Author(s):
Herman Y. L. Wihastyoko, Setyawati Soeharto, Edi Widjajanto, Kusworini, Bambang Pardjianto
Email(s):
wihastyokohyl@gmail.com
DOI:
10.52711/0974-360X.2021.00862
Address:
Herman Y. L. Wihastyoko1,2, Setyawati Soeharto3, Edi Widjajanto4, Kusworini4, Bambang Pardjianto2,5
1Doctoral Program, Faculty of Medicine, Brawijaya University, Malang 65145, Indonesia.
2Plastic, Aesthetic and Reconstruction Consultant, Saiful Anwar General Hospital, Malang 65111, Indonesia.
3Pharmacology Department, Faculty of Medicine, Brawijaya University, Malang 65145, Indonesia.
4Clinical Pathology Department, Faculty of Medicine, Brawijaya University, Malang 65145, Indonesia.
5Faculty of Medicine and Health Sciences, State Islamic University of Malang, Malang 65144, Indonesia.
*Corresponding Author
Published In:
Volume - 14,
Issue - 9,
Year - 2021
ABSTRACT:
Aims: This study aims to identify the potential of papain as a candidate for the treatment modality for abnormal scars via in silico studies. Methods: We determined the potential mechanism of the process of collagen degradation by papain by investigating its cleavage site-specificity and identifying human papain-like enzymes that have comparable biological activity in degrading collagen in the extracellular matrix using Merops, Bioedit, String DB and Cytoscape software. Results: Papain targets QQ_D (Glutamine-Glutamine Aspartic acid) motif for degradation while collagen only has QQ (Glutamine-Glutamine) motif. Additionally, the homology result showed that Cathepsin B has a closer relationship with papain compared with another candidate, Cathepsin K. Conclusion: Papain is a potential therapeutical modality candidate in degrading collagen in abnormal scars with an indirect mechanism as indicated by its cleavage site-specificity and its relationship with Cathepsin B, which degrades collagen via ubiquitin (UBC) proteasome.
Cite this article:
Herman Y. L. Wihastyoko, Setyawati Soeharto, Edi Widjajanto, Kusworini, Bambang Pardjianto. Biological Activity of Papain and Papain-like (Cathepsin-K and Cathepsin-B) Enzymes as Therapeutical Modality Candidates in Degrading Collagen in Abnormal Scar. Research Journal of Pharmacy and Technology. 2021; 14(9):4957-2. doi: 10.52711/0974-360X.2021.00862
Cite(Electronic):
Herman Y. L. Wihastyoko, Setyawati Soeharto, Edi Widjajanto, Kusworini, Bambang Pardjianto. Biological Activity of Papain and Papain-like (Cathepsin-K and Cathepsin-B) Enzymes as Therapeutical Modality Candidates in Degrading Collagen in Abnormal Scar. Research Journal of Pharmacy and Technology. 2021; 14(9):4957-2. doi: 10.52711/0974-360X.2021.00862 Available on: https://rjptonline.org/AbstractView.aspx?PID=2021-14-9-76
REFERENCES:
1. Lee DE, Trowbridge RM, Ayoub NT, Agrawal DK. High-mobility group box protein-1, matrix metalloproteinases, and vitamin D in keloids and hypertrophic scars. Plast Reconstr Surg Glob Open 2015; 3(6): 1-9.
2. Berman B, Maderal A, Raphael B. Keloids and hypertrophic scars: Pathophysiology, classification, and treatment. Dermatol Surg 2017; 43: 3–18.
3. Alster TS, Tanzi EL. Hypertrophic scars and keloids: Etiology and Management. Am J Clin Dermatol 2003; 4(4): 235-243.
4. Suarez E, Syed F, Rasgado TA, Walmsley A, Mandal P, Bayat A. Skin equivalent tensional force alters keloid fibroblast behavior and phenotype. Wound Repair Regen 2014; 22(5): 557-568.
5. Nicholas RS, Falvey H, Lemonas P, Damodaran G, Ghanem AM, Selim F, Navsaria H, Myers S. Patient-related keloid scar assessment and outcome measures. Plast Reconstr Surg 2012; 129(3): 648-656.
6. Bayat A, Mc Grouther DA, Ferguson MW. Skin scarring. Brit Med J 2003; 326(7380): 88-92.
7. Seifert O. Keloids: A fibroproliferative disease. Forum Nordic Dermato-Venereo 2008; 14(2): 48-49.
8. Sudheer CP, Anoop M, Rao GVS, Laxman B. Treatment of postaural keloid-case report. J Evo Med Dent Sci 2013; 2(46): 8980–8982.
