Undecaprenyl pyrophosphate phosphatase (UPPP) (UPPP)

The undecaprenyl pyrophosphate (UPP) phosphatase system is a critical component of bacterial cell wall biosynthesis, responsible for recycling the essential C55-isoprenoid lipid carrier (UniProt P0A921). This system is primarily centered on the enzyme undecaprenyl pyrophosphate phosphatase (UPPP), also known as BacA or UppP, which dephosphorylates UPP to undecaprenyl phosphate (UP) (El Ghachi et al., 2004, J. Biol. Chem.). UP is required to transport peptidoglycan, teichoic acid, and O-antigen precursors from the cytoplasm across the cell membrane (Manat et al., 2014, Antibiotics). Since the total amount of undecaprenyl lipids in the cell is limited, the efficient recycling of UPP back to UP is necessary to maintain cell wall integrity and bacterial viability. Inhibition of this recycling process leads to the accumulation of UPP and a deficiency of UP, effectively halting the assembly of the peptidoglycan layer and leading to cell lysis. The antibiotic bacitracin is the most prominent drug targeting this system; it forms a complex with UPP in the presence of divalent metal ions, thereby preventing the phosphatase from acting on its substrate (Stone and Strominger, 1971, PNAS). This target is highly effective against Gram-positive bacteria, although the systemic use of drugs like bacitracin is limited by potential nephrotoxicity (PubChem CID 439542).

Other names

BacAUppPC55-isoprenyl pyrophosphate phosphataseBactoprenyl-diphosphataseUndecaprenyl-diphosphatase

Inhibition of undecaprenyl pyrophosphate dephosphorylation by sequestering the substrate (UPP) or inhibiting the phosphatase enzyme (UPPP), preventing the recycling of the C55-lipid carrier required for cell wall synthesis.