Quaternary variations in the structural assembly of N‐acetylglucosamine‐6‐phosphate deacetylase from Pasteurella multocida

N‐acetylglucosamine 6‐phosphate deacetylase (NagA) catalyzes the conversion of N‐acetylglucosamine‐6‐phosphate to glucosamine‐6‐phosphate in amino sugar catabolism. This conversion is an essential step in the catabolism of sialic acid in several pathogenic bacteria, including Pasteurella multocida,...

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Published in:Proteins, structure, function, and bioinformatics structure, function, and bioinformatics, 2021-01, Vol.89 (1), p.81-93
Main Authors: Manjunath, Lavanyaa, Coombes, David, Davies, James, Dhurandhar, Mugdha, Tiwari, Vikas R., Dobson, Renwick C. J., Sowdhamini, R., Ramaswamy, S., Bose, Sucharita
Format: Article
Language:English
Subjects:
amino sugar metabolism
Catabolism
Conversion
Crystal structure
Crystallography
Dimers
Displays
E coli
Glucosamine
Homology
metal binding
N-Acetylglucosamine
N‐acetylglucosamine‐6‐phosphate deacetylase
Pasteurella multocida
Protein structure
Quaternary structure
quaternary variations
sialic acid catabolism
Structure-function relationships
Substrates
Therapeutic targets
Zinc
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Summary:N‐acetylglucosamine 6‐phosphate deacetylase (NagA) catalyzes the conversion of N‐acetylglucosamine‐6‐phosphate to glucosamine‐6‐phosphate in amino sugar catabolism. This conversion is an essential step in the catabolism of sialic acid in several pathogenic bacteria, including Pasteurella multocida, and thus NagA is identified as a potential drug target. Here, we report the unique structural features of NagA from P. multocida (PmNagA) resolved to 1.95 Å. PmNagA displays an altered quaternary architecture with unique interface interactions compared to its close homolog, the Escherichia coli NagA (EcNagA). We confirmed that the altered quaternary structure is not a crystallographic artifact using single particle electron cryo‐microscopy. Analysis of the determined crystal structure reveals a set of hot‐spot residues involved in novel interactions at the dimer‐dimer interface. PmNagA binds to one Zn2+ ion in the active site and demonstrates kinetic parameters comparable to other bacterial homologs. Kinetic studies reveal that at high substrate concentrations (~10‐fold the KM), the tetrameric PmNagA displays hysteresis similar to its distant neighbor, the dimeric Staphylococcus aureus NagA (SaNagA). Our findings provide key information on structural and functional properties of NagA in P. multocida that could be utilized to design novel antibacterials.
ISSN:0887-3585
1097-0134
DOI:10.1002/prot.25996