title: Crystal structures of Klebsiella pneumoniae pantothenate kinase in complex with N-substituted pantothenamides.
abstract: N-Substituted pantothenamides are derivatives of pantothenate, the precursor in the biosynthesis of the essential metabolic cofactor coenzyme A (CoA). These compounds are substrates of pantothenate kinase (PanK) in the first step of CoA biosynthesis and possess antimicrobial activity against various pathogenic bacteria. Here we solved the crystal structure of the Klebsiella pneumoniae PanK (KpPanK) in complex with N-pentylpantothenamide (N5-Pan) to understand the molecular basis of its antimicrobial activity. The structure reveals a polar pocket interacting with the pantothenate moiety of N5-Pan and an aromatic pocket loosely protecting the pentyl tail, suggesting that the introduction of an aromatic ring to a new pantothenamide may enhance the compound's affinity to KpPanK. To test this idea, we synthesized N-pyridin-3-ylmethylpantothenamide (Np-Pan) and solved its co-crystal structure with KpPanK. The structure reveals two alternat conformations of the aromatic ring of Np-Pan bound at the aromatic pocket, providing the basis for further improvement of pantothenamide binding to KpPanK.
authors.affiliation: Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Buren
authors.initials: B
authors.lastname: Li
authors.forename: Wolfram
authors.initials: W
authors.lastname: Tempel
authors.forename: David
authors.initials: D
authors.lastname: Smil
authors.forename: Yuri
authors.initials: Y
authors.lastname: Bolshan
authors.forename: Matthieu
authors.initials: M
authors.lastname: Schapira
authors.forename: Hee-Won
authors.initials: HW
authors.lastname: Park
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D007711:Klebsiella pneumoniae / Q000737:chemistry / Q000201:enzymology* / Q000378:metabolism; D008958:Models, Molecular; D010205:Pantothenic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000737:chemistry* / Q000378:metabolism*
chemical_list: C470569:N-pentylpantothenamide; D010205:Pantothenic Acid; D017853:Phosphotransferases (Alcohol Group Acceptor); C023088:pantothenate kinase
keywords: CoA synthesis inhibitors; X-ray crystallography; enzyme-substrate analog complex; pantothenate kinase; vitamin B5 analogs