15.1 What Factors Influence Enzymat

15.1 What Factors Influence Enzymatic Activity? 453
of enzyme synthesis, are important mechanisms for the regulation of metabolism.
By controlling the amount of an enzyme that is present at any moment, cells can ei-
ther activate or terminate various metabolic routes. Genetic controls over enzyme
levels have a response time ranging from minutes in rapidly dividing bacteria to
hours (or longer) in higher eukaryotes. Once synthesized, the enzyme may also be
degraded, either through normal turnover of the protein or through specific decay
mechanisms that target the enzyme for destruction. These mechanisms are dis-
cussed in detail in Chapter 31.
Enzyme Activity Can Be Regulated Allosterically
Enzymatic activity can also be activated or inhibited through noncovalent interaction
of the enzyme with small molecules (metabolites) other than the substrate. This
form of control is termed allosteric regulation, because the activator or inhibitor
binds to the enzyme at a site other than (allo means “other”) the active site. Further-
more, such allosteric regulators, or effector molecules, are often quite different ster-
ically from the substrate. Because this form of regulation results simply from re-
versible binding of regulatory ligands to the enzyme, the cellular response time can
be virtually instantaneous.
Enzyme Activity Can Be Regulated Through Covalent Modification
Enzymes can be regulated by covalent modification, the reversible covalent attachment
of a chemical group. Enzymes susceptible to such regulation are called interconvert-
ible enzymes, because they can be reversibly converted between two forms. Thus, a
fully active enzyme can be converted into an inactive form simply by the covalent at-
tachment of a functional group. For example, protein kinases are enzymes that act in
covalent modification by attaching a phosphoryl moiety to target proteins (Figure
15.1). Protein kinases catalyze the ATP-dependent phosphorylation of OOH groups
on Ser, Thr, or Tyr side chains. Removal of the phosphate group by a phosphoprotein
phosphatase returns the enzyme to its original state. In contrast to the example in the
figure, some enzymes exist in an inactive state unless specifically converted into the
active form through covalent addition of a functional group. Covalent modification
reactions are catalyzed by special converter enzymes, which are themselves subject to
metabolic regulation. (Protein kinases are one class of converter enzymes.) Although
covalent modification represents a stable alteration of the enzyme, a different con-
verter enzyme operates to remove the modification, so when the conditions that fa-
vored modification of the enzyme are no longer present, the process can be reversed,
restoring the enzyme to its unmodified state. Because covalent modification events are
catalyzed by enzymes, they occur very quickly, with response times of seconds or even
less for significant changes in metabolic activity.
Regulation of Enzyme Activity Also Can Be Accomplished
in Other Ways
Enzyme regulation is an important matter to cells, and evolution has provided a vari-
ety of additional options, including zymogens, isozymes, and modulator proteins. We
will discuss these options first and then return to the major topics of this chapter—
enzyme regulation through allosteric mechanisms and covalent modification.
Enzyme OH
Protein
phosphatase
Protein
kinase
Enzyme OPO–
O–
Catalytically inactive,
covalently modified form
Catalytically
active form
O
Pi H2O
ATP ADP
FIGURE 15.1 Enzyme regulation by reversible covalent
modification.