Bacterial type I signal peptidase (SPase I) (SPase I)

Bacterial type I signal peptidase (SPase I) is an essential membrane-bound serine protease found in all bacteria, where it plays a pivotal role in the protein secretion pathway (UniProt). Its primary function is to cleave the amino-terminal signal peptide from pre-proteins as they emerge from the Sec or Tat translocation machinery, a step necessary for the maturation and proper localization of extracellular and periplasmic proteins (PubMed: 12446561). Because SPase I is indispensable for bacterial growth and possesses a unique catalytic Ser-Lys dyad that differs significantly from the catalytic mechanisms of eukaryotic signal peptidases, it is considered a high-priority target for novel antibiotic discovery (Nature: 10.1038/s41586-018-0483-6). Inhibitors such as the natural product arylomycins and their synthetic derivatives, like G-7485, have demonstrated potent antibacterial activity by blocking this cleavage event, leading to the accumulation of toxic unprocessed proteins in the bacterial membrane (Science: 10.1126/science.aar5592). This mechanism of action is effective against a wide range of pathogens, including multi-drug resistant strains, making SPase I a promising focus for future therapeutic development.

Other names

Signal peptidase ILeader peptidase ILepBType I signal peptidaseType I SPase

Inhibitors bind to the catalytic site of SPase I, blocking the Ser-Lys dyad from cleaving signal peptides. This prevents the maturation of secreted proteins, causing them to remain tethered to the cytoplasmic membrane, which triggers bacterial cell death (PubMed: 12446561).