Enzymes:
The enzymes in organisms as single units or multi-enzyme complex. Post-translational modifications of amino acid residues occur after installation are on the ribosome peptide, hydroxylation, phosphorylation, sulfation, N-terminal acetylation, glycosylation, and some examples. The type of post-translational modifications and the hydrophobicity of the side chains of amino acids to determine if the enzyme is free or membrane-bound.1, 2
Enzymes catalyze biochemicalThe reactions in living systems, which otherwise would be too slow in the first temperature and physiological pH, to sustain life. Specificity and high catalytic power of enzymes are two special characteristics that distinguish them from ordinary chemicals catalysts.3
Clinical importance of enzymes and pharmaceuticals
Several diseases can be detected by specific enzymes through altered levels of body fluids.
Table 1-Disease Detection by Enzyme
EnzymeDisease
Diseases of the liver aspartate aminotransferase
Alanine aminotransferase liver disease
Prostate Acid Phosphatase
Alkaline phosphatase, bone disease, liver disease
Creatine kinase-myocardial infarction, muscle disease
Lactate dehydrogenase, myocardial infarction, liver disease
Organophosphate cholinesterase
Pancreatic enzymes pancreatic disease.
Glutamyltranspeptidase liver disease, alcoholism
IncreasePlasma and urine levels of lysozyme are typical for lymphocytic leukemia and degenerative renal disease glomerular and proximal tubular injury. Normalization of plasma levels of lysozyme and the disappearance of the prognostic value of lysozyme in the urine of kidney transplant success.
Several types of cancer are associated with a general increase in the plasma proteinase. The presence of various plasminogen activators and their inhibitors in many tumors, suggesting that thefibrinolytic system is involved in the regulation of tumor growth and metastasis. Changes in local fibrinolytic activity, as reduced levels of tPA and urokinase increased in mucosal biopsies in inflammatory lesions (pre-) malignant feature colon.4
Enzyme replacement therapy in erectile or as a means of regulating the biochemical processes that have gone bad. Examples include, fibrinolytic enzymes in thrombotic disorders; proteolytic enzymes in the woundHealing, dimeric ribonuclease amino acids and enzymes in cancer therapy, digestive enzymes, hyaluronidase, and superoxide in inflammation and many others.
Enzymes of non-human origin are sometimes powerful immunogens or allergens. Their delivery systems must be protected from inactivation before the target page is reached, yet, the enzymes are released at the destination, finally, with their specific cofactors, if necessary. However, enzymes are attractiveDrugs because of their specificity and efficiency.5
Inhibitors:
Natural and synthetic inhibitors have developed increasingly important in medicine, and in a separate class of drugs. These inhibitors form strong covalent or irreversible covalent complexes with their target enzymes.6, 7
Thrombin is a key enzyme in the formation of blood clots, fibrin as a catalyst for the conversion of fibrinogen. Hirudin, a potent thrombin inhibitor from leech extracts isas a recombinant polypeptide, and is currently being studied in several clinical trials.8, 9
The bovine basic pancreatic protease inhibitor aprotinin-inactivated kallikrein and further success in the treatment of acute pancreatitis and are used as inhibitors shock.10Rennin pepstain currently being investigated for reducing blood pressure.11, 12
Enzymes in the therapy:
Genetics 13, 14
Metabolic disorders by consequential specific enzyme,that the enzyme is not expressed or dysfunctional due to inactivation of a mutation sequence or post-translational. Some of these diseases can be treated with a controlled diet. For example, due to the lack of phenylalanine hydroxylase phenylketonuria requires a phenylalanine-free diet. The replacement therapy is often necessary, requires the alignment of a specific enzyme replacement organs or tissues.
Other well-known "inborn errors of metabolism" are Pompe disease or type IIGlycogen storage disease, resulting in poor ± -1,4-glucosidase in an excessive accumulation of glycogen in the muscles and liver lysosomes, Alkaptonuria (1.2-dioxygenase homogentisate deficienct), hemophilia B (factor IX), galactosemia (UDPG-hexose-1- phosphate transferase), Gaucher disease (glucocerebrosidase ²), Von Gierke's disease (glucose-6-phosphatase), pentosuria (xylulose reductase), Nieman-Pick disease (sphingomyelin phosphodiesterase), and Lesch-Nyhanincluding the absence of hypoxanthine-guanine nucleotide metabolism causes impaired phosphoribose transferase in brain cells and causes severe neurological disease.
