Enzymes II: Regulation
attempt to normalize the overall process. This type of con-
trol, known as
feedback inhibition
(see below), ensures
a high degree of efficiency in the utilization of materials
and of energy in living systems.
Regulation may be achieved in other ways. The absolute
amount of a regulatory enzyme may be altered through
mechanisms that control gene expression (Chapter 26).
This regulation at the genetic level occurs during various
phases of reproduction, growth, and development, with
different metabolic pathways being turned on or off in
accordance with the special requirements of each phase.
In eukaryotic cells, regulation at the genetic level is rel-
atively a long-term process. Several short-term regula-
tory mechanisms control metabolic activity rapidly (see
below). Both substrates and some hormones play signifi-
cant roles in regulating the concentration of key enzymes
at this level. Many drugs or other chemicals can increase
levels of enzymes that affect their own metabolism. Thus,
phénobarbital and polycyclic hydrocarbons increase the
levels of microsomal enzyme systems involved in their
Regulation of metabolic processes can be accomplished
by other methods. One is the use of a
multienzyme com-
(e.g., pyruvate dehydrogenase complex or fatty acid
synthase complex) in which various enzymes are orga-
nized such that the product of one becomes the substrate
for an adjacent enzyme. A single polypeptide chain may
contain multiple catalytic centers that carry out a sequence
of transformations (e.g., the mammalian fatty acid syn-
thase; see Chapter 18). Such multifunctional polypeptides
increase catalytic efficiency by abolishing the accumula-
tion of free intermediates and by maintaining a stoichiom-
etry of
1 : 1
between catalytic centers.
Another type of regulation is accomplished by a series
in which activation of the initial proen-
zyme by a biological signal activates the second proen-
zyme which, in turn, activates the third, and so on. Such
an enzyme cascade process provides great amplification
in terms of the amount of final product formed. Exam-
ples are blood coagulation, the dissolution of blood clots,
complement activation, and glycogen breakdown.
Regulation is also accomplished by compartmentaliza-
tion of enzyme systems involved in anabolic and catabolic
pathways into different cell organelles. For example,
fatty acid synthesis occurs in the soluble fraction of the
cytoplasm, whereas fatty acid oxidation takes place in mi-
tochondria. Heme synthesis begins and is completed in
mitochondria, but some of the intermediate reactions take
place in the cytosol. Heme catabolism is initiated in the
smooth endoplasmic reticulum. Transport of key metabo-
lites across an organelle membrane system is also a form
of regulation.
Many enzymes occur in several molecular forms called
(or isozymes), and those which are genetically
determined may be called primary isoenzymes. The dif-
ferent primary isoenzymes catalyze the same chemical re-
action but may differ in their primary structure and kinetic
properties. The tissue distribution of isoenzymes imparts
distinctive properties and specific patterns of metabolism
to organs of the body. The presence of isoenzymes may re-
veal differences not only between organs but also between
cells that make up an organ or between organelles of a cell.
During different stages of differentiation and development
from embryonic life to adulthood, the isoenzyme distribu-
tion in an organ undergoes characteristic changes. When
an adult organ reverts to the embryonic or fetal state (e.g.,
in cancer), the isoenzyme distributions change to those
characteristic of that developmental state. The existence
of isoenzymes in human tissues has important implications
in the study of human disease.
Zymogen (e.g., trypsinogen and chymotrypsinogen)
synthesis, secretion, transport, and activation and the rate
of inactivation of the active enzyme by inhibitors may all
be considered means of enzyme regulation.
Enzyme activity can be regulated by covalent modifi-
cation or by noncovalent (allosteric) modification. A few
enzymes can undergo both forms of modification (e.g.,
glycogen phosphorylase and glutamine synthetase). Some
covalent chemical modifications are phosphorylation and
dephosphorylation, acetylation and deacetylation, adeny-
lylation and deadenylylation, uridylylation and deuridyly-
lation, and méthylation and déméthylation. In mammalian
systems, phosphorylation and dephosphorylation are most
commonly used as means of metabolic control. Phos-
phorylation is catalyzed by protein kinases and occurs at
specific seryl (or threonyl) residues and occasionally at
tyrosyl residues; these amino acid residues are not usually
part of the catalytic site of the enzyme. Dephosphorylation
is accomplished by phosphoprotein phosphatases:
Protein kinase
Z---- *
Enzyme-Ser-0— P— O
V Protein kinase
/ Phosphoprotein \
HO— P— O "
The overall process of phosphorylation and déphosphory-
lation is a cascade of reactions and consists of an extracel-
lular signal, commonly referred to as
first messenger
hormones, such as glucagon); a specific receptor on the cell
membrane of the target cell; a transducer coupled to the
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