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Enzymes:
Enzymes are present in organisms as single units or in multienzyme complexes. Posttranslational modifications of amino acid residues take place after peptide assemblage on the ribosome; hydroxylation, phosphorylation, sulfation, N-terminal acetylation, and glycosylation are a few examples. The nature of posttranslational modifications and the hydrophobicity of amino acid side chains determine whether the enzyme is free or membrane-bound.1, 2
Enzymes catalyze biochemical reactions in living schemes which would other than as supposed or expected proceed too tardily at physiological temperature and pH to sustain life. Specificity and high catalytic power are two special traits of enzymes which distinguish them from popular chemical catalysts.3
Clinical and pharmaceutical importance of enzymes
A assortment of diseases may be detected through modified body liquid levels of specific enzymes.
Table 1 Disease detection thru enzymes
Enzyme Disease
Aspartate aminotransferase Liver disease
Alanine aminotransferase Liver disease
Acid phosphatase Prostate carcinoma
Alkaline phosphatase Bone disease, Hepatobiliary disease
Creatine kinase Myocardial infarction, Muscle disease
Lactate dehydrogenase Myocardial infarction, Liver disease
Cholinesterase Organophosphate poisoning
Pancreas enzymes Pancreatic diseases.
glutamyltranspeptidase Liver disease, Alcoholism
Elevated plasma and urine lysozyme levels are typical for lymphocytic leukemia’s and degenerative kidney impairment of normal physiological functions with glomerular and proximal tubular damage. Normalization of lysozyme plasma levels and disappearance of lysozyme in the urine are of prognostic value in successful kidney transplants.
Various types of cancer are affiliated with a ordinary increase in plasma proteinases. The presence of respective plasminogen activators and their inhibitors in a lot of malignancies proposes that the fibrinolytic system is involved in the regulation of tumor growth and metastatis. Local changes in fibrinolytic action such as scaled down tPA and increased urokinase levels in biopsies of the intestinal mucosa are characteristic in inflammatory and (pre)malignant processes in the colon.4
Replacement therapy in enzyme dysfunction or as adjusting agents in biochemical processes that have gone awry. Examples include, Fibrinolytic enzymes in thrombotic disorders; Proteolytic enzymes in wound healing; Amino acid degrading enzymes and Dimeric ribonuclease in cancer therapy; Digestive enzymes; Hyaluronidase and superoxide dismutase in inflammations, and a great deal of others.
Enzymes of nonhuman origin most times are potent immunogens or allergens. Their deliverance systems must protect them from inactivation before the target side is reached, and yet grant the enzymes to be freed at the target site, finally with their specific cofactors if required. Nonetheless enzymes are beautiful drugs because of their specificity and efficiency.5
Enzyme inhibitors:
Natural and synthetic enzyme inhibitors have become more and more primary in medicine, and have devised into a discerned class of drugs. These inhibitors form tight noncovalent or irreversible covalent complexes with their target enzymes.6,7
Thrombin is a key enzyme in clot formation, acting as a catalyst of conversion of fibrinogen to fibrin. Hirudin, a potent thrombin inhibitor from leech extracts, is available as a recombinant polypeptide and is presently under investigation in respective clinical trials.8,9
The bovine basic pancreatic proteinase inhibitor aprotinin inactivates kallikrein and is used with great success in supplementary treatment of acute pancreatitis and shock.10Rennin inhibitors such as pepstain are presently underneath investigation to lower blood pressure.11,12
Enzyme in therapy:
Genetic defects 13, 14
Metabolic diseases are caused by specific enzyme defects, in which the enzyme is not conveyed or is dysfunctional due to a sequence mutation or posttranslational inactivation. Some of these diseases may be treated with controlled diets. For example, phenylketonuria caused by phenylalanine-hydroxylase deficiency requires a phenylalanine-free diet. More oftentimes substitute therapy is needed, calling for the targeting of a alternate enzyme toward specific organs or tissues.