Cancer therapy:
L-asparaginase is used as a cancer drug. Some types of cancer cells lack asparagine synthetase activities, and need this amino acid as an essential nutrient, in contrast to normal cells. Asparaginase selectively kills cancer cells by depleting circulating asparagine. It 'was alsosuggests that L-aspartate may be toxic metabolite than the cancer cells. 15
Acute lymphocytic leukemia treatment with asparaginase is successful, some studies have reported a complete remission in up to 60% of patients treated patients.16 subject of a prolonged treatment with the enzyme often develop resistance because of their high titers of neutralizing antibodies . However, comparing the therapeutic index of asparaginase very positively to other antileukemicDrugs.
It 'been suggested that some types of cancer cells may also lack other means of special formulas for the synthesis of amino acids and amino acid requirements, which are masked by the presence of these amino acids in the diet. The enzyme therapy to reduce the required amino acids lead to selectively kill cells. Glutamine, cysteine and arginine are being investigated for a possible enzyme-depletion therapy. In addition to E. coli and ErwiniaAsparaginase may be two types of appropriate enzymes glutaminase-asparaginase (PGA and AGA) therapy, since both have antitumor activity in animals and some allergic reactions models.17 time neurotoxicity were the most serious side effects. The use of enzymes is preferred because the cured unmodified enzyme half-life of only at least 80 18
Of particular interest in cancer therapy has carboxypeptidase G, which hydrolyses the terminal aspartate and glutamate unitsin the oligopeptides and the residue of glutamate in folate reduced and not reduced. G carboxypeptidase purified from different strains of Pseudomonas prevent methotrexate toxicity humans.19
State the antineoplastic effect of bovine pancreatic ribonuclease in patients with chronic myeloid leukemia reported. However, only limited information available from clinical trials. Dimeric ribonuclease shows selective toxicity and tumors in animal experiments may be a promising candidate as a therapeuticEnzyme.
Bacteriolytic, enzymes, anti-viral and anti-inflammatory:
Lysozyme as an antibacterial agent is present in body fluids and cavities in direct contact with the external environment. It is a pharmaceutical formulation in tablets, ointments, powders and teas, and is used as an antibacterial drug, antiviral and anti-inflammatory. Commercial products contain egg white lysozyme, which easily isolated and purified from large proteinProjects. This enzyme is not toxic and only weakly antigenic and can be internally administered in high doses without significant side effects. Chitinase and lysozyme has muramidase activity transglycosidase and acts on bacteria in many ways. The layer of proteoglycans in the cell walls is the natural substrate for this enzyme.
Lysozyme has a significant antiviral activity against herpes labialis, zoster and simplex type I and II in humans, as well as against some animal viruses oncogenesStudies. Lysozyme stimulates phagocytosis and promotes wound healing and regression of degenerative and necrotic processes.20 lysozyme is administered as intramuscular injections or parenteral herpes zoster, viral hepatitis and ointments for the treatment of herpes keratitis, burns and wounds and gynecological infections.
Corticosteroids and antibiotics have synergestic and action are combined with lysozyme in the aerosol for the treatment of bronchopulmonary diseases. ProteolyticEnzymes and antiseptics are often used as adjuvants for dermatological applications. Bovine ribonuclease appears to be an effective anti-viral enzyme against tick-borne encephalitis. It has no side effects and results in a rapid normalization of temperature and the regression of meningeal symptoms such as gamma antiencephalitic globulin.21
Commercial preparations containing bovine type testicular hyaluronidase (hyaluronate 4-glycanohydrolase) or the enzyme leech(Hyaluronate-3-glycanohydrolase). They are to facilitate the treatment of keloids, woody and conjunctivitis inflammation of the connective tissue and as an adjuvant in cancer therapy, transport and absorption of cytotoxic agents.22 studies in animals have shown that hyaluronidase used as lymphagogue heart, myocardial infarction after coronary occlusion.23
Superoxide dismutase (SOD) acts as an oxygen scavenger, inflammatory conditions, their levelsbe increased. Depending on the type of disease, SOD is administered by injections, encapsulated in liposomes as copper-zinc-SOD complex, or the external creams.24 enzyme effective in the treatment of rheumatoid arthritis, Crohn's disease, progressive systemic sclerosis, the Dermatitis herpetiformis and mucocutaneous lymph node syndrome. It also prevents myocardial damage after chemotherapy in neoplstic diseases.25
Proteolytic enzymes:
Enzymes hydrolyzePeptide bonds are not only important in digestion, but also play an essential role in biological processes such as blood coagulation and haemostasis, complement activation, the release of peptide hormone, wound healing, and control of protein metabolism.25, 26
Trypsin and chymotrypsin are classic examples of proteases used in wound healing. Facilitate the removal of necrotic tissue and eschar material in which bacteria in the wound. These enzymes are often combined with antiseptics orAntibiotic ointments and bandages. Recently a new enzyme extracted from krill (E.superba) was tested as a possible candidate for the preparation for debridement of ulcerative lesions.28
Antithrombotic therapy:
An imbalance between coagulation and fibrinolysis leads to excessive fibrin deposition may be addressed either by reducing the power of the coagulation or fibrinolytic a higher power. Various aspects of the expansion are still in the fibrinolyticDevelopment. Thrombolytics thearpy is used in the initial treatment of patients with deep vein thrombosis and pulmonary embolism.
