Interaction of clavulanate with the β-lactamases of Streptomyces albus G and Actinomadura R39

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Abstract
The reactions of .beta.-lactamases of Actinomadura R39 and S. albus G with clavulanate proceed along branched pathways. Both enzymes perform the hydrolysis of this .beta.-lactam with rather high efficiencies (kcat = 18 s-1 and 52s-1, respectively). If large clavulanate/enzyme ratios are used, complete inactivation of the enzymes is observed. At lower ratios, inactivation is only partial. Irreversible inactivation occurs after 400 and 20,000 turnovers for the Actinomadura R39 and S. albus G enzymes, respectively. With the Actinomadura R39 .beta.-lactamase, a transiently inhibited complex is also formed that remains undetectable with the S. albus G .beta.-lactamase. Kinetic models are presented and studied for the interaction between clavulanate and both enzymes. A tentative general reaction scheme is also discussed.