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Proteins. 2014 Jul;82(7):1542-8. doi: 10.1002/prot.24524. Epub 2014 Feb 18.

Structural characterization of a new N-substituted pantothenamide bound to pantothenate kinases from Klebsiella pneumoniae and Staphylococcus aureus.

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1
Department of Pharmacology, University of Toronto, Toronto, Ontario, M5G 1L7.

Abstract

Pantothenate kinase (PanK) is the rate-limiting enzyme in Coenzyme A biosynthesis, catalyzing the ATP-dependent phosphorylation of pantothenate. We solved the co-crystal structures of PanKs from Staphylococcus aureus (SaPanK) and Klebsiella pneumonia (KpPanK) with N-[2-(1,3-benzodioxol-5-yl)ethyl] pantothenamide (N354-Pan). Two different N354-Pan conformers interact with polar/nonpolar mixed residues in SaPanK and aromatic residues in KpPanK. Additionally, phosphorylated N354-Pan is found at the closed active site of SaPanK but not at the open active site of KpPanK, suggesting an exchange of the phosphorylated product with a new N354-Pan only in KpPanK. Together, pantothenamides conformational flexibility and binding pocket are two key considerations for selective compound design.

KEYWORDS:

X-ray crystallography; coenzyme A biosynthesis; ligand conformational flexibility; novel antibiotic targets; pantothenate substrate analogs; rational design

PMID:
24470271
DOI:
10.1002/prot.24524
[Indexed for MEDLINE]
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