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ILNS > Volume 57 > Understanding the Exacerbating Role of the...
Understanding the Exacerbating Role of the Metalloproteinase Meprin during AKI, an <i>In Silico</i> Approach
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Understanding the Exacerbating Role of the Metalloproteinase Meprin during AKI, an In Silico Approach

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Abstract:

Acute kidney injury (AKI) is a syndrome characterised by the rapid loss of the kidney’s excretory function and is typically diagnosed by the accumulation of end products of nitrogen metabolism (urea and creatinine) or decreased urine output, or both. It is the clinical manifestation of several disorders that affect the kidney acutely. No specific therapies have yet emerged that can attenuate AKI or expedite recovery; thus, the only treatment is supportive therapies and intensive care. The present study was aimed to provide an insight into the importance of a metalloproteinase involved in the pathological conditions of AKI and potentially is a unique target for therapeutic intervention during the disease; Meprin. The data obtained using literature search from PubMed and interaction networks analysis software STRING strongly support the concept that meprin acts as a major matrix degrading enzyme in the kidney, and thus creating an environment that leads to impairment in cellular function rather than cellular stability in response to AKI. The present study discerns the structure of meprin alpha subunit using in silico tools SWISS-MODE, Phyre2 web server and identify the active site and critical amino acid residues in the active site using AADS (IIT Delhi), 3DLigandSite and DoGSiteScorer. Further it is documented that actinonin, a naturally occurring antibacterial agent as a pharmacologically active intervention for the metalloproteinase’s α subunit by blocking its active sites from the environment which was validated using molecular docking algorithms of SWISS-DOCK and FlexX.

Info:

Periodical:
International Letters of Natural Sciences (Volume 57)
Pages:
18-25
DOI:
https://doi.org/10.18052/www.scipress.com/ILNS.57.18
Citation:
D. Chatterjee "Understanding the Exacerbating Role of the Metalloproteinase Meprin during AKI, an In Silico Approach", International Letters of Natural Sciences, Vol. 57, pp. 18-25, 2016
Online since:
August 2016
Authors:
Deepyan Chatterjee
Keywords:
Actinonin, AKI, Bioinformatics, In Silico Studies, Interaction Networks, Meprin, Metalloproteinase, Molecular Docking, Protein Tertiary Structure Prediction
Export:
RIS, BibTeX, Text
Distribution:
Open Access

Creative Commons License
This work is licensed under a
Creative Commons Attribution 4.0 International License

References:

[1] Bellomo R, Ronco C, Kellum, Acute renal failure: definition, outcome, measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group, Crit Care, 8, (2004).

DOI: https://doi.org/10.3410/f.1047455.497408

[2] Dissension AR, Acute renal failure: definition and pathogenesis, Kidney int, 66, (1988), 7-10.

[3] David P, Melissa D, Anderson B, Timothy A, Pathophysiology of Acute kidney Injury, Compr Physiol, 2, (2012), 1303-1353.

[4] Chertow GM, Burdick E, Honour M, Bonventre JV, Bates DW, Acute Kidney Injury, mortality, length of stay, and cost in hospitalisation, Journal of the american society of nephrology, 16, (2005), 80-91.

[5] Bond JS, Beynon RJ, Reckelhoff JF, David CS, Mep-1 gene controlling a kidney metalloendopeptidas is linked to the major histocompatibility complex in mice, Natural academy of science, 81, (1984), 5542-5545.

DOI: https://doi.org/10.1073/pnas.81.17.5542

[6] Craig SS, Reckelhoff JF, Bond JS, Distribution of meprin in kidneys from mice with high and low meprin activity, Am J Cell Physiol, 253, (1987), 535-540.

[7] Bond, J. S., Rojas, K., Overhauser, J., Zoghbi, H. Y., Jiang, W. The structural genes, MEP1A and MEP1B, for the alpha and beta subunits of the metalloendopeptidase meprin map to human chromosomes 6p and 18q, respectively. Genomics, 25, (1995).

DOI: https://doi.org/10.1016/0888-7543(95)80142-9

[8] Kaushal GP, Randy S, Christian H, Sudhir V, Meprin A metlloproteinase and its role in acute kidney injury, Am J renal physiol, 304, (2013), 1150-1158.

[9] Carmago S, Shaw SV, Walker PD, Meprin, a brush-border enzyme, plays an important role in hypoxic/ischemic acute renal tubular injury in rat, Kidney Int, 61, (2002), 959-966.

DOI: https://doi.org/10.1046/j.1523-1755.2002.00209.x

[10] Szklarczyk D, Franceschini A, Wyder S, Forslund K, Heller D, Huerta-Cepas J, Simonovic M, Roth A, Santos A, Tsafou KP, Kuhn M, Bork P, Jensen LJ, von Mering C, STRING v10: protein-protein interaction networks, integrated over the tree of life, Nucleic Acids Res, 43, (2015).

