orglett.9b00967

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