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FEBS Lett. 2016 Dec;590(23):4414-4428. doi: 10.1002/1873-3468.12462. Epub 2016 Nov 7.

Structure and inhibition of N-acetylneuraminate lyase from methicillin-resistant Staphylococcus aureus.

Author information

1
Biomolecular Interaction Centre, School of Biological Sciences, University of Canterbury, Christchurch, New Zealand.
2
Department of Chemistry, University of Canterbury, Christchurch, New Zealand.
3
Protein Science and Engineering, Callaghan Innovation, University of Canterbury, Christchurch, New Zealand.
4
Department of Chemistry and Molecular Biology, University of Gothenburg, Sweden.
5
Centre for Antibiotic Resistance Research (CARe), University of Gothenburg, Sweden.
6
Department of Structural Biology, School of Medicine, Stanford University, CA, USA.
7
Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Australia.

Abstract

N-Acetylneuraminate lyase is the first committed enzyme in the degradation of sialic acid by bacterial pathogens. In this study, we analyzed the kinetic parameters of N-acetylneuraminate lyase from methicillin-resistant Staphylococcus aureus (MRSA). We determined that the enzyme has a relatively high KM of 3.2 mm, suggesting that flux through the catabolic pathway is likely to be controlled by this enzyme. Our data indicate that sialic acid alditol, a known inhibitor of N-acetylneuraminate lyase enzymes, is a stronger inhibitor of MRSA N-acetylneuraminate lyase than of Clostridium perfringens N-acetylneuraminate lyase. Our analysis of the crystal structure of ligand-free and 2R-sialic acid alditol-bound MRSA N-acetylneuraminate lyase suggests that subtle dynamic differences in solution and/or altered binding interactions within the active site may account for species-specific inhibition.

KEYWORDS:

N-acetylneuraminate lyase; antibiotic resistance; drug discovery; inhibitor; methicillin-resistant Staphylococcus aureus; sialic acid degradation; structure

PMID:
27943302
DOI:
10.1002/1873-3468.12462
[Indexed for MEDLINE]
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