9. Ogawa R. Keloid and hypertrophic scars are the result of chronic inflammation in the reticular dermis. Int J Mol Sci 2017; 18(3): 606.
10. Butzelaar L, Ulrich MM, Mink van der Molen AB, Niessen FB, Beelen RH. Currently known risk factors for hypertrophic skin scarring: A review. J Plast Reconstr Aesthet Surg 2016; 69(2): 163-169.
11. Zhu Z, Ding J, Tredget EE. The molecular basis of hypertrophic scars. Burns Trauma 2016; 4(2): 1-12.
12. Quong WL, Kozai Y, Ogawa R. A case of keloids complicated by Castleman’s disease: Interleukin-6 as a keloid risk factor. Plast Reconst Surg Glob Open 2017; 5(5): 1-4.
13. Rosenstein RK, Bezbradica JS, Yu S, Medzhitov R. Signaling pathways activated by a protease allergen in basophils. Proc Natl Acad Sci 2014; 111(46): 4963-4971.
14. Da Silva CRD, Oliveira MB, Motta ES, de Almeida GS, Varanda LL, de Pádula M, et al. Genotoxic and cytotoxic safety evaluation of papain (Carica papaya L.) using in vitro assays. J Biomed Biotechnol 2010; 2010: 197898.
15. Wihastyoko HYL, Hanafi. The effect of papain enzyme against collagen density in keloid tissue culture. J Global Pharm Tech 2018; 10: 175-179.
16. Khaket TP, Singh J. Potential of plant’s dipeptidyl peptidase I & II homologs in generation of ace inhibitory peptides. Int J Pept Res Ther 2017; 23(1): 81-90.
17. Shekhter AB, Balakireva AV, Kuznetsova NV, Vukolova MN, Litvitsky PF, Zamyatnin AA Jr. Collagenolytic enzymes and their applications in biomedicine. Curr Med Chem 2019; 26(3): 487-505.
18. Hardiany NS. Cathepsin dan Calpain: Enzim Pemecah Protein dalam Sel. eJKI 2013; 1(1): 1-7.
19. Verma S, Dixit R, Pandey KC. Cysteine Proteases: Modes of activation and future prospects as pharmacological targets. Front Pharmacol; 7(107); 1-12.
20. Rossi A, Deveraux Q, Turk B, Sali A. Comprehensive search for cysteine cathepsins in the human genome. Biol Chem 2004; 385(5): 363-372.
21. Arockiaraj J, Kumaresan V, Chaurasia KM, Bhatt P, Palanisamy R, Pasupuleti M, et al. Molecular characterization of a novel cathepsin B from striped murrel Channa striatus: Bioinformatics analysis, gene expression, synthesis of peptide and antimicrobial property. Turk J Fisher Aqua Sci 2014; 14: 379-389.
22. Buck MR, Karustis DG, Day NA, Honn KV, Sloane BF. Degradation of extracellular-matrix proteins by human cathepsin B from normal and tumour tissues. Biochem J 1992; 282(Pt. 1): 273-278.
23. Li X, Wu Z, Ni J, Liu Y, Meng J, Yu W, et al. Cathepsin B regulates collagen expression by fibroblasts via prolonging TLR2/NF-κB activation. Oxid Med Cell Longev 2016; 2016: 7894247.
24. Tracy LE, Minasian RA, Caterson EJ. Extracellular matrix and dermal fibroblast function in the healing wound. Adv Wound Care (New Rochelle) 2016; 5(3): 119-136.
25. Drake MT, Clarke BL, Oursler MJ, Khosla S. Cathepsin K inhibitors for osteoporosis: Biology, potential clinical utility, and lessons learned. Endocrine Rev 2017; 38(4): 325-350.
26. Lecaille F, Chowdhury S, Purisima E, Bromme D, Lalmanach G. The S2 subsites of cathepsins K and L and their contribution to collagen degradation. Protein Sci 2007; 16(4): 662-670.
27. Rawlings ND, Barrett AJ, Thomas PD, Huang X, Bateman A, Finn RD. The MEROPS database of proteolytic enzymes, their substrates and inhibitors in 2017 and a comparison with peptidases in the PANTHER database. Nucleic Acids Res 2018; 46: D624-D632.
