The Relative Catalytic Efficiency of β-Lactamase Catalyzed Acyl and Phosphyl Transfer

Acylating Agents as Enzyme Inhibitors and Understanding Their Reactivity for Drug Design

“…There is usually also a minimum and maximum chemical reactivity required for an inhibitor to react with the target enzyme, for example, as an effective acylating agent, and a k OH of 0.01 to 1.0 M -1 s -1 is also a useful guide to this. The second-order rate constant for the rate of inactivation of an enzyme, k inact , is related to the rate constant for hydrolysis of the inhibitor, k OH , through the enzyme rate enhancement factor (EREF) 3,6 given by the ratio (k inact )/k OH . These ratios are indicators of the enzyme's ability to use its catalytic apparatus to increase the rate of a reaction.…”

“…In general, this involves the covalent modification of an active site residue that is not subsequently and readily regenerated. For example, many inhibitors are acylating, phosphylating, or sulfylating agents of the active site serine residue of serine proteases. The mechanism of these processes involves, in the case of acylation, the displacement of a leaving group, Lg, from the acylating agent: The structure of the acylenzyme is such that the regeneration of the enzyme by its further reaction with nucleophiles, such as water, is a relatively slow process, and this leads to effective inhibition.…”

The efficiency of C-4 substituents in activating the β-lactam scaffold towards serine proteases and hydroxide ion

“…(k inact /K i )/k OH or (k obs /[I])/k OH . 37,43 Remarkably, the 3,3-diethyl β-lactams 5e-j exhibit EREF values ca. 10 4 higher than those of their C-3 unsubstituted analogues 5b-d (Table 1).…”

Synthetic Methods for Azaheterocyclic Phosphonates and Their Biological Activity

“…Proline derivative 184 completely and irreversibly inactivates the class C β-lactamase from Enterobacter cloacae P99. 89 β-Lactamases catalyze the hydrolysis of penicillins and cephalosporins and can be subdivided into three classes. Classes A and C are serine lactamases and are the most prevalent and clinically important β-lactamases.…”