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

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. Proteins 2014; 82:1542–1548. © 2014 Wiley Periodicals, Inc.