Interaction between non-classical beta-lactam compounds and the Zn2+-containing G and serine R61 and R39 D-alanyl-D-alanine peptidases.
Streptomyces albus G secretes a Zn2+-containing D-alanyl-D-alanine peptidase. Streptomyces R61 and Actinomadura R39 secrete D-alanyl-D-alanine-cleaving serine peptidases. The effect of non-classical beta-lactam antibiotics on these three model enzymes has been studied. Mecillinam, cefoxitin, quinacillin, quinacillin sulphone, clavulanate and N-formimidoylthienamycin have no effect on the Zn2+-containing enzyme. 6-Amino-penicillanic acid slowly inactivates this enzyme and 7-aminocephalosporanic acid behaves as a reversible inhibitor. Cefoxitin and N-formimidoylthienamycin are potent anti-bacterial agents; they effectively inactivate the serine R39 enzyme and, to a lesser extent, the serine R61 enzyme. All the other beta-lactam compounds tested, including mecillinam, are slow inactivators of these serine enzymes. The intermediates formed between 6-aminopenicillanic acid and the R61 and R39 enzymes are long- and short-lived respectively, whereas those formed between 7-aminocephalosporanic acid and the same R61 and R39 enzymes are short- and long-lived respectively. Breakdown of the short-lived intermediates thus obtained gives rise to several ninhydrin-positive degradation products. The intermediates formed between clavulanate and the serine enzymes are long-lived. With the R39 enzyme, the inactivated complex formed in a first step undergoes subsequent monomolecular rearrangement to give rise to a second species exhibiting a high absorbance at 273 nm.
D000191:Actinomycetaceae / Q000201:enzymology*; D000560:Amdinocillin / Q000494:pharmacology; D002268:Carboxypeptidases / Q000037:antagonists & inhibitors*; D002440:Cefoxitin / Q000494:pharmacology; D002511:Cephalosporins / Q000494:pharmacology; D019818:Clavulanic Acid; D004347:Drug Interactions; D010450:Endopeptidases; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015378:Imipenem; D007700:Kinetics; D010397:Penicillanic Acid / Q000378:metabolism / Q000031:analogs & derivatives; D010406:Penicillins / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D046929:Serine-Type D-Ala-D-Ala Carboxypeptidase; D013302:Streptomyces / Q000201:enzymology*; D015032:Zinc; D047090:beta-Lactams / Q000494:pharmacology
D002511:Cephalosporins; D004791:Enzyme Inhibitors; D010406:Penicillins; D011810:Quinoxalines; D047090:beta-Lactams; D019818:Clavulanic Acid; D002440:Cefoxitin; D015378:Imipenem; C033810:quinacillin sulfone; C011097:quinacillin; D010397:Penicillanic Acid; C030735:7-aminocephalosporanic acid; D002268:Carboxypeptidases; D010450:Endopeptidases; D046929:Serine-Type D-Ala-D-Ala Carboxypeptidase; D015032:Zinc; C004408:aminopenicillanic acid; D000560:Amdinocillin