Structural characterization of a new N-substituted pantothenamide bound to pantothenate kinases from Klebsiella pneumoniae and Staphylococcus aureus.
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.
Department of Pharmacology, University of Toronto, Toronto, Ontario, M5G 1L7.
Scott J
SJ
Hughes
Tetyana
T
Antoshchenko
Kyung Phil
KP
Kim
David
D
Smil
Hee-Won
HW
Park
D000577:Amides / Q000737:chemistry / Q000378:metabolism; D003065:Coenzyme A; D018360:Crystallography, X-Ray; D007711:Klebsiella pneumoniae / Q000201:enzymology*; D008958:Models, Molecular; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000737:chemistry* / Q000378:metabolism*; D011487:Protein Conformation; D013211:Staphylococcus aureus / Q000201:enzymology*
D000577:Amides; D017853:Phosphotransferases (Alcohol Group Acceptor); C023088:pantothenate kinase; D003065:Coenzyme A
X-ray crystallography; coenzyme A biosynthesis; ligand conformational flexibility; novel antibiotic targets; pantothenate substrate analogs; rational design