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Enzymes in therapy
1. ENZYMES IN THERAPY
Presented by
Dr. Sajeena Jose. C
Department of Pharmacology
Amala Institute of Medical Sciences
2. INTRODUCTION
• The role of enzymes in medicine as markers,
diagnostic and prognostic applications are widely
known.
• These enzymes are now considered as new biological
drug in the treatment of certain disorders and hence
emerged as an offshoot of therapy.
3. • The favoured kinetics of the enzymes used in therapy
should be of low Km and high Vmax in order to be
maximally efficient at low concentration of the enzymes
and its substrate.
• Another prerequisite is a purified and specific enzymes;
hence lyophilized preparations with compatible buffering
salts and mannitol as dilute are preferable.
5. • Chymotrypsin:
• Chymotrypsin is a proteolytic enzyme Naturally produced
by the pancreas of the human body.
• Chymotrypsin breaks down protein into dipeptide and
some single amino acids by hydrolysis of peptide bond in
small intestine.
• Bromelain, rennin, papain:
• Bromelain is a group of proteolytic enzymes to cures
digestive disorders.
6. • Rennin helps to digest milk protein.
• Papain helps to digest protein and loosen necrotic tissues
and waste material from the cell wall.
• Cellulase:
• Cellulase is an enzyme that breaks down cellulose to β-
glucose, produced by bacterial fungi and grazing animals
such as cow.
• Cellulose is non-digestible by human because we do not
produce Cellulase.
7. DNase l
• Cystic fibrosis (CF) is one of the most commonly
occuring genetic diseases (1 in 2500 in northern
Europe)
• Cystic fibrosis (CF), also known as mucoviscidosis,
affects most critically the lungs, and also the
pancreas, liver and intestine
8. • It is characterized by abnormal transport of chloride and
sodium across an epithelium, leading to thick, viscous
secretions i.e., Underlying cause is identified to the
mulfunction of ion transport.
• Major clinical symptom is the production of viscous
mucus in the respiratory track.
• The role of DNase I can hydrolyse long polymeric DNA
chains into shorter oligonucleotides and the purified
enzyme can be delivered in an aerosol mist to the lungs of
CF patients to prevent respiratory distress.
9. • The enzyme could decrease the mucus viscosity in the
lungs and allow patients for easy breathing, thus reducing
the severity and pain of the patient.
• This enzyme was approved for use by the US FDA in
1994.
10. Alginate lyase
• The excretion of alginate by mucoid strains of
pseudomonas aeruginosa may infect the lungs of
cystic fibrosis patient contributing significantly to the
viscosity of the mucous.
• Hence treatment of cystic fibrosis depends on the
DNase l therapy and depolymeriztion of the alginate
which would help to clear blocked airways.
• Since the enzyme alginate lyase can liquefy viscous
bacterial alginate which in addition to DNase l is
good therapeutic agent of cystic fibrosis.
11. Adenosine deaminase
• Deficiency of ADA (adenosine deaminase), a
cytoplasmic enzyme found in high concentrations in
lymphoid cells, causes SCID due to
lymphocytotoxic effects of adenosine and
deoxyadenosine.
• Deoxyadenosine cause dATP pool expansion, which
blocks DNA replication by inhibiting ribonucleotide
reductase and has other side effects. Deoxyadenosine
also inactivates enzyme S-adenosylhomocysteine
hydrolase.
12. • Pathology of ADA deficiency is well defined and limited
to haemopoietic cells, so enzyme replacement therapy is
straight-forward.
• However the two problems associated with enzyme
therapy are very short circulating life of the injected
enzyme and risk of provoking allergic or other
immunologic response in chronic treatment.
• Enzyme replacement therapy in ADA deficiency disease
is approved by the US Food and Drug Administration
(FDA).
13. Dihydrofolate reductase
• Methotrexate (MTX) is widely used as anticancer
drug damaging dihydrofolate reductase enzyme. This
enzyme is required by cancer cells.
• MTX is not selective in action and also affects normal
cells.
14. • Since different patients break down the drug at different
rates, it is important to monitor the level of MTX in the
body.
• This can be done by in-vitro testing by the effect on
enzyme dihydrofolate reductase enzyme of MTX from
blood sample. Here enzyme obtained is from
Lactobacillus casei.
15. Lipase
• Gaucher's disease or Gaucher disease is a genetic
disease in which a fatty substance (lipid)
accumulates in cells and certain organs.
• The disorder is characterized by fatigue, anemia, low
blood platelets, and enlargement of the liver and
spleen.
• It is caused by a hereditary deficiency of the enzyme
glucocerebrosidase. This enzyme acts on the
glycolipid glucocerebroside.
16. • When the enzyme is defective, glucocerebroside
accumulates, particularly in white blood cells, most often
macrophages.
• Glucocerebroside can collect in the spleen, liver, kidneys,
lungs, brain and bone marrow.
• Manifestations may include enlarged spleen and liver,
liver malfunction, skeletal disorders and bone lesions that
may be painful, severe neurologic complications, swelling
of lymph nodes and (occasionally) adjacent joints,
distended abdomen, a brownish tint to the skin, anemia,
low blood platelets and yellow fatty deposits on the white
of the eye.
17. • Persons affected most seriously may also be more
susceptible to infection.
• Some forms of Gaucher's disease may be treated with
enzyme replacement therapy.
• The disease is named after the French doctor Philippe
Gaucher, who originally described it in 1882
18. Streptokinase
• Streptokinase is the microbial enzyme derived from the
streptococcus species.
