GEOFFREY EPHRAIM MWANGI

HSP201-0003/2023

THE ROLE OF ENZYMES IN PHARMACOTHERAPY

Enzymes play a crucial role in pharmacotherapy in several ways:

1. Prodrug activation
Enzymes can convert inactive prodrugs into their active forms, allowing them to exert their therapeutic effects.
Currently, there are three major categories of enzyme/prodrug strategies:
(a) delivery of genes that encode prodrug-activating enzymes into tumor tissue (gene encoding prodrug-activating
enzyme therapy, GDEPT, and virus-directed enzyme prodrug therapy, VDEPT),
(b) targeted delivery of active enzymes in tumor tissue where the therapeutic enzyme is conjugated with an antibody,
small molecular ligand, or peptide that binds to antigens preferentially expressed on the surface of tumor cells or in
the tumor vasculature or interstitium (targeting group-directed enzyme/prodrug therapy, TDEPT),
(c) vasculature permeability-dependent enzyme/prodrug therapy (VPDEPT) in which the intratumoral delivery of the
enzyme is realized through the higher permeability of tumor vasculature compared with normal vasculature as well as
the prolonged circulation lifetime of the macromolecular enzyme [enhanced permeability and retention (EPR) effect] .

In TDEPT and VPDEPT, after the clearance of unbound enzyme from normal tissues, the nontoxic prodrug,
which is a substrate of the enzyme, is administered. In GDEPT and VDEPT, the injection of the prodrug can be
done after confirming the expression of the enzyme in the tumor. The prodrug is converted to the anticancer
drug by the enzyme in the tumor, while normal tissues lacking the enzyme are spared from toxicity. Conversion
of the prodrug by residual enzyme in normal tissues may lead to toxicity if the prodrug is injected too early, and
to low tumor concentrations of the active drug if the prodrug is injected too late, as the enzyme concentration can
decrease due to clearance or proteolytic degradation.

2. Drug metabolism:
Enzymes like cytochrome P450 and various other phase I and phase II enzymes are responsible for metabolizing
drugs in the body. This metabolism can lead to drug activation, inactivation, or conversion to more easily excretable
forms. Understanding the enzyme pathways involved in drug metabolism is crucial for predicting drug interactions
and individualizing pharmacotherapy
 3. Enzyme replacement therapy:
Enzyme replacement therapy (ERT) is a medical treatment that involves the introduction of specific enzymes into the
body to compensate for a deficiency or absence of those enzymes. ERT is commonly used in the treatment of
genetic disorders where the body is unable to produce certain enzymes on its own. Here are five specific examples
of enzyme replacement therapy:

1. Gaucher's Disease: ERT is used to treat Gaucher's disease, a genetic disorder that results in the body's inability to
break down certain lipids. Enzyme replacement therapy involves the administration of glucocerebrosidase, the
enzyme that is deficient in individuals with Gaucher's disease.
2. Fabry Disease: ERT is also used to treat Fabry disease, a rare genetic disorder that results in the accumulation of
a particular type of fat within cells. Enzyme replacement therapy for Fabry disease involves the administration of
alpha-galactosidase A, the enzyme that is deficient in individuals with the condition.
3.Hurler Syndrome: ERT is employed in the treatment of Hurler syndrome, a genetic disorder that leads to the
accumulation of certain substances in the body's cells. Enzyme replacement therapy for Hurler syndrome involves
the administration of alpha-L-iduronidase, the enzyme that is deficient in individuals with the condition.
4. Hunter Syndrome: ERT is also used to treat Hunter syndrome, a rare genetic disorder that results in the body's
inability to break down certain complex molecules. Enzyme replacement therapy for Hunter syndrome involves the
administration of idursulfase, the enzyme that is deficient in individuals with the condition.

4. Diagnostic purposes

There are several enzymes used as biocatalysts in the diagnostic tests for the detection and also for the treatment of
specific diseases , there are some examples presented as below:

1. Glucose oxidase enzyme is widely used to measure glucose level in the diagnosis of diabetes;
2. Cholesterol oxidase enzyme activity can be used to measure the amount of cholesterol present in the blood for
diagnosis of condition of hyperlipidemia;
3. Urease enzyme is used to measure the level of urea in blood sample to diagnose liver and kidney lesions;
4. DNA polymerase has its application in testing the state of gene, for normal or any presence of oncogene in the body;
5. Glutaminase enzyme activity is required in the measurement of glutamine content in cerebrospinal fluid for the
correct diagnosis of cirrhosis;
6. Trypsin enzyme can be used to dissolve blood clotting, to accelerate the process of wound healing, to remove
necrotic tissue as well as in inhibiting the propagation of infecting microflora;
7. L-asparaginase can be used to treat cancer by depriving nutrients needed by the growth of cancer cells;
8. Protease enzyme easily available now in health shops is used to treat digestive disorders, and used by a person for
easy digestion of protein-rich diets.
5.Enzyme inhibition

The majority of drugs which act on enzymes act as inhibitors; one exception is metformin, which appears to stimulate
activity of AMP‐activated protein kinase, albeit through an imprecisely‐defined mechanism. Kinetic assays allow
discrimination of competitive, non‐competitive, and un‐competitive inhibitors. The majority of inhibitors are
competitive (acting at the enzyme's ligand recognition site), non‐competitive (acting at a distinct site; potentially
interfering with co‐factor or co‐enzyme binding) or of mixed type. One rare example of an uncompetitive inhibitor is
lithium ions, which are effective inhibitors at inositol mono-phosphatase only in the presence of high substrate
concentrations. Some inhibitors are irreversible, including a group known as suicide substrates, which bind to the
ligand recognition site and then couple covalently to the enzyme.