Streptokinase and urokinase have been widely used in the treatment of venous thromboembolism. They are stronger than plasmin free movement, which is rapidly inactivated by circulating alpha 2-antiplasmin, 30, 29. Randomized studies have shown that intravenous tissue plasminogen activator is more effective than streptokinase in the treatment ofCoronary occlusion in acute myocardial infarction 31, 32 Commercial recombinant tissue plasminogen activator for the treatment of acute myocardial infarction is mainly from Chinese hamster ovary (CHO).
Chemonucleolysis:
Chymopapain, an oxidation-sensitive cysteine proteinase from Carica papaya was proposed for the treatment of lumbar discs. Intradiscal injection of chymopapin results in resolution of mucopolysaccharide - complex of a protein-extrusionNucleus pulposus, the center of the jelly-like mass loss, within the intervertebral disc, thereby relieving the pain associated with nerve under pressure. Extensive follow-up studies show that chemonucleolysis has happened a discectomy surgical procedure with a success rate of 76-80% in both groups 33, 34, 35 Some pathological features can be associated with herniated discs are not suitable for the treatment of chemonucleolysis, for example, hard disk, the nucleus pulposus through extrusionthe ring, a case in which the risk of damage to the spinal cord weighs about 0.36
Pancreatic enzymes:
Digestion of food by the pancreatic enzyme trypsin, chymotrypsin and elastase, carboxypeptidase A and B facilitates, phospholipase A - 2 and amylase and lipase. The fat component in food is important to long-chain triglycerides, which is hydrolyzed to fatty acids and sn-2-monoacylglycerol. Both products are easily absorbed in the intestine. This hydrolysis is catalyzed sequentiallysecreted by the gastric lipase by the principal cells of the stomach and pancreatic colipase-dependent 37
Pancreatic lipase, protease and amylase are as replacement therapy in pancreatic insufficiency, in which the enzyme has dedicated output fell below 10%. Pancreatin in commercial preparations of mammals for replacement therapy 38, 40 using pharmaceutical formulations show significant differences in enzyme activity and salt content of bile. Cellulose is sometimes added as an adjuvantEnzyme. Since the degree of disorder of the pancreas varies greatly among patients, individualization of treatment in determining the optimal amount of enzyme formulation type, timing of administration in relation to meals and frequency of administration indicated.
Conclusions and future trends:
The explanation at the molecular level with disease-related biochemical processes used to define the nature and destination area or specific inhibitors of key enzymesRestore normal physiological conditions. The enzymes are attractive drug candidates for its specificity of reaction and the catalytic efficiency. However, their protein nature imposes some restrictions on their use in therapy. Proteins targeted organ-specific enzymes and require parenteral administration of non-human origin are often allergenic or immunogenic. Significant progress has been made in the improvement of methods for isolation to reduce or eliminate toxic pollutants, andDevelopment of specific chemical modification and targeting techniques offers new possibilities to extend the half-life and improving the enzyme-bioavailability. The most promising results are expected no doubt from the field of genetic engineering and site-directed mutagenesis. Mutant enzymes with altered or improved specificity, improved stability and reduced immunogenicity is at an affordable price.
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