PDBsum entry 6tdf

Transferase

PDB id: 6tdf

Contents

Protein chain

165 a.a.

Ligands

ACO

N3Q

G6P

Waters ×45

PDB id:

6tdf

Name:

Transferase

Title:

Crystal structure of aspergillus fumigatus glucosamine-6-phosphate n- acetyltransferase 1 in complex with compound 3

Structure:

Glucosamine 6-phosphate n-acetyltransferase. Chain: a. Engineered: yes

Source:

Aspergillus fumigatus af293. Organism_taxid: 330879. Gene: afua_6g02460. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

2.01Å R-factor: 0.213 R-free: 0.264

Authors:

O.G.Raimi,M.Stanley,D.Lockhart

Key ref:

D.E.A.Lockhart et al. (2020). Targeting a critical step in fungal hexosamine biosynthesis. J Biol Chem, 295, 8678-8691. PubMed id: 32341126 DOI: 10.1074/jbc.RA120.012985

Date:

08-Nov-19 Release date: 29-Apr-20

Protein chain

Q4WCU5  (Q4WCU5_ASPFU) -  Glucosamine 6-phosphate N-acetyltransferase from Aspergillus fumigatus (strain ATCC MYA-4609 / CBS 101355 / FGSC A1100 / Af293)

Seq: 190 a.a.

Struc: 165 a.a.

Enzyme reactions

• Enzyme class: E.C.2.3.1.4 - glucosamine-phosphate N-acetyltransferase.
• Pathway: UDP-N-acetylglucosamine Biosynthesis
• Reaction: D-glucosamine 6-phosphate + acetyl-CoA = N-acetyl-D-glucosamine 6-phosphate + CoA + H⁺

D-glucosamine 6-phosphate (Bound ligand (Het Group name = ACO) corresponds exactly) + acetyl-CoA (Bound ligand (Het Group name = G6P) matches with 88.24% similarity) = N-acetyl-D-glucosamine 6-phosphate + CoA + H(+)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1074/jbc.RA120.012985

J Biol Chem 295:8678-8691 (2020)

PubMed id: 32341126

Targeting a critical step in fungal hexosamine biosynthesis.

D.E.A.Lockhart, M.Stanley, O.G.Raimi, D.A.Robinson, D.Boldovjakova, D.R.Squair, A.T.Ferenbach, W.Fang, D.M.F.van Aalten.

ABSTRACT

Aspergillus fumigatus is a human opportunistic fungal pathogen whose cell wall protects it from the extracellular environment including host defenses. Chitin, an essential component of the fungal cell wall, is synthesized from UDP-GlcNAc produced in the hexosamine biosynthetic pathway. As this pathway is critical for fungal cell wall integrity, the hexosamine biosynthesis enzymes represent potential targets of antifungal drugs. Here, we provide genetic and chemical evidence that glucosamine 6-phosphate N-acetyltransferase (Gna1), a key enzyme in this pathway, is an exploitable antifungal drug target. GNA1 deletion resulted in loss of fungal viability and disruption of the cell wall, phenotypes that could be rescued by exogenous GlcNAc, the product of the Gna1 enzyme. In a murine model of aspergillosis, the Δgna1 mutant strain exhibited attenuated virulence. Using a fragment-based approach, we discovered a small heterocyclic scaffold that binds proximal to the Gna1 active site and can be optimized to a selective submicromolar binder. Taken together, we have provided genetic, structural, and chemical evidence that Gna1 is an antifungal target in A. fumigatus.