Pantethine Rescues Phosphopantothenoylcysteine Synthetase and Phosphopantothenoylcysteine Decarboxylase Deficiency in Escherichia coli but Not in Pseudomonas aeruginosa

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 ofcoaBC , a single gene encoding a bifunctional protein catalyzing two consecutive steps in the CoA pathway converting 4′-phosphopantothenate to 4′-phosphopantetheine, was confirmed inEscherichia coli . Utilizing this regulatedcoaBC strain, it was further demonstrated thatE. coli can effectively metabolize pantethine to bypass the requirement forcoaBC . Interestingly, pantethine cannot be used byPseudomonas aeruginosa to obviatecoaBC . 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 bycoaA inE. coli andcoaX inP. aeruginosa .