28. Chen CH, Bhasin S, Khanna P, Joshi M, Joslin PMN, Saxena R. Study of cathepsin B inhibition in VEGFR TKI treated human renal cell carcinoma xenografts. Oncogen 2019; 8: 1-18.
29. De Pasquale V, Moles A, Pavone LM. Cathepsins in the pathophysiology of Mucopolysaccharidoses: New perspectives for therapy. Cells 2020; 9(4): 1-22.
30. Qader NN, Khafaji H. Motif discovery and data mining in bioinformatics. Int J Comp Tech 2014; 13(1): 4082-4095.
31. Crooks GE, Hon G, Chandonia JM, Brenner SE. Weblogo: A Sequence Logo Generator. Genome Res 2004; 14: 1188-1190.
32. Hayashi M, Nomoto S, Hishida M, Inokawa Y, Kanda M, Okamura Y, Nishikawa Y, Tanaka C, Kobayashi D, Yamada S, nakayama G, Fujii T, Sugimoto H, Koike M, Fujiwara M, Takeda S, Kodera Y. Identification of the collagen type 1 alpha 1 gene (COL1A1) as a candidate survival-related factor associated with hepatocellular carcinoma. BMC Cancer 2014; 14: 108.
33. Lister Hill National Center for Biomedical Communications. 2019. COL1A1 gene. [cited in 2020]. Available from https://ghr.nlm.nih.gov/gene/COL1A1
34. Myung J, Kim KB, Crews CM. The ubiquitin‐proteasome pathway and proteasome inhibitors. Med Res Rev 2001; 21(4): 245-273.
35. Glickman JF. Assay development for protein kinases and phosphatases. Bota Raton: CRC Press; 2010.
36. Huang OW, Ma X, Yin J, Flinders J, Maurer T, Kayagaki N, et al. Phosphorylation-dependent activity of the deubiquitinase DUBA. Nat Struct Mol Biol 2012; 19(2): 171-175.
37. Tepel C, Bromme D, Herzog V, Brix K. Cathepsin K in thyroid epithelial cells: Sequence, localization and possible function in extracellular proteolysis of thyroglobulin. J Cell Sci 113: 4487-4498.
38. Boraschi-Diaz I, Wang J, Mort JS, Komarova SV. Collagen type I as a ligand for receptor-mediated signaling. Front Phys 2017; 5(12): 1-11.
39. Kafienah W, Bromme D, uttle DJ, Croucher LJ, Hollander AP. Human cathepsin K cleaves native type I and II collagens at the N-terminal end of the triple helix. Biochem J 1998; 331: 727-732.
40. Novinec M, Lenarcic B. Cathepsin K: a unique collagenolytic cysteine peptidase 2013;394(9): 1163-1179.
41. Yeh G, Hoge S. Using PEPscreen TM to study protein phosphorylation and kinase activity. Biofiles 2012; 8(13): 1-2.
42. Suhartono MT. Enzim dan Bioteknologi [Enzyme and Biotechnology]. Bogor, Indonesia: IPB Press; 1989.
43. Junior ZSS, Botta SB, Ana PA, Franca CM, Fernandes KPS, Mesquita-Ferrari RA, et al. Effect of papain-based gel on type I collagen - spectroscopy applied for microstructural analysis. Sci Rep 2014; 5(1148): 11448.
44. Ramundo J, Gray M. Enzymatic wound debridement. J Wound Ostomy Continence Nurs 2008; 35(3): 273-280.
45. Manosroi A, Chankhampan C, Manosroi W, Manosroi J. Transdermal absorption enhancement of papain loaded in elastic niosomes incorporated in gel for scar treatment. Eur J Pharm Sci 2013; 48(3): 474-483.
46. Manosroi A, Charinya C, Worapaka M, Jiradej M. Antioxidant and gelatinolytic activities of papain from papaya latex and bromelain from pineapple fruits. Chiang Mai J Sci 2014; 41(3): 635-648.
47. Sahu K, Kaurav M, Pandey RS. Protease loaded permeation enhancer liposomes for treatment of skin fibrosis arisen from second degree burn. Biomed Pharmacother 2017; 94: 747-757.
48. Butler PD, Longaker MT, Yang, GP. Current progress in keloid research and treatment. J Am Coll Surg, 2008; 206(4): 731-741.
49. Chen YY, Lu YH, Ma CH, Tao WW, Zhu JJ, Zhang X. A novel elastic liposome for skin delivery of papain and its application on hypertrophic scar. Biomed Pharmacother 2017; 87: 82-