GEOFFREY EPHRAIM MWANGI

HSP201-0003/2023

Mechanisms through which enzyme catalysis is regulated

Allosteric regulation:
There are two types of allosteric regulation on the basis of substrate and effector molecules: Homotropic
Regulation: Here, the substrate molecule acts as an effector also. It is mostly enzyme activation and also called
cooperativity, e.g. binding of oxygen to haemoglobin. Heterotrophic Regulation: When the substrate and effector are
different. The effector may activate or inhibit the enzyme, e.g. binding of CO2 to haemoglobin. On the basis of action
performed by the regulator, allosteric regulation is of two types, inhibition and activation. Allosteric Inhibition: When
an inhibitor binds to the enzyme, all the active sites of the protein complex of the enzyme undergo conformational
changes so that the activity of the enzyme decreases. In other words, an allosteric inhibitor is a type of molecule
which binds to the enzyme specifically at an allosteric site. Allosteric Activation: When an activator binds, it increases
the function of active sites and results in increased binding of substrate molecules. There are two models proposed
for the mechanism of regulation of allosteric enzymes:

1. Simple Sequential Model- In this model, the binding of substrate induces a change in the conformation of
the enzyme from T (tensed) to R (relaxed). The substrate binds according to the induced fit theory. A
conformational change in one unit stimulates similar changes in other subunits. This explains the
cooperative binding. The same way inhibitors and activators bind, the T form is binding favored, when the
inhibitor binds and R form is favored, when the activator binds. The at one subunit affects the conformation
of other subunits. The sequential model explains the negative cooperativity in enzymes, e.g. tyrosyl tRNA
synthetase, where the binding of substrate inhibits the binding of another substrate.
2. Concerted or Symmetry Model-According to this model, there is a simultaneous change in all the subunits
of an enzyme. All the subunits are either present in R form (active form) or T form (inactive form), having
less affinity to a substrate. An inhibitor shifts the equilibrium of T ⇄ R, towards T, and activator shifts the
equilibrium towards R form and favors the binding. It explains the cooperative regulation of activators as well
as inhibitors.

Feedback inhibition:
In enzymology, suppression of the activity of an enzyme, participating in a sequence of reactions by which a
substance is synthesized, by a product of that sequence. When the product accumulates in a cell beyond an optimal
amount, its production is decreased by inhibition of an enzyme involved in its synthesis. After the product has been
utilized or broken down and its concentration thus decreased, the inhibition is relaxed, and the formation of the
product resumes. Such enzymes, whose ability to catalyze a reaction depends upon molecules other than their
substrates (the ones upon which they act to form a product), are said to be under allosteric control. Feedback
inhibition is a mechanism by which the concentration of certain cell constituents is limited.

Covalent modification:
Enzymes can be activated or inhibited through the addition or removal of functional groups, such as phosphorylation,
Prenylation or acetylation.

Reversible inhibitors are extremely important in regulating enzyme activity. They can turn enzymes on or off, acting
as activators or inhibitors, respectively. In addition, enzymes can be regulated via covalent modification or post-
translational modification. That means that, after the enzyme has been assembled in the cell, its structure can be
modified further by adding special groups to specific locations. In the case of regulation, these groups are added
reversibly. Even though the group is added covalently -- it is bonded to the protein -- a reaction path exists for the
removal of the group again.

There are three examples of these modifications that we will look at here. In each case, the behaviour of the protein
is modified because of changes in the intermolecular attractions within the protein (or between the protein and
another molecule).

Phosphorylation is a very common modification. In phosphorylation, a phosphate group is attached to an amino

Phosphorylation is typically carried out under the control of another enzyme called a kinase. That's right, one enzyme
will bind another, tying a phosphate group onto it before releasing it again. A phosphate group can be removed again
via another enzyme called a phosphatase. The fact that these modifications are carried out by specific enzymes
helps to explain their specificity. A particular kinase may bind to its target protein in a well-defined position,
phosphorylating it only at that position (although some kinases may be less selective). The key result of
phosphorylation is that a neutral serine is suddenly masked by an anionic phosphate group. That negative charge
alters intermolecular attractions quite starkly, because suddenly attractive and repulsive forces pop up where there
were none before.

Acetylation is also quite common. Acetylation is the addition of an acetyl or ethanoyl group; usually, the group is
added to a lysine. The forward reaction is driven by the strong amide bond that results. Acetylation is carried out by
an acetylase or an acyltransferase. Like phosphatases, these are enzymes that bind their target proteins in order to
modify their structures. Because lysins are normally positively charged at biological pH, acetylation results in the
sudden disappearance of charged species because they are masked with neutral acyl groups. Intermolecular
attractions can be dramatically affected as a result.

Prenylation is the addition of a hydrocarbon side chain, most often to a cysteine side chain. Sulfur is a particularly
good nucleophile for carbon chains of this sort, enhancing selectivity for cysteine. As in the other cases, however, the
reaction is carried out under the control of an enzyme (a geranyltransferase, for example, or a farnesyltransferase),
and so other side chains might be targeted, instead.
Gene expression control:
The production of enzymes can be regulated at the transcriptional and translational levels, ensuring the synthesis of
enzymes when needed.