Reversible and Efficient Inhibition of UDP‐Galactopyranose Mutase by Electrophilic, Constrained and Unsaturated UDP‐Galactitol Analogues

Ansiaux, Christophe; N’Go, Inès; Vincent, Stéphane

doi:10.1002/chem.201202302

Cited by 32 publications

(18 citation statements)

References 89 publications

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“…The galactose–N5-flavin covalent adduct we isolated suggests that CeUGM uses a nucleophilic flavin cofactor to catalyze isomerization of UDP-Gal p and UDP-Gal f (Figure 2). We and others 50 posit that the nucleophilic character of the UGM flavin can be targeted by small molecules for potent and selective inhibition of UDP-Gal f biosynthesis.…”

Section: Resultsmentioning

confidence: 99%

UDP-Galactopyranose Mutase in Nematodes

et al. 2013

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Nematodes represent a diverse phylum of both free living and parasitic species. While the species Caenorhabditis elegans (C. elegans) is a valuable model organism, parasitic nematodes or helminths pose a serious threat to human health. Indeed, helminths cause many neglected tropical diseases that afflict humans. Nematode glycoconjugates have been implicated in evasive immunomodulation, a hallmark of nematode infections. One monosaccharide residue present in the glycoconjugates of several human pathogens is galactofuranose (Galf). This five-membered ring isomer of galactose has not been detected in mammals, making Galf metabolic enzymes attractive therapeutic targets. The only known pathway for biosynthetic incorporation of Galf into glycoconjugates depends upon generation of the glycosyl donor UDP-Galf by the flavoenzyme uridine 5’-diphosphate (UDP) galactopyranose mutase (UGM or Glf). A putative UGM encoding gene (glf-1) was recently identified in C. elegans. Because Galf has yet to be identified in any nematode glycan, we sought to assess the catalytic activity of the C. elegans glf-1 gene product (CeUGM). We found that CeUGM catalyzes the isomerization of UDP-Galf and UDP-galactopyranose (UDP-Galp). In the presence of enzyme, substrate, and a hydride source, a galactose–N5-FAD adduct was isolated, suggesting the CeUGM flavin adenine dinucleotide (FAD) cofactor serves as a nucleophile in covalent catalysis. Homology modeling and protein variants indicate that CeUGM possesses an active site similar to that of prokaryotic enzymes, despite the low sequence identity (~15%) between eukaryotic and prokaryotic UGM proteins. Even with the primary sequence differences, heterocyclic UGM inhibitors developed against prokaryotic proteins also inhibit CeUGM activity. We postulate that these inhibitors can serve as chemical probes of Galf in nematodes and as anthelmintic leads. Together, our data suggest that CeUGM facilitates the biosynthetic incorporation of Galf into nematode glycoconjugates through generation of the glycosyl donor UDP-Galf.

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Section: Resultsmentioning

confidence: 99%

UDP-Galactopyranose Mutase in Nematodes

et al. 2013

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“…In 2012, our group took advantage of this elegant epoxidation–DBCE sequence to attribute the absolute configuration of several uridine diphosphate (UDP) galactitols . These molecules were designed as inhibitors of the UDP galactopyranose mutase (UGM), which catalyzes a key step of Mycobacterium tuberculosis cell‐wall biosynthesis.…”

Section: Activation Of An Alkene Positioned γ To a Benzyloxy Groupmentioning

confidence: 99%

Debenzylative Cycloetherification: An Overlooked Key Strategy for Complex Tetrahydrofuran Synthesis

Tikad

Delbrouck

Vincent

2016

Chemistry A European J

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Tetrahydrofuran (THF) is a major structural feature found in many synthetic and natural products displaying a variety of biological properties. This review summarizes the main synthetic approaches that have been developed to construct tetrahydrofuran moieties involving debenzylative cycloetherification reactions (DBCE). Interestingly, this reaction is regio- and stereoselective without the requirement of a selective protection/deprotection strategy. Many applications of this process have been reported, including carbafuranoside synthesis, regioselective deprotection of the benzyl group positioned γ to an alkene, and total synthesis of natural products. The stereochemical outcome and the mechanism of these interesting transformations are also discussed.

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“…Nucleoside phosphoroimidazolidates have been used in the synthesis of nucleoside polyphosphates and their conjugates for decades (Scheme ) . Activated compounds 17 can be obtained in dry DMF by the treatment of nucleoside phosphates 16 with carbonyl diimidazole/trialkylamine (Scheme A) or by Ph 3 P/(Py 2 S) (Scheme B) in the presence of imidazole ,. A convenient method for the preparation of phosphoroimidazolidates 17 in aqueous medium by treatment of nucleotides 16 with 2‐chloro‐1,3‐dimethylimidazolinium chloride (DMC) and imidazole (Scheme C) was proposed …”

Section: The Use Of Compounds Containing P−n Bondsmentioning

confidence: 99%

How To Form a Phosphate Anhydride Linkage in Nucleotide Derivatives

Sherstyuk

Abramova

2015

ChemBioChem

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The fundamental roles of nucleoside triphosphates and nucleotide cofactors such as NAD(+) in biochemistry are well known. In recent decades, continuing research has revealed the key role of 5'-capped RNA and 5',5'-dinucleoside polyphosphates in the regulation of vitally important physiological processes. Last but not least, the commercial potential of nucleoside triphosphate synthesis can hardly be overestimated. Nevertheless, despite decades of investigation and the obvious topicality of the research on the chemical synthesis of the nucleotide compounds containing phosphate anhydride linkages, none of the existing procedures can be considered an up-to-date "gold standard". However, there are a number of fruitful synthetic approaches to forming phosphate anhydride linkages in satisfactory yield. These are summarized in this concise review, organized by the type of active phosphorous intermediate and reagents used.

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Reversible and Efficient Inhibition of UDP‐Galactopyranose Mutase by Electrophilic, Constrained and Unsaturated UDP‐Galactitol Analogues

Cited by 32 publications

References 89 publications

UDP-Galactopyranose Mutase in Nematodes

UDP-Galactopyranose Mutase in Nematodes

Debenzylative Cycloetherification: An Overlooked Key Strategy for Complex Tetrahydrofuran Synthesis

How To Form a Phosphate Anhydride Linkage in Nucleotide Derivatives

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