Other well-known” inborn errors of metabolism” are Pompe’s sickness or type II glycogen-storage sickness in which deficient ±-1,4-glucosidase results in exuberant accumulation of glycogen in liver and muscle cell lysosomes, Alcaptonuria (deficienct homogentisate 1,2-dioxygenase), Hemophilia B (factor IXa), Galactosemia( UDPG-hexose-1-phosphate transferase), Gaucher’s disease (²-glucocerebrosidase), Von Gierke’s disease (glucose-6-phosphatase), Pentosuria (xylulose reductase), Nieman-Pick sickness (Sphingomyelin phosphodiesterase), and the Lesch-Nyhan syndrome in which the absence of hypoxanthine-guanine phosphoribose transferase causes impaired nucleotide metamorphosis in brain cells and results in a severe neurological disorder.
Cancer therapy:
L-Asparaginase is employed as an anticancer drug. Certain tumor cell types lack asparagines synthetase action and need this amino acid as an necessary nutrient, in contrast to normal cells. Asparaginase selectively kills the tumor cells by depleting the circulating level of asparagines. It has likewise been suggested that L-aspartate as a metabolite may be toxic toward neoplastic cells. 15
Acute lymphocytic leukemia treatment with asparaginase is comparatively successful; a good deal of studies report finish remission in up to 60% of the treated patients.16 Patients subject to prolonged treatment with the enzyme ofttimes formulate a resistence due to the high titer of their neutralizing antibodies. Nevertheless, the therapeutic index of asparaginase compares very favorably to other antileukemic drugs.
It was speculated that sure types of cancer cells might likewise lack other queer pathways for amino acid synthesis and thence have amino acid requirements that are dissembled because of the presence of these amino acids in the diet. Enzyme therapy depleting the required amino acid would lead to the selective killing of these cells. Glutamine, Cysteine, and Arginine have been the subject of studies for possible enzyme-depletion therapy. In addition to the E.coli and Erwinia asparaginase, two types of glutaminase-asparaginase (PGA and AGA) might be suitable therapeutic enzymes since both have antitumor action in experimental animal models.17 Allergic reactions and a great deal of times neurotoxicity were the most severe side effects. The use of polymerized enzyme is preferred, since the unmodified enzyme has a plasma half-life of only 80 min.18
Of peculiar interest in cancer therapy is Carboxypeptidase G which hydrolyzes the terminal aspartate and glutamate moieties in oligopeptides and the glutamate moiety in scaled down and nonreduced folates. Purified carboxypeptidase G from respective Pseudomonas strains prevents methotrexate toxicity in humans.19
The antineoplastic effect of bovine pancreas ribonuclease has been reported in chronic myelocytic leukemia patients. However, fixed info is available from clinical trials. Dimeric ribonuclease displays selective toxicity in animal tumors and may be a promising campaigner as therapeutic enzyme.
Bacteriolytic, antiviral, and anti-inflammatory enzymes:
Lysozyme is present as an antibacterial agent in body fluids and cavities in direct contact with the external environment. It is available as a pharmaceutical preparation in tablets, ointments, powders, and infusions and is used as an antibacterial, antiviral, and anti-inflammatory drug. The mercantile preparations comprise hen egg-white lysozyme which is effortlessly apart and purified from egg whites in large-scale projects. This enzyme is nontoxic and only weakly antigenic and may be administered internally in huge doses without significant side effects. Lysozyme has chitinase, muramidase, and transglycosidase action and acts upon bacteria in a lot of ways. The proteoglycan layer in cell walls is the natural substrate for this enzyme.
Lysozyme has a distinct antiviral action versus herpes labialis, zoster, and simplex I and II types in humans, as well as versus galore oncogenic viruses in animal studies. Lysozyme stimulates phagocytosis and favors wound healing and regression of degenerative and necrotic processes.20 Lysozyme is administered in intramuscular or parenteral injections in herpes zoster and viral hepatitis, and in ointments for the treatment of herpetic keratitis, burns, and wounds and gynecological infections.