• The enzyme is thrombolytic in nature, can break down the
blood clots in veins and prevent coronary artery disease.
• Dissolution of clot by converting intrinsic plasminogen
present in the clot to active plasmin.
• In 1987, FDA has approved this enzyme for treating heart
attacks which is produced in bulk based on r-DNA
technology.
19. Rhodnase
• Rhodanese is a mitochondrial enzyme that
detoxifies cyanide (CN-) by converting it to
thiocyanate (SCN-).
• Rhodanese and a sulfur compound given
therapeutically to mice when symptoms of cyanide
poisoning had occurred, also had a very good antidote
effect
20. Enzymes for the treatment of
infectious diseases
• Lysozyme has been used as a naturally occurring
antibacterial agent in many foods and consumer
products, because of its ability to break carbohydrate
chains in the cell wall of bacteria.
• RNase A and urinary RNase U, which selectively
degrade viral RNA opening some exciting
possibilities for the treatment of HIV infection.
21. • Naturally occurring antimicrobial agents are the
chitinases.
• As an element of the cell wall of various pathogenic
organisms, including fungi,protozoa and helminths, chitin
is a good target for antimicrobials.
22. Alzheimer disease.
• There is increasing evidence that deficient clearance β-
amyloid (Aβ) contributes to its accumulation in late-onset
Alzheimer disease (AD).
• Several Aβ-degrading enzymes, including Neprilysin
(NEP), Insulin-degrading enzyme, and Endothelin-
converting enzyme reduce Aβ levels and protect against
cognitive impairment in mouse models of AD.
23. • Experimental data indicate that increasing the activity of
these enzymes (NEP in particular) has therapeutic
potential in AD, although targeting their delivery to the
brain remains a major challenge.
24. Urate oxidase, or uricase
• Urate oxidase, or uricase , is a peroxisomal liver
enzyme that catalyses the enzymatic oxidation of uric
acid into the more water-soluble allantoin.
• It is used in humans for the control of increased
serum uric acid in patients with acute tumour lysis
syndrome after receiving chemotherapy.
25. • Rasburicase , a recombinant urate oxidase expressed in
Saccharomyces cerevisiae, has been demonstrated to be
superior to allopurinol in the control of uric acid in a
randomized trial of paediatric and adult patients at risk of
acute tumour lysis syndrome.
26. Enzyme replacement therapy
• The concept of enzyme replacement therapy for
LYSOSOMAL STORAGE DISEASES was
enunciated by DE Duve in 1964.
• Enzyme replacement therapy (ERT) is a medical
treatment replacing an enzyme in patients in whom
that particular enzyme is deficient or absent.
• Usually this is done by giving the patient an
intravenous (IV) infusion containing the enzyme
27. • Enzyme replacement therapy is currently available for
some lysosomal diseases:
• Gaucher disease-THE ENZYME DEFICIENT IS
glucocerebrosidase
• Fabry disease-THE ENZYME DEFICIENT IS Alpha
galactosidase A
• MPS I -THE ENZYME DEFICIENT IS α-Liduronidase
28. • MPS II (Hunter syndrome)-THE ENZYME DEFICIENT
IS Iduronate sulfatase
• MPS VI and
• Glycogen storage disease type II.-THE ENZYME
DEFICIENT IS Acid maltase
29. FEW ENZYMES UNDER
INVESTIGATIONS
• Superoxide dismutase (human)-Protection of donor
organ tissue from damage or injury mediated by
oxygen-derived free radicals that are generated during
the necessary periods of ischemia (hypoxia, anoxia),
and especially reperfusion
• Butyrylcholinesterase-Reduction and clearance of
toxic blood levels of cocaine encountered during a
drug overdose and treatment of post-surgical apnea
30. • PEGylated arginine deiminase-Treatment of invasive
malignant melanoma
Treatment of hepatocellular carcinoma
• Clostridial collagenase-Treatment of advanced
(involutional or residual stage) Dupuytren’s disease
• Lipase, amylase and protease-Treatment of pancreatic
insufficiency
• Recombinant human porphobilinogen deaminase-
Treatment of acute intermittent porphyria attacks.
33. Enzyme Reaction use Enzyme Reaction use
aAmylase Starch
hydrolysis
Diagestive
disorders
Rhodanase Degradation
of
cyanide
Cyanide
poisoing
Collagena
se
Collagen
hydrolysis
Skin ulcers RNase RNA digestion Antiviral RNA
hydrolysis
Ficin,
Papain,
Proteinase
Protein
hydrolysis
Deworming,
digestive-
disorders,na
rcotic tissue
removal
b lactamase Pencillin Penc
illoate
Pencillin
allergy
Glutaminase Gln Glu Leukemia Streptokinase Plasminogen
plasmin
Blood clot
dissolving
Aspargina
Se
Asn Asp Leukemia uricase UA allatoin Gout
Lysozyme Bacterial CW
hydrolysis
As Antibiotics Hyaluronidase ?HUA
hydrolysis
Viral infection
Bilirubin
oxidase
Bilirubin
hydroxylase
hyperbilirubin
emia
SOD 2O2+2H+ H2
O2+O2
antioxidant
34. APPLICATIONS OF THERAPEUTIC ENZYMES
• As specific detoxification agents in case of acute
chemical poisoning
• As antineoplastic agent
• As a replacement therapy in enzyme deficient genetic
disorders
• As agent to limit tissues damage in reperfusion
injuries
35. LIMITATIONS OF ENZYMES
• Avoiding rapid clearance of enzyme from blood
• Improvement in purification technology
• Cost effective enzymes
• Should be nonimmunogenic