1、C4 Enzyme inhibition,Enzyme inhibition Irreversible inhibition Reversible inhibition,1. The inhibition of enzymatic activity by specific small molecules and ions is important. 1.1 It serves as a major control mechanism in biological systems. 1.2 Many drugs and toxic agents act by inhibiting enzymes.

2、 1.3 Inhibition can be a source of insight into the mechanism of enzyme action: residues critical for catalysis can often be identified by using specific (irreversible) inhibitors.,2. Reversible inhibition can usually be divided into different types. 2.1 Reversible inhibitors bind to enzyme noncoval

3、ently. 2.2 In competitive inhibition, the inhibitor competes with the substrate for the active site (binding of one prevents binding of the other, forming ES or EI complexes but no ESI complexes.). 2.3 Competitive inhibitors are often compounds that resemble the substrates.,a=1+I/KI,2.4 Vmax is not

4、affected by the presence of a competitive inhibitor (There is always some high substrate concentration that will replace the inhibitor from the enzymes active site). 2.5 Km is increased due to the presence of a competitive inhibitor. Higher substrate concentration is needed to achieve Vmax/2.,2.6 In

5、 noncompetitive inhibition, the inhibitor binds to a site distinct from that (the active site) which binds the substrate. 2.7 Inhibitor binding does not affect substrate binding and vice versa (i.e., inhibitor can bind to ES complex, substrate can bind to EI complex). 2.8 The enzyme is inactivated w

6、hen inhibitor is bound (whether or not substrate is also present). (e.g.) 2.9 The apparent Vmax is lowered (due to the concentration decrease of active enzymes),Noncompetitive inhibition,Mixed or noncompetitive inhibition, plots similar to the sequential binding in ternary complexes,2.10 In uncompet

7、itive inhibition, the inhibitor binds only to the ES complex (unable to bind to free enzyme).,Uncompetitive inhibition,3 Irreversible inhibitors bind very tightly (covalently or noncovalently) to the enzymes. 3.1 Many irreversible inhibitors modify critical catalytic residues covalently, thus inactivating the enzymes. 3.2 Diisopropylphosphofluoridate (DIPF, one component of the toxic nerve gases) reacts with a critical Ser residue on acetylcholineesterase. 3.3 Critical c