suicide inactivation, enzyme-activated irreversible inhibition and other terms.
An excellent primer on mechanism-based enzyme inactivation is provided by
Silverman (1998). The enzymatic scheme for this kind of inactivation is shown
in Scheme 4.5.
Due to the nature of this process (necessary reactive intermediate formation
[I^0 ] and subsequent permanent inactivation of the enzyme [EI^00 ]), the effects of
this inhibition not only tend to reach a maximum effect more slowly but also
last for a longer period of time (i.e., until the inactivated enzyme is replaced by
synthesis of a new, functional enzyme molecule. Furthermore, since not every
reactive intermediate [I^0 ] goes on to form an inactivator complex, some
molecules (generally the majority) go on to form product (Scheme 4.5), again
adding to the length of time for full inactivation. Unlike competitive inhibition,
withdrawal of the drug causing the inactivation does not immediately result in
restoration of enzyme function. In fact, it can take several days for complete
turnover of an enzyme pool and restoration of full metabolic function.
Silverman (1998) has defined seven criteria that must be satisfied in order for
a process to be characterized as involving mechanism-based inactivation. These
are time dependence, saturation, substrate protection, irreversibility, stoichio-
metry of inactivation, involvement of a catalytic step, and inactivation occurs
prior to release of the activated species. This review will not expound on each
SCHEME 4.5 Mechanism-based enzyme inactivation.FIGURE 4.11 Plots representative of the decreasing enzyme activity with respect to
the time and concentration dependence of mechanism-based inactivation kinetics.
MECHANISM-BASED ENZYME INACTIVATION KINETICS 109