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.; Miller, Gavin J.

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.

Citation

Ahmadipour, S., Pergolizzi, G., Rejzek, M., Field, R. A., & Miller, G. J. (2019). Chemoenzymatic Synthesis of C6-Modified Sugar Nucleotides To Probe the GDP-d-Mannose Dehydrogenase from Pseudomonas aeruginosa. Organic Letters, 21(12), 4415-4419. https://doi.org/10.1021/acs.orglett.9b00967

• Journal Article Type: Article
• Online Publication Date: May 30, 2019
• Publication Date: Jun 21, 2019
• Deposit Date: Jun 15, 2023
• Journal: Organic Letters
• Print ISSN: 1523-7060
• Electronic ISSN: 1523-7052
• Publisher: American Chemical Society
• Peer Reviewed: Peer Reviewed
• Volume: 21
• Issue: 12
• Pages: 4415-4419
• DOI: https://doi.org/10.1021/acs.orglett.9b00967
• Keywords: Organic Chemistry; Physical and Theoretical Chemistry; Biochemistry