term allosterism is also used frequently in the P450 literature to refer to the
ability of a ligand (a.k.a. effector molecule other than the substrate molecule
being metabolized) that binds in a distinct, noncatalytic site on the enzyme and
affects the rate of substrate metabolism. This effector can be a second (or
potentially third or fourth, etc.) substrate molecule binding to the same enzyme
molecule or it can be a structurally distinct molecule. Several studies suggest
that these ‘‘allosteric’’ sites may be distinct binding regions within the same
enzyme pocket that the substrate occupies, leading to the conclusion that
multiple molecules may bind within the enzyme active site pocket simulta-
neously (Dabrowski et al., 2002; Hummel et al., 2004; Hutzler et al., 2003;
Korzekwa et al., 1998; Rock et al., 2003; Shou et al., 1994), though the
possibility of effectors binding outside the active site pocket cannot be
excluded. Though this does not provide a mechanistic explanation for atypical
kinetics, this simultaneous binding of substrate and effector provides a
reasonable foundation for explaining the phenomena of atypical kinetic
profiles and cooperativity. In the following sections, various types of atypical
kinetic profiles will be discussed including homotropic cooperativity (sigmoi-
dal, biphasic, and substrate inhibition kinetics) wherein two molecules of the
same substrate are responsible for the kinetics observed and heterotropic
cooperativity (activation and substrate dependent inhibition) where two
structurally distinct molecules are involved.
4.5.2 Homotropic Cooperativity
4.5.2.1 Sigmoidal Kinetics (with a single substrate) Cooperativity resulting
in sigmoidicity of substrate–velocity plots (Fig. 4.5) has been most commonly
associated with multimeric enzymes, such as hemoglobin, where the substrate
FIGURE 4.5 Representative plot depicting sigmoidal kinetics (homotropic
cooperativity).
ATYPICAL KINETICSALLOSTERIC EFFECTS 95