Molecular mechanism for the antigonococcal action of lysosomal cathepsin G.
Human lysosomal cathepsin G (cat G) appears to be an important mediator of non-oxidative killing of Neisseria gonorrhoeae ingested by human polymorphonuclear leucocytes (PMNLs). Nearly isogenic strains of gonococci having variations in the structure of penicillin-binding protein 2 (PBP2) also exhibit different levels of susceptibility to the lethal action of cat G in vitro. Accordingly, we examined the relationship between gonococcal susceptibility to cat G and PBP2 structure. The results of this study suggest that cat G has the capacity to interact with PBP2, as evidenced by its ability to inhibit binding of [3H]-benzylpenicillin to PBP2. We also found that changes in the amino acid sequence within the transpeptidase domain of PBP2, because of certain penA mutations, modulated such interactions. We propose that PBP2 is an intracellular target for cat G and that levels of gonococcal susceptibility to cat G may be related to PBP2 structure and/or intracellular availability.
Shafer
W M
WM
Laboratories of Microbial Pathogenesis, Department of Veterans' Affairs Medical Center (Atlanta), Decatur, Georgia 30033.
Onunka
V C
VC
Jannoun
M
M
Huthwaite
L W
LW
D000818:Animals; D001426:Bacterial Proteins; D001483:Base Sequence; D002352:Carrier Proteins; D056649:Cathepsin G; D002403:Cathepsins / Q000378:metabolism* / Q000494:pharmacology; D003001:Cloning, Molecular; D003720:Densitometry; D005798:Genes, Bacterial; D006602:Hexosyltransferases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008247:Lysosomes / Q000201:enzymology*; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism*; D002267:Muramoylpentapeptide Carboxypeptidase; D009154:Mutation; D009344:Neisseria gonorrhoeae / Q000187:drug effects / Q000378:metabolism*; D009504:Neutrophils / Q000201:enzymology*; D010400:Penicillin G / Q000378:metabolism; D046915:Penicillin-Binding Proteins; D010458:Peptidyl Transferases / Q000235:genetics / Q000378:metabolism*; D012697:Serine Endopeptidases
D001426:Bacterial Proteins; D002352:Carrier Proteins; D009097:Multienzyme Complexes; D046915:Penicillin-Binding Proteins; D010458:Peptidyl Transferases; D006602:Hexosyltransferases; D002403:Cathepsins; D002267:Muramoylpentapeptide Carboxypeptidase; D012697:Serine Endopeptidases; C534094:CTSG protein, human; D056649:Cathepsin G; D010400:Penicillin G