title: Pantethine rescues phosphopantothenoylcysteine synthetase and phosphopantothenoylcysteine decarboxylase deficiency in Escherichia coli but not in Pseudomonas aeruginosa.
abstract: Coenzyme A (CoA) plays a central and essential role in all living organisms. The pathway leading to CoA biosynthesis has been considered an attractive target for developing new antimicrobial agents with novel mechanisms of action. By using an arabinose-regulated expression system, the essentiality of coaBC, a single gene encoding a bifunctional protein catalyzing two consecutive steps in the CoA pathway converting 4'-phosphopantothenate to 4'-phosphopantetheine, was confirmed in Escherichia coli. Utilizing this regulated coaBC strain, it was further demonstrated that E. coli can effectively metabolize pantethine to bypass the requirement for coaBC. Interestingly, pantethine cannot be used by Pseudomonas aeruginosa to obviate coaBC. Through reciprocal complementation studies in combination with biochemical characterization, it was demonstrated that the differential characteristics of pantethine utilization in these two microorganisms are due to the different substrate specificities associated with endogenous pantothenate kinase, the first enzyme in the CoA biosynthetic pathway encoded by coaA in E. coli and coaX in P. aeruginosa.
authors.affiliation: Department of Infectious Diseases, Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA. carl.balibar@novartis.com
authors.forename: Carl J
authors.initials: CJ
authors.lastname: Balibar
authors.forename: Micah F
authors.initials: MF
authors.lastname: Hollis-Symynkywicz
authors.forename: Jianshi
authors.initials: J
authors.lastname: Tao
mesh_terms: D053898:Biosynthetic Pathways / Q000235:genetics; D002262:Carboxy-Lyases / Q000172:deficiency*; D004926:Escherichia coli / Q000201:enzymology* / Q000378:metabolism*; D029968:Escherichia coli Proteins; D017353:Gene Deletion; D020043:Genes, Essential; D005816:Genetic Complementation Test; D009097:Multienzyme Complexes / Q000172:deficiency; D010204:Pantetheine / Q000031:analogs & derivatives* / Q000378:metabolism; D010453:Peptide Synthases / Q000172:deficiency*; D011550:Pseudomonas aeruginosa / Q000201:enzymology* / Q000378:metabolism*
chemical_list: C499667:Dfp protein, E coli; D029968:Escherichia coli Proteins; D009097:Multienzyme Complexes; D010204:Pantetheine; C005425:pantethine; D002262:Carboxy-Lyases; C022373:Phosphopantothenoyl-cysteine decarboxylase; D010453:Peptide Synthases; C022374:phosphopantothenoyl-cysteine synthetase