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Enzymatic therapy

  1. Enzymatic Therapy By :- Sajjad Fadhil Kazim.
  2. It is the technique of using enzymes in the treatment of various genetic and microbial diseases. This technique is considered one of the branches of Protein Therapeutics, which forms a wide section of medical biotechnology. Although it was not long after its discovery so it is also considered one of the sections of modern biotechnology. Genetically engineered enzymes may be used as therapeutic agents. For example, both recombinant DNase I and alginate lyase have been used in an aerosol form to decrease the viscosity of the mucus found in the lungs of patients with cystic fibrosis. Certain therapeutic enzymes may be delivered directly to their target cells by expressing the genes for these proteins in a bacterium that is normally associated with human tissues and has been shown to be safe. Enzymatictherapy
  3. Enzymes have been used as therapeutic drugs for diverse pathologies. Advances in both biotechnology and protein engineering have shed light on the study of enzymes’ potential as therapeutic tools and on the metabolic pathways involved in different diseases. As a result, recombinant enzymes have emerged as new treatments for many diseases such as genetic abnormalities (LSD, CF, et cetera) and cancer, among other medical applications. To become widely used drugs, enzyme therapies must overcome enzyme rapid clearance in vivo, the unwanted off-target interactions and patient immune response. The encapsulation and molecular modifications of enzymes, together with active monitoring of immune response, are the most remarkable therapy improvement techniques addressed to date Enzymatictherapy
  4. Enzymes may be used therapeutically in a variety of ways. For example:- • They may be used to augment an existing metabolic pathway, thereby increasing the amount of a particular compound or metabolite that is a product of that pathway. • Alternatively, some enzymes may be used to relieve the disease pressure caused by a pathogen or may help to lower the level of an overproduced metabolite Enzymesusing
  5. Scientists isolated the cDNA for the human enzyme deoxyribonuclease I (DNase I) and subsequently expressed the cDNA in CHO cells in culture. DNase I can hydrolyze long polymeric DNA chains into much shorter oligonucleotides. The purified enzyme is delivered in an aerosol mist to the lungs of patients with cystic fibrosis. The DNase I decreases the viscosity and adhesivity of the mucus in the lungs and makes it easier for these patients to breathe. While this treatment is not a cure for cystic fibrosis, it nevertheless relieves the most severe symptom of the disease in most patients. EnzymaticTherapyExamples 1.DNaseI
  6. Figure (1) : (A) Schematic representation of a portion of a human lung occluded by a combination of live alginate- secreting bacterial cells, lysed bacterial cells, and leukocytes and their released DNA being cleared by digestion by aerosol-delivered DNase I. (B) Digestion of DNA by DNase I.
  7. The excretion of alginate by mucoid strains of the bacterium Pseudomonas aeruginosa that infect the lungs of patients with cystic fibrosis significantly contributes to the viscosity of the mucus in the airways In which the alginate prevents added antibiotics from coming into contact with the bacterial cells. In one experiment, it was shown that the addition of the enzyme alginate lyase, which can liquefy bacterial alginate, together with or prior to antibiotic treatment significantly decreased the number of bacteria found in biofilms. Thus, alginate lyase treatment not only decreases the viscosity of the mucus but also facilitates the ability of added antibiotics to kill the infecting bacterial cells. This result suggests that in addition to the DNase I treatment, depolymerization of the alginate might help clear blocked airways of individuals with cystic fibrosis. 2.AlginateLyase EnzymaticTherapyExamples
  8. Figure (2) : Time courses of the killing of bacteria in biofilms with and without treatment with alginate lyase.
  9. 3.PhenylalanineAmmoniaLyase EnzymaticTherapyExamples Is a stable enzyme that does not require a cofactor and could potentially prevent the accumulation of phenylalanine in phenylketonuria patients. To test this concept, the gene for phenylalanine ammonia lyase from the yeast Rhodosporidium toruloides was cloned and overexpressed in E. coli. Plasma phenylalanine levels were lowered when phenylalanine ammonia lyase was injected intravenously or encapsulated enzyme was administered orally. It act by onverts phenylalanine to ammonia and trans-cinnamic acid and this enhance the remove of phenylalanine from patient’s body.
  10. Figure (3) : Patients with phenylketonuria are unable to metabolize phenylalanine in the liver as healthy people do. They metabolize phenylalanine in the intestine alternatively through oral administration of the engineered probiotic TYS8500.
  11. 4.Glycosidases EnzymaticTherapyExamples The ABO blood group system is based upon the presence or absence of specific carbohydrate residues on the surfaces of erythrocytes, endothelial cells, and some epithelial cells. The monosaccharide that determines blood group A is a terminal α- 1,3-linked N-acetylgalactosamine. while the corresponding monosaccharide of blood group B is α-1,3- linked galactose.
  12. 4.Glycosidases EnzymaticTherapyExamples it is advantageous to have a large supply of plasma that is from blood group O (e.g., in an emergency situation, there may not be sufficient time to check a patient’s blood group). Fortunately, digestion of specific carbohydrate residues on the surfaces blood cells from either type A or B with specific glycosidases can cause types A, B, and AB to be converted into type O . These enzymes were found following an extensive screening process of 2,500 fungal and bacterial isolates. Eventually: • An active α-N-acetylgalactosamidase, which converts group A to group O, was found in the gram-negative bacterium Elizabethkingia meningoseptica. • converts group B to group O, was found in the gram-negative bacterium Bacteroides fragilis.
  13. Figure (4) : Group O red cells are called ‘universal’ because they are suitable for transfusion to individuals of all ABO groups. Group A red cells can be given safely only to A and AB individuals, and group B red cells can be given only to B and AB individuals. Modification of A and B red cells by novel glycosidases removes the immunodominant sugars (GalNAc and Gal), in principle rendering them suitable for transfusion to anyone.
  14. References:- From:- medical biotechnology by Bernard R. Glick , Terry L. Delovitch & Cheryl L. Patten :- capture 9 ((Protein Therapeutics : Enzyme )) p.497-507. • Ulmer, G. S., A. Herzka, K. J. Toy, D. L. Baker, A. H. Dodge, D. Sinicropi, S. Shak, and R. A. Lazarus. 1996. Engineering actin- resistant human Dnase I for treatment of cystic fi brosis. • Alkawash, M. A., J. S. Soothill, and N. L. Schiller. 2006. Alginate lyase enhances antibiotic killing of mucoid Pseudomonas aeruginosa in biofi lms. • Article , Enzyme Therapy: Current Challenges and Future Perspectives by:- National Center for Biotechnology Information (NCBI). • Article , Phenylalanine degrading enzymes-displayed probiotics are more effective live biotherapeutic for phenylketonuria. • Nature biotechnology : Towards universal red blood cells by Geoff Daniels & Stephen G withers. • Sarkissian, C. H., and A. Gámez. 2005. Phenylalanine ammonia lyase, substitution therapy for phenylketonuria, where are we now? Mol. Genet. Metab. • Liu, Q. P., G. Sulzenbacher, H. Yuan, E. P. Bennett, G. Pietz, K. Saunders, J. Spence, E. Nudelman, S. B. Levery, T. White, J. M. Neveu, W. S. Lane, Y. Bourne, M. L. Olsson, B. Henrissat, and H. Clausen. 2007. Bacterial glycosidases for the production of universal red blood cells. Nat. Biotechnol.
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