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

Department of Infectious Diseases, Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
Journal of bacteriology (Impact Factor: 2.81). 07/2011; 193(13):3304-12. DOI: 10.1128/JB.00334-11
Source: PubMed


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.

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    • "Only type I and II PanKs (PanK I and PanK II ) phosphorylate pantothenamides, thereby allowing the formation of CoA antimetabolites. Organisms like Pseudomonas aeruginosa that have type III PanK (PanK III ) enzymes that exclude these compounds from their active sites are therefore refractory to the effects of Npentylpantothenamide and similar analogues (Balibar, et al., 2011). This suggests that the basis for CJ-15,801's unique specificity for S. aureus and P. falciparum may also be based on the type-specificity of their PanKs, both of which have been characterized as atypical type II enzymes (Hong, et al., 2006; Leonardi, et al., 2005; Spry, et al., 2010). "
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