Corticoids and antibiotics have a synergestic action and are combined with lysozyme in aerosols for the treatment of bronchopulmonary diseases. Proteolytic enzymes and antiseptics are ofttimes used as adjuvant agents for dermatological applications. Bovine pancreatic ribonuclease appears to be an effective antiviral enzyme versus tick-borne encephalitis. It has no side effects and results in more rapid temperature normalization and regression of meningeal sensations or changes than antiencephalitic gamma globulin.21
Commercial hyaluronidase preparations comprise the bovine-testicular type (hyaluronate-4-glycanohydrolase) or the leech-type enzyme (hyaluronate-3-glycanohydrolase). They are employed in the treatment of keloids, ligneous conjunctivitis, and connective-tissue inflammation and as adjuvant in cancer therapy to facilitate transport and resorption of cytostatic agents.22 Animal studies revealed that hyaluronidase likewise acts as a cardiac lymphagogue, thereby reducing myocardial infarction after coronary artery occlusion.23
Superoxide dismutase (SOD) acts as an oxygen radical scavenger; under inflammatory conditions it is levels are increased. Depending on the nature of the disease, SOD is administered in injections, encapsulated in liposomes as a copper-zinc-SOD complex, or externally in creams.24 the enzyme is effective in the treatment of rheumatoid arthritis, crohn’s disease, progressive systemic sclerosis, dermatitis herpetiformis, and mucocutaneous lymph-node syndrome. It also prevents myocardial injury as a consequence of chemotherapy in neoplstic diseases.25
Proteolytic enzymes:
Enzymes hydrolyzing peptide bonds are not only important in feed digestion, but also play necessary roles in biological processes such as coagulation and hemostasis, supplement activation, peptide hormone release, wound healing, and control of protein metabolism.25,26
Trypsin and chymotrypsin are classical examples of proteinases applied in wound healing. They facilitate the remotion of necrotic tissue and scab material trapping bacteria inside the wound. These enzymes are often combined with antiseptics or antibiotics in ointments and bandages. Recently a new enzyme extract from Antarctic krill (E.superba) has been tested as a possible nominee preparation for the debridement of ulcerative lesions.28
Antithrombotic therapy:
An imbalance amidst coagulation and fibrinolysis leading to exuberant fibrin deposition may be neared either by the reduction of the coagulation potency or by an increase of the fibrinolytic potency. Various distinct features of fibrinolytic enhancement are still under development. Thrombolytic thearpy is applied in the firstborn management of people who are in need of medical care with deep venous thrombosis and pulmonary embolism.
Streptokinase and urokinase have been employed spacious in the treatment of venous thromboembolism. They are more potent than free circulating plasmin, which is speedily inactivated by circulating alpha 2-antiplasmin 30, 29. Randomized studies have demonstrated that intravenous tissue plasminogen activator is more effective than streptokinase in the treatment of coronary occlusion in acute myocardial infarction 31, 32. Commercial recombinant tissue plasminogen activator for the treatment of acute myocardial infarct is mainly received from Chinese hamster ovary cells (CHO).
Chemonucleolysis:
Chymopapain, an oxidation-sensitive cysteine proteinase from Carica papaya has been proposed for the treatment of herniated lumbar discs. Intradiscal injection of chymopapin results in dissolution of the mucopolysaccharide – protein complex of an extruding nucleus pulposus, the centre cushioning of gelatinous mass lying within the intervertebral disc, thereby relieving the pain related with a pressurized nerve. Large-scale follow-up studies indicate that chemonucleolysis is as successful a procedure as surgical discectomy, with a 76-80% success rate in both groups 33, 34, 35. Some pathological peculiarities related with herniated discs might be unfit for treatment by chemonucleolysis, for example, discs extruding nucleus pulposus through the annulus, a case in which the risk of harm to the spinal cord is predominant .36
Pancreas enzymes:
Digestion of feed is facilitated by the pancrease enzyme trypsin, chymotrypsin and elastase, carboxypeptidase A and B, phospholipase A – 2 and lipase and amylase. The main lipid factor in feed is long-chain triacylglycerol, which is hydrolyzed into fatty acids and sn-2-monoacylglycerol. Both merchandise are readily absorbed in the intestine. This hydrolysis is catalyzed sequentially by gastric lipase secreted by the chief cells of the stomach and by colipase-dependent pancrease 37.
