Inhibiting the Actions of Essential Biomolecule Phosphopantetheine.

TL;DRAbstract

Phosphopantetheine is an essential biomolecule required for life. The enzyme phosphopantothenoylcysteine synthetase (PPCS) incorporates the reactive thiol moiety in the Coenzyme A (CoA) biosynthetic pathway. Two types of PPCS exist in bacteria: bifunctional fusion protein Type 1 and monofunctional Type 3. Previously developed cytidylate mimics were determined to have stronger binding affinity for Type 3 Streptococcus pneumoniae PPCS compared to Type 1. To explore the structure activity relationship of Type 3 PPCS, completely conserved residues of bacterial PPCS were probed via saturation mutagenesis in a developed knockout system. Mutagenesis revealed that conserved S. pneumoniae PPCS residues K123 and D93 were stringent, as only K123N/R/M and D93E/N were viable mutations. D93 was determined to be responsible for the association of divalent cations and CTP to the active site, as D93E and D93N exhibited a 1.5-2.7 fold (151-267 μM apparent Km) less affinity for CTP and D93N resulted in a

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