Phosphopantetheine Adenylyltransferase: A promising drug target to combat antibiotic resistance.
2021
Phosphopantetheine Adenylyltransferase (PPAT) is an enzyme that catalyzes the penultimate step in the biosynthesis of Coenzyme A (CoA), which is the active and physiologically functional form of dietary Vitamin B5. CoA serves as a cofactor for numerous metabolic reactions which makes it essential for cellular survival. This enzyme is also subject to feedback inhibition by CoA to maintain its cellular concentration. The steps of the CoA biosynthesis pathway remain conserved from prokaryotes to eukaryotes, with humans and pathogenic micro-organisms showing significant diversity on a sequence, structure and mechanistic level. This suggests that the development of selective inhibitors of microbial CoA biosynthesis should be possible using these enzymes as targets for drug development. Bacterial PPAT shows significant mechanistic difference from its human counterpart CoA synthase, which is a dual protein carrying the activity of both PPAT and next step in the pathway catalyzed by the enzyme Dephospho CoA kinase (DPCK). This review covers the detailed description of the mechanistic, structural and functional aspects of this enzyme. Also, all the attempts to design high efficiency inhibitors of this enzyme using the approach of structure based drug design have been discussed in detail. This comprehensive structural and functional discussion of PPAT will help in further exploiting it as a drug target.
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