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A mechanism-inspired UDP-N-acetylglucosamine pyrophosphorylase inhibitor

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A mechanism-inspired UDP-N-acetylglucosamine pyrophosphorylase inhibitor. / Raimi, Olwale G.; Hurtado-Guerrero, Ramon; Borodkin, Vladimir et al.
In: RSC Chemical Biology, Vol. 2020, No. 1, 24.03.2020, p. 13-25.

Research output: Contribution to Journal/MagazineJournal articlepeer-review

Harvard

Raimi, OG, Hurtado-Guerrero, R, Borodkin, V, Ferenbach, A, Urbaniak, M, Ferguson, MAJ & van Aalten, DMF 2020, 'A mechanism-inspired UDP-N-acetylglucosamine pyrophosphorylase inhibitor', RSC Chemical Biology, vol. 2020, no. 1, pp. 13-25. https://doi.org/10.1039/C9CB0017H

APA

Raimi, O. G., Hurtado-Guerrero, R., Borodkin, V., Ferenbach, A., Urbaniak, M., Ferguson, M. A. J., & van Aalten, D. M. F. (2020). A mechanism-inspired UDP-N-acetylglucosamine pyrophosphorylase inhibitor. RSC Chemical Biology, 2020(1), 13-25. Advance online publication. https://doi.org/10.1039/C9CB0017H

Vancouver

Raimi OG, Hurtado-Guerrero R, Borodkin V, Ferenbach A, Urbaniak M, Ferguson MAJ et al. A mechanism-inspired UDP-N-acetylglucosamine pyrophosphorylase inhibitor. RSC Chemical Biology. 2020 Mar 24;2020(1):13-25. Epub 2020 Mar 24. doi: 10.1039/C9CB0017H

Author

Raimi, Olwale G. ; Hurtado-Guerrero, Ramon ; Borodkin, Vladimir et al. / A mechanism-inspired UDP-N-acetylglucosamine pyrophosphorylase inhibitor. In: RSC Chemical Biology. 2020 ; Vol. 2020, No. 1. pp. 13-25.

Bibtex

@article{ad68c6815e294ec58b8ec03458de69d7,
title = "A mechanism-inspired UDP-N-acetylglucosamine pyrophosphorylase inhibitor",
abstract = "UDP-N-acetylglucosamine pyrophosphorylase (UAP1) catalyses the last step in eukaryotic biosynthesis of uridine diphosphate-N-acetylglucosamine (UDP-GlcNAc), converting UTP and GlcNAc-1P to the sugar nucleotide. Gene disruption studies have shown that this gene is essential in eukaryotes and a possible antifungal target, yet no inhibitors of fungal UAP1 have so far been reported. Here we describe the crystal structures of substrate/product complexes of UAP1 from Aspergillus fumigatus that together provide snapshots of catalysis. Astructure with UDP-GlcNAc, pyrophosphate and Mg2+ provides the first Michaelis complex trapped for this class of enzyme, revealing the structural basis of the previously reported Mg2+ dependence and direct observation ofpyrophosphorolysis. We also show that a highly conserved lysine mimics the role of a second metal observed in structures of bacterial orthologues. A mechanism-inspired UTP α,β-methylenebisphosphonate analogue (meUTP) was designed and synthesized and was shown to be a micromolar inhibitor of the enzyme. The mechanistic insights and inhibitor described here will facilitate future studies towards the discovery of small molecule inhibitors of this currently unexploited potential antifungal drug target.",
author = "Raimi, {Olwale G.} and Ramon Hurtado-Guerrero and Vladimir Borodkin and Andrew Ferenbach and Mick Urbaniak and Ferguson, {Michael A J} and {van Aalten}, {Daan M. F.}",
year = "2020",
month = mar,
day = "24",
doi = "10.1039/C9CB0017H",
language = "English",
volume = "2020",
pages = "13--25",
journal = "RSC Chemical Biology",
publisher = "Royal Society of Chemistry",
number = "1",

}

RIS

TY - JOUR

T1 - A mechanism-inspired UDP-N-acetylglucosamine pyrophosphorylase inhibitor

AU - Raimi, Olwale G.

AU - Hurtado-Guerrero, Ramon

AU - Borodkin, Vladimir

AU - Ferenbach, Andrew

AU - Urbaniak, Mick

AU - Ferguson, Michael A J

AU - van Aalten, Daan M. F.

PY - 2020/3/24

Y1 - 2020/3/24

N2 - UDP-N-acetylglucosamine pyrophosphorylase (UAP1) catalyses the last step in eukaryotic biosynthesis of uridine diphosphate-N-acetylglucosamine (UDP-GlcNAc), converting UTP and GlcNAc-1P to the sugar nucleotide. Gene disruption studies have shown that this gene is essential in eukaryotes and a possible antifungal target, yet no inhibitors of fungal UAP1 have so far been reported. Here we describe the crystal structures of substrate/product complexes of UAP1 from Aspergillus fumigatus that together provide snapshots of catalysis. Astructure with UDP-GlcNAc, pyrophosphate and Mg2+ provides the first Michaelis complex trapped for this class of enzyme, revealing the structural basis of the previously reported Mg2+ dependence and direct observation ofpyrophosphorolysis. We also show that a highly conserved lysine mimics the role of a second metal observed in structures of bacterial orthologues. A mechanism-inspired UTP α,β-methylenebisphosphonate analogue (meUTP) was designed and synthesized and was shown to be a micromolar inhibitor of the enzyme. The mechanistic insights and inhibitor described here will facilitate future studies towards the discovery of small molecule inhibitors of this currently unexploited potential antifungal drug target.

AB - UDP-N-acetylglucosamine pyrophosphorylase (UAP1) catalyses the last step in eukaryotic biosynthesis of uridine diphosphate-N-acetylglucosamine (UDP-GlcNAc), converting UTP and GlcNAc-1P to the sugar nucleotide. Gene disruption studies have shown that this gene is essential in eukaryotes and a possible antifungal target, yet no inhibitors of fungal UAP1 have so far been reported. Here we describe the crystal structures of substrate/product complexes of UAP1 from Aspergillus fumigatus that together provide snapshots of catalysis. Astructure with UDP-GlcNAc, pyrophosphate and Mg2+ provides the first Michaelis complex trapped for this class of enzyme, revealing the structural basis of the previously reported Mg2+ dependence and direct observation ofpyrophosphorolysis. We also show that a highly conserved lysine mimics the role of a second metal observed in structures of bacterial orthologues. A mechanism-inspired UTP α,β-methylenebisphosphonate analogue (meUTP) was designed and synthesized and was shown to be a micromolar inhibitor of the enzyme. The mechanistic insights and inhibitor described here will facilitate future studies towards the discovery of small molecule inhibitors of this currently unexploited potential antifungal drug target.

U2 - 10.1039/C9CB0017H

DO - 10.1039/C9CB0017H

M3 - Journal article

VL - 2020

SP - 13

EP - 25

JO - RSC Chemical Biology

JF - RSC Chemical Biology

IS - 1

ER -