Pancreatic lipases, proteases and amylases are prescribed as alternate therapy in pancreatic insufficiency where the enzyme output has fallen underneath 10%. Pancreatin of mammal origin is employed in mercantile preparations for substitution treatment 38, 40. Pharmaceutical formulations show substantial variation in enzyme action and bile salt content. Cellulose is at times added as adjuvant enzyme. Since the extent of pancreas malfunction varies significantly among patients, individualization of the treatment is indicated in determining the optimal enzyme dosage, formulation type, time of administration with respect to meals and frequency of administration.
Conclusion and future trends:
The elucidation on a molecular level of disease-related biochemical processes enables the definition of the type and specific target area of key enzymes or inhibitors necessary for restoring normal physiological conditions. Enzymes are beautiful drug campaigners because of their reaction specificity and catalytic efficiency. However, their protein nature imposes a good deal of limitations on their use in therapy. Organ specific aimed enzymes require parenteral administration and proteins of non-human origin are ofttimes allergenic or immunogenic. Considerable progression has been made in the refinement of isolation procedures to reduce or eliminate toxic contaminants, and the development of specific chemical modification and targeting proficiencies offers new possiblenesses for prolonging half life and bettering enzyme bioavailability. The most promising results are undoubtedly to be expected from the field of genetic engineering and internet site specific mutagenesis. Mutant enzymes with altered or bettered specificity, heightened stability, and scaled down immunogenicity will become available at an lowpriced cost.
References:
1. Chou, P. Y., and Fasman, G. D., Biochemistry, 13:222 (1974).
2. Moss, D. W., Henderson, A. R., and Kachmar., J. F., Enzymes. In: Textbook of Clinical alchemy (N. W. Tietz, ed.), W. B. Saunders, Philadelphia, 1986, pp. 619-774.
3. Ruyssen, R., and Lauwers, A. R., eds. Pharmaceutical enzymes, E. Story-Scientia, Ghent, Belgium, 1978.
4. Bickerstaff, G. F., and New Studies in Biology: enzymes in industry and medicine, Edward Arnold publish ltd., London, Baltimore, 1987.
5. Holcenberg, J. S., and Roberts, J., Enzymes as drugs, Wiley, New York, 1981.
6. Horl, H., and Heildland, A., eds., proteases: potential role in health and disease, In: advances in experimental medicine and biology, vol. 167, plenum press, new York and London. 1982.
7. Olson, S. T., and Shore, J. D., J. Biol. Chem., 257:14895-14895 (1982).
8. Kuada, T., and Abiko, Y., Thromb. Res., 24:285-298 (1981).
9. Witting J. I., Pouliott, C., Catalfamo, J. L., Fareed, J., and Fenton, II, J.F., Thromh res., 50:461-468 (1988).
10. Reimerdes, E. H., and Klostermeyer, H., Methods Enzymol., 15:26-28 (1976)
11. Illiano, L., Demeester, J., and Lauwers, A., Arch. Int. Phsiol. Biochem. 90(1):B36-37 (1982).
12. Schnebli, H. P., and Braun, N. J., Proteinase inhibitors as drugs, In: Research monographs in cell and tissue physiology, vol. 12, Proteinase inhibitors (A. J. Barrett and G. Salvesen, ed.,), Elsevier, New York, Amsterdam, 1986, pp. 613-627.
13. Powers, J. C., Am. Rev. Resp. Dis., 127 (supplP: S54 (1983).
14. Asgar, S. S., Pharmacol., Rev., 36:223-244(1984).
15. Kidd, J. G., Exp. Med., 98:565-581, (1953).
16. Capizzi, R. L., and Cheng, Y. C., therapy of neoplasia with asparaginase. In: Enzymes as drugs (J. S. Holcenberg and J. Roberts, eds.,) Wiley, New York, 1981, pp. 1-24.
17. Roberts, J., Schmid, F. A., and Rosenfeld, H. J., Cancer Treat Rep. 63:1045-54 (1979)
18. Spiers, A. S. D., and Wase, H. E., Cancer Treat Rep. 63:1019-24 (1979)
19. Abelson, H. T., Ensminger, W., Ropsowki, A., and Uren, J., Cancer Treat Rep. 62:1549-52 (1978)
20. Canfield, R. E., Collins, J.C., and Sobel, J. H., Lysozyme, 1st ed., Academic Press, New York, 1974
21. Levy, C. C., and Karpetsky, T. P., Human Ribonucleases. In: Enzymes as drugs (J. S. Holcenberg and J. Roberts, eds.,) Wiley, New York, 1981, pp. 156.
