Exploring anomeric glycosylation of phosphoric acid: Optimisation and scope for non-native substrates

Beswick, Laura; Ahmadipour, Sanaz; Hofman, Gert-Jan; Wootton, Hannah; Dimitriou, Eleni; Reynisson, Jóhannes; Field, Robert A.; Linclau, Bruno; Miller, Gavin J.

doi:10.1016/j.carres.2019.107896

Cited by 7 publications

(9 citation statements)

References 45 publications

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“…Chemical Synthesis of Glycosyl 1-Phosphates. A recently developed synthesis of glycosyl 1-phosphates 3 – 6 , using a modified MacDonald anomeric phosphorylation procedure, meant that these compounds were already available for enzymatic pyrophosphorylation . Accordingly, the chemical synthesis of 4-position analogue 11 and carboxylate analogues 14 and 15 was completed (Scheme ).…”

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confidence: 99%

“…A recently developed synthesis of glycosyl 1-phosphates 3−6, using a modified MacDonald anomeric phosphorylation procedure, meant that these compounds were already available for enzymatic pyrophosphorylation. 15 Accordingly, the chemical For the synthesis of 4-deoxy 4-fluoro mannose 1-phosphate 11, the synthesis began with available thioglycoside 7 16 (Scheme 1a). Treatment of 7 with DAST to effect 4-position fluorination was low yielding (45%) and afforded a mixture of D-mannose and D-idose configured products 8 and 9, corresponding to observations made previously on a related mannose derivative.…”

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confidence: 99%

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Inhibition of the GDP-d-Mannose Dehydrogenase from Pseudomonas aeruginosa Using Targeted Sugar Nucleotide Probes

et al. 2020

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Alginate, an anionic polysaccharide composed of acetylated, β-1,4 linked Dmannuronic acid and α-1,4 linked L-guluronic acid residues, constitutes the major exopolysaccharide component of mucoid Pseudomonas aeruginosa infections. Such infections are particularly deleterious for cystic fibrosis patients, 1 contributing to the establishment of a biofilm environment and augmenting the antibiotic resistance profile of the bacterium. The molecular genetics and regulation of alginate biosynthesis in P. aeruginosa have been wellcharacterised. 2,3 However, our understanding of the chemical biology underpinning polysaccharide production and modification is still incomplete. This represents a significant opportunity to comprehend and exploit such pathways, especially within the global obligation to develop new anti-bacterial strategies; epitomised by recent work developing small molecule inhibitors for c-di-GMP binding to the receptor protein Alg44, which activates alginate production in P. aeruginosa. 4 Pivotal to the alginate biosynthetic pathway is GDP-D-mannose dehydrogenase (GMD), which is required to form the alginate sugar nucleotide feedstock, guanosine diphosphate mannuronic acid (GDP-D-ManA). 5,6 Since there is no corresponding enzyme in humans, specific inhibition of GMD could be envisaged as a tactic to stop alginate production in chronic, mucoid P. aeruginosa infections. 7 GMD belongs to a small group of NAD + -dependent fourelectron-transfer dehydrogenases, 8,9 and converts GDP-D-Man 1 to GDP-D-ManA 2 (Figure 1a); the NAD + -mediated oxidation is proposed to have four discrete steps, facilitated by an active site Cys 268 residue. 10 We recently reported the first series of C6-modified sugar nucleotides to investigate this oxidative mechanism, establishing evidence of a C6-ketone intermediate from oxidation of a C6-CH3 modified analogue. 11 Pursuant of a substrate-based inhibitor of GMD and to further expand structure-activity relationship knowledge (to underpin future small molecule inhibition strategies), we report herein the design, synthesis and evaluation of a matrix of C4-, C5-and C6-modified GDP-D-Man analogues (Figure 1b). Our strategy focused on analogues of the pyranose component within the sugar nucleotide, specifically: i) C6-OH replacements, removing capability for oxidation, but retaining the potential to bind GMD ii) C6 modifications to mimic the product carboxylic acid in 2 and iii) C4 and C5 functional group changes to probe steric and electronic effects involved in substrate binding.

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Inhibition of the GDP-d-Mannose Dehydrogenase from Pseudomonas aeruginosa Using Targeted Sugar Nucleotide Probes

et al. 2020

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“…Synthesis of 6-deoxy-6-thio-ᴅ-mannose 1-phosphate (18) was completed from 14 via C6 substitution with thioacetate and MacDonald phosphorylation [9]. Details of this synthesis were reported by us previously [10]. In this work, we attempted to use these optimised MacDonald conditions to directly access 17 from 14, but the reaction exhibited extensive degradation upon multiple attempts.…”

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confidence: 99%

“…We previously demonstrated the GDP-Man-PP from S. enterica exhibited relaxed specificity towards C4 & C5 pyranose modification, although there is a fine balance to be struck between size and charge when modifying C6 [4]. Substrate 18 was known to form a disulfide in solution [10], presumably resulting in the glycosyl-1-phosphate being unable to access the enzyme active site; unfortunately, the addition of higher concentrations of reducing agent (DTT) and solid-supported PPh 3 to access the reduced form for pyrophosphorylation had no positive effect. In the case of no observable reactivity for substrate 13, likely protonation of the amine would result in unfavourable positive charge within the active site and the absence of vital H-bond contacts.…”

Section: Enzymatic Synthesis Of C6-modified Sugar Nucleotidesmentioning

confidence: 99%

Synthesis of C6-modified mannose 1-phosphates and evaluation of derived sugar nucleotides against GDP-mannose dehydrogenase

Ahmadipour¹,

Wahart²,

Dolan³

et al. 2022

Beilstein J. Org. Chem.

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Sufferers of cystic fibrosis are at significant risk of contracting chronic bacterial lung infections. The dominant pathogen in these cases is mucoid Pseudomonas aeruginosa. Such infections are characterised by overproduction of the exopolysaccharide alginate. We present herein the design and chemoenzymatic synthesis of sugar nucleotide tools to probe a critical enzyme within alginate biosynthesis, GDP-mannose dehydrogenase (GMD). We first synthesise C6-modified glycosyl 1-phosphates, incorporating 6-amino, 6-chloro and 6-sulfhydryl groups, followed by their evaluation as substrates for enzymatic pyrophosphorylative coupling. The development of this methodology enables access to GDP 6-chloro-6-deoxy-ᴅ-mannose and its evaluation against GMD.

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“…[9] Details of this synthesis were reported by us previously. [10] In this work, we attempted to use these optimised MacDonald conditions to directly access 16 from 13, but the reaction exhibited extensive degradation upon multiple attempts.…”

Section: Chemical Synthesis Of 6-chloro-6-deoxy-and 6-amino-6-deoxyma...mentioning

confidence: 99%

Synthesis of C6-modified mannose 1-phosphates and evaluation of derived sugar nucleotides against GDP‑mannose dehydrogenase

Ahmadipour¹,

Wahart²,

Dolan³

et al. 2022

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Exploring anomeric glycosylation of phosphoric acid: Optimisation and scope for non-native substrates

Cited by 7 publications

References 45 publications

Inhibition of the GDP-d-Mannose Dehydrogenase from Pseudomonas aeruginosa Using Targeted Sugar Nucleotide Probes

Inhibition of the GDP-d-Mannose Dehydrogenase from Pseudomonas aeruginosa Using Targeted Sugar Nucleotide Probes

Synthesis of C6-modified mannose 1-phosphates and evaluation of derived sugar nucleotides against GDP-mannose dehydrogenase

Synthesis of C6-modified mannose 1-phosphates and evaluation of derived sugar nucleotides against GDP‑mannose dehydrogenase

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