Abstract
Phosphopantetheine adenylyltransferase (PPAT) catalyzes the reversible transfer of an adenylyl group from ATP to 4'-phosphopantetheine (Ppant) to form dephospho-CoA (dPCoA) and pyrophosphate in the Coenzyme A (CoA) biosynthetic pathway. Importantly, PPATs are the potential target for developing antibiotics because bacterial and mammalian PPATs share little sequence homology. Previous structural studies revealed the mechanism of the recognizing substrates and products. The binding modes of ATP, ADP, Ppant, and dPCoA are highly similar in all known structures, whereas the binding modes of CoA or 3'-phosphoadenosine 5'-phosphosulfate binding are novel. To provide further structural information on ligand binding by PPATs, the crystal structure of PPAT from Enterococcus faecalis was solved in three forms: (i) apo form, (ii) binary complex with ATP, and (iii) binary complex with pantetheine. The substrate analog, pantetheine, binds to the active site in a similar manner to Ppant. The new structural information reported in this study including pantetheine as a potent inhibitor of PPAT will supplement the existing structural data and should be useful for structure-based antibacterial discovery against PPATs.