22. Baumgartner, G., and Neumann, H., Laryngol, Rhinol, Otol. Stuttg., 66:195 (1987)
23. Szlavy, L., Koster, K., De Courten, A., and Hollenberg, N. K., Angiolgy, 38:73- 84 (1987)
24. Bulkley, G. B., Br. J. Cancer Suppl., 8:66-73 (1987)
25. Niwa, Y., somiya, K., Michelson, A. M., and Puget, K., Free Radic. Res. Commun., 1:137-153(1985)
26. Reich, E., Rifkin, D. B., and Shaw, E., ed., Proteases and Biological control, cold spring harbor laboratory, cold spring harbor, New York, 1975
27. Ribbons, D. W., and Brew, K., eds. Proteolysis and Physiological Regulations, Academic Press, New York, 1976
28. Anheller, J. E., Hellgren, L., Karlstam, B., and Vincent. J., Arch., Dermotal., Res., 281:105-110 (1989)
29. Smith, R. A. G., Dupe, R. J., English, P. D., and green, J., nature, 290:505-508 (1981)
30. Ranby, M., and Wallen, P., In: Thrombolysis: biological and therapeutic properties of new thrombolytic agents ( D. Collem and H. R. Lijnen ed.,), Churchill livingstone, Edinburgh, 1985, pp. 31-48
31. Verstraete, M., Bernart, R., Bory. M., et al., Lancet, 1985:842-847
32. Trials in Myocardial infarction, phase I findings, N. Engl. J. Med., 312:932-936 (1985)
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34. Bock-Lamberlin, P.R., rose, F. W., and Schwonbeck, M., Zeitschr, Ortchop., 126:661-665 (1988)
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37. Szypryt, E. P., Gibson, M. J., Mulholland, R. C., and Worthington, B. S., Spine, 12:707-711 (1987)
38. Takenake, Y., Revel, M., Kahan, A., and Amor, B., Spine, 12:556-560 (1987)
39. Moreau, H., Gargouri, Y., Bernadal, A., Peironi, G., and Verger, R., Rev. Fr. Corps Gras, 35:169-176 (1988)
40. Peschke, G. J., Pancreatic enzyme (pancreatin). In : Topic in pharmaceutical sciences, 1989 (D. D. Breimer, D. J. A. Crommelin, and K. K. Midha eds., ), SDU publishers, the hague, Netherlands, 1989, pp. 129-142.
In the last few years, both the usage and popularity of affect drivers has risen as a result of it is affect size and non-reactionary torque. DEWALT developed this 38-piece Impact Driver Ready Accessory Set, ranked to be used with Impact Drivers and Wrenches. The set includes eight no. 2 phillips 1-inch insert bits, one affect ready 3/8-inch drive 9/16-inch deep socket , eight no. 2 phillips 1-inch drywall scaled down diameter insert bits, five no. 2 phillips 2-inch black oxide power bits, eight no. 2 phillips 1-inch double ended bit tips, one 1/4-inch affect ready nut driver, one 5/16-inch affect ready nut driver, one 3/8 -inch affect ready socket adaptor, one affect ready 3/8-inch drive 3/8-inch deep socket, one affect ready 3/8-inch drive 7/16-inch deep socket, one affect ready 3/8-inch drive 1/2-inch deep socket , one affect ready pivoting bit tip holder, and one affect ready 3-inch stainless steel bit tip nolder with hog ring.
DEWALT DW2169 38-Piece Impact Driver Ready Accessory Set
12 38 B 532 C 932 D Image
12 38 B 532 C 932 D Image
12 38 B 532 C 932 D Photo
12 38 B 532 C 932 D Picture
Most helpful client reviews
23 of 24 persons found the following review helpful.
 Same bits
By M. Sullivan
All the screw driver bits are Phillips size 2. It would have been better had they included a couple of dissimilar sizes and a regular flat blade. I also have had a problem with the Impact Ready Pivoting Bit Tip Holder snapping in two. I have been competent to get it back together, but it has happened more then once. All other bits work well.
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A little more potpourri would help
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 worth it
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