Computational Analysis of Arginine Deiminase Sequences to Provide a Guideline for Protein Engineering

Author(s): Mahboubeh Zarei, Mohammad Reza Rahbar, Navid Nezafat, Manica Negahdaripour, Mohammad Hossein Morowvat, Younes Ghasemi*.

Journal Name: Current Proteomics

Volume 17 , Issue 2 , 2020

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Abstract:

Background: Arginine deiminase of Mycoplasma hominis, an arginine catabolizing enzyme, is currently in clinical trial for the treatment of arginine auxotrophic cancers. However, some drawbacks such as instability and antigenicity have limited its application as a protein drug. Arginine Deiminase (ADI) belongs to the guanidino-group modifying enzyme superfamily. Despite differences in the primary amino acid sequences of various members of this superfamily, the folding and secondary structures are conserved in all members. Despite structural similarities, ADIs in various species have different levels of catalytic activity and physicochemical properties due to the differences in their primary amino acid sequences. Therefore, investigating and comparing sequences between different ADI producing bacterial strains could be helpful in the rational engineering of ADI.

Objective: In the current research, we used an in-silico approach to characterize and classify the available reviewed protein sequences of ADI.

Results: 102 ADI sequences from SwissProt database were extracted. Subsequently, based on clustering analyses, the sequence sets were divided into five distinct groups. Different physicochemical properties, solubility, and antigenicity of the enzymes were determined. Some ADI sequences were introduced as well-suited candidates for protein engineering; Lactobacillus fermentum ADI for low pI value, Mycobacterium avium ADI for high aliphatic index, Bacillus licheniformis ADI for low GRAVY index, Bradyrhizobium diazoefficiens ADI for low antigenicity and high stability index, and among Mycoplasma ADIs, Mycoplasma arthritidis ADI for high stability and aliphatic index, and Mycoplasma capricolum for low antigenicity.

Keywords: Arginine deiminase, protein engineering, in silico, antitumor activity, sequence-based classification, pH.