DOI: https://doi.org/10.1093/nar/gku1003

[11] Dawn ZC, Dinesh VP, Corinne JH, Wen W, Geoffrey D, Dennis CY, Peter SM, Charlotte W, Joaquim T, Richard JW, Zhengyu Y, Actinonin a naturally occurring antibacterial agent, is a potent defromylase inhibitor, Biochemistry, 39, (2000) 1256-1262.

DOI: https://doi.org/10.1021/bi992245y

[12] Bauvois B, Dauzonne D, Aminopeptidase-N/CD13 (EC 3. 4. 11. 2) inhibitors: chemistry, biological evolution, and therapeutic prospects, Med. Res, 26, (2006), 88-130.

DOI: https://doi.org/10.1002/med.20044

[13] Asmaa S, Simon LD, Borhane A, Cell based evidence for aminoprotease N/CD 13 inhibitor actinonin targeting of MT1-MMP-meiated pro MMP 2 activation, Elsevier, 279, (2009), 171-176.

DOI: https://doi.org/10.1016/j.canlet.2009.01.032

[14] Aurelien Grosdidier, Vincent Zoete, Olivier Michielin, SwissDock, a protein-small molecule docking web service based on EADock DSS, Nucleic Acids Res, 39, (2011), 270-277.

DOI: https://doi.org/10.1093/nar/gkr366

[15] Cross, Simon SJ, Improved FlexX docking using FlexS-determined base fragment placement, Journal of chemical information and modeling, 45, (2005), 993-1001.

DOI: https://doi.org/10.1021/ci050026f

[16] Torsten Schwede, Jurgen Kopp, Nicolas Guex, Manuel C. Peitsch, SWISS-MODEL: an automated protein homology-modeling server, Nucleic Acids Res, 31 (13), (2003), 3381-3385.

DOI: https://doi.org/10.1093/nar/gkg520

[17] Kelley LA, Mezulis S, Yates CM, Wass MN, Sternberg MJ, The Phyre2 web portal for protein modeling, prediction and analysis, Nat Protoc, 10 (6), (2015), 845-858.

DOI: https://doi.org/10.1038/nprot.2015.053

[18] Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, Ferrin TE, UCSF Chimera-a visualization system for exploratory research and analysis, J Comput Chem, 25 (13), (2004), 1605-1612.

DOI: https://doi.org/10.1002/jcc.20084

[19] Singh T, Biswas D, Jayaram B, AADS-An automated active site identification, docking, and scoring protocol for protein targets based on physicochemical descriptors, Journal of chemical information and modelling, 51 (10), (2011), 2515-2527.

DOI: https://doi.org/10.1021/ci200193z

[20] Mark NW, Lawrence AK, and Michael JE, 3DLigandSite: predicting ligand-binding sites using similar structures, Nucleic Acids Res, 38, (2010), 469-473.

DOI: https://doi.org/10.1093/nar/gkq406

[21] Volkamer A, Kuhn D, Rippmann F, Rarey M, DoGSiteScorer: a web server for automatic binding site prediction, analysis and druggability assessment, Bioinformatics, 28 (15), (2012), 2074-(2075).

DOI: https://doi.org/10.1093/bioinformatics/bts310

[22] Greg PB, Benjamin E, Turk J, Simon JH, Gail LM, John EB, jacqueline MC, Lewis C, Judith SB, Marked difference between metalloproteases Meprin A and B in substrate and peptide bond specificity, JBC, 276 (16), (2001), 248-255.

DOI: https://doi.org/10.1074/jbc.m011414200

[23] Stocker W, Bode W, Structural features of a superfamily of zinc- endopeptidases: the metzincins, Curr Opin Struct Biol, 5, (1995) 383-390.

DOI: https://doi.org/10.1016/0959-440x(95)80101-4

[24] LALIGN, Pairwise Sequence Alignment, EMBL-EBI, http: /www. ebi. ac. uk/Tools/psa/lalign/, March 21, (2016).

[25] Arolas JL, Broder C, Jefferson T, Guevara T, Sterchi EE, Bode W, Stocker W, Pauly C, Gomis Ruth F, Structural basis for the sheddase function of human meprin β metalloproteinase at the plasma membrane, Proc Natl Acad Sci USA, 109 (40), (2012).

DOI: https://doi.org/10.1073/pnas.1211076109

[26] Protein Data Bank (PDB), An Information Portal for Biological Macromolecular Structures http: /www. rcsb. org/pdb/explore/explore. do?structureId=4GWN March 15, (2016).

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