Structure of Staphylococcus aureus adenylosuccinate lyase (PurB) and assessment of its potential as a target for structure-based inhibitor discovery.
The medium-resolution structure of adenylosuccinate lyase (PurB) from the bacterial pathogen Staphylococcus aureus in complex with AMP is presented. Oxalate, which is likely to be an artifact of crystallization, has been modelled in the active site and occupies a position close to that where succinate is observed in orthologous structures. PurB catalyzes reactions that support the provision of purines and the control of AMP/fumarate levels. As such, the enzyme is predicted to be essential for the survival of S. aureus and to be a potential therapeutic target. Comparisons of this pathogen PurB with the enzyme from Escherichia coli are presented to allow discussion concerning the enzyme mechanism. Comparisons with human PurB suggest that the close similarity of the active sites would make it difficult to identify species-specific inhibitors for this enzyme. However, there are differences in the way that the subunits are assembled into dimers. The distinct subunit-subunit interfaces may provide a potential area to target by exploiting the observation that creation of the enzyme active site is dependent on oligomerization.
Fyfe
Paul K
PK
Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD15EH, Scotland.
Dawson
Alice
A
Hutchison
Marie Theres
MT
Cameron
Scott
S
Hunter
William N
WN
D000264:Adenylosuccinate Lyase / Q000037:antagonists & inhibitors / Q000737:chemistry*; D000595:Amino Acid Sequence; D000818:Animals; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D054730:Protein Interaction Domains and Motifs; D020836:Protein Structure, Quaternary; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013211:Staphylococcus aureus / Q000201:enzymology*; D040681:Structural Homology, Protein
D004791:Enzyme Inhibitors; D000264:Adenylosuccinate Lyase