[1]
Ni, Y.; Schwaneberg, U.; Sun, Z-H. Arginine deiminase, a potential anti-tumor drug. Cancer Lett., 2008, 261(1), 1-11.
[http://dx.doi.org/10.1016/j.canlet.2007.11.038] [PMID: 18179862]
[2]
Zarei, M.; Nezafat, N.; Morowvat, M.H.; Dehshahri, A.; Ghoshoon, M.B.; Berenjian, A.; Ghasemi, Y. Medium optimization for recombinant soluble arginine deiminase expression in Escherichia coli using response surface methodology. Curr. Pharm. Biotechnol., 2017, 18(11), 935-941.
[http://dx.doi.org/10.2174/1389201019666180115144752] [PMID: 29336257]
[3]
Zarei, M.; Rahbar, M.R.; Morowvat, M.H.; Nezafat, N.; Negahdaripour, M.; Berenjian, A.; Ghasemi, Y. Arginine deiminase: Current understanding and applications. Recent Pat. Biotechnol., 2019, 13(2), 124-136.
[http://dx.doi.org/10.2174/1872208313666181220121400] [PMID: 30569861]
[4]
Smith, D.W.; Ganaway, R.L.; Fahrney, D.E. Arginine deiminase from Mycoplasma arthritidis. Structure-activity relationships among substrates and competitive inhibitors. J. Biol. Chem., 1978, 253(17), 6016-6020.
[PMID: 681336]
[5]
Zúñiga, M.; Pérez, G.; González-Candelas, F. Evolution of arginine deiminase (ADI) pathway genes. Mol. Phylogenet. Evol., 2002, 25(3), 429-444.
[http://dx.doi.org/10.1016/S1055-7903(02)00277-4] [PMID: 12450748]
[6]
Glazer, E.S.; Piccirillo, M.; Albino, V.; Di Giacomo, R.; Palaia, R.; Mastro, A.A.; Beneduce, G.; Castello, G.; De Rosa, V.; Petrillo, A.; Ascierto, P.A.; Curley, S.A.; Izzo, F. Phase II study of PEGylated arginine deiminase for nonresectable and metastatic hepatocellular carcinoma. J. Clin. Oncol., 2010, 28(13), 2220-2226.
[http://dx.doi.org/10.1200/JCO.2009.26.7765] [PMID: 20351325]
[7]
Ott, P.A.; Carvajal, R.D.; Pandit-Taskar, N.; Jungbluth, A.A.; Hoffman, E.W.; Wu, B-W.; Bomalaski, J.S.; Venhaus, R.; Pan, L.; Old, L.J.; Pavlick, A.C.; Wolchok, J.D. Phase I/II study of PEGylated arginine deiminase (ADI-PEG 20) in patients with advanced melanoma. Invest. New Drugs, 2013, 31(2), 425-434.
[http://dx.doi.org/10.1007/s10637-012-9862-2] [PMID: 22864522]
[8]
Yang, T.S.; Lu, S.N.; Chao, Y.; Sheen, I.S.; Lin, C.C.; Wang, T.E.; Chen, S.C.; Wang, J.H.; Liao, L.Y.; Thomson, J.A.; Wang-Peng, J.; Chen, P.J.; Chen, L.T. A randomised phase II study of PEGylated arginine deiminase (ADI-PEG 20) in Asian advanced hepatocellular carcinoma patients. Br. J. Cancer, 2010, 103(7), 954-960.
[http://dx.doi.org/10.1038/sj.bjc.6605856] [PMID: 20808309]
[9]
Holtsberg, F.W.; Ensor, C.M.; Steiner, M.R.; Bomalaski, J.S.; Clark, M.A. Poly(Ethylene Glycol) (PEG) conjugated arginine deiminase: Effects of PEG formulations on its pharmacological properties. J. Control. Release, 2002, 80(1-3), 259-271.
[http://dx.doi.org/10.1016/S0168-3659(02)00042-1] [PMID: 11943403]
[10]
Zhu, L.; Tee, K.L.; Roccatano, D.; Sonmez, B.; Ni, Y.; Sun, Z.H.; Schwaneberg, U. Directed evolution of an antitumor drug (arginine deiminase PpADI) for increased activity at physiological pH. ChemBioChem, 2010, 11(5), 691-697.
[http://dx.doi.org/10.1002/cbic.200900717] [PMID: 20157910]
[11]
Zhu, L.; Verma, R.; Roccatano, D.; Ni, Y.; Sun, Z.H.; Schwaneberg, U. A potential antitumor drug (arginine deiminase) reengineered for efficient operation under physiological conditions. ChemBioChem, 2010, 11(16), 2294-2301.
[http://dx.doi.org/10.1002/cbic.201000458] [PMID: 20954230]
[12]
Cheng, F.; Zhu, L.; Lue, H.; Bernhagen, J.; Schwaneberg, U. Directed arginine deiminase evolution for efficient inhibition of arginine-auxotrophic melanomas. Appl. Microbiol. Biotechnol., 2015, 99(3), 1237-1247.
[http://dx.doi.org/10.1007/s00253-014-5985-z] [PMID: 25104032]
[13]
Cheng, F.; Yang, J.; Bocola, M.; Schwaneberg, U.; Zhu, L. Loop engineering reveals the importance of active-site-decorating loops and gating residue in substrate affinity modulation of arginine deiminase (an anti-tumor enzyme). Biochem. Biophys. Res. Commun., 2018, 499(2), 233-238.
[http://dx.doi.org/10.1016/j.bbrc.2018.03.134] [PMID: 29567479]
[14]
Jamil, S.; Liu, M.H.; Liu, Y.M.; Han, R.Z.; Xu, G.C.; Ni, Y. Hydrophobic mutagenesis and semi-rational engineering of arginine deiminase for markedly enhanced stability and catalytic efficiency. Appl. Biochem. Biotechnol., 2015, 176(5), 1335-1350.
[http://dx.doi.org/10.1007/s12010-015-1649-4] [PMID: 26041055]
[15]
Zarei, M.; Nezafat, N.; Rahbar, M.R.; Negahdaripour, M.; Sabetian, S.; Morowvat, M.H.; Ghasemi, Y. Decreasing the immunogenicity of arginine deiminase enzyme via structure-based computational analysis. J. Biomol. Struct. Dyn., 2019, 37(2), 523-536.
[http://dx.doi.org/10.1080/07391102.2018.1431151] [PMID: 29363409]
[16]
Amer, M.N.; Mansour, N.M.; El-Diwany, A.I.; Dawoud, I.E.; Rasha, F.M. Isolation of probiotic lactobacilli strains harboring L-asparaginase and arginine deiminase genes from human infant feces for their potential application in cancer prevention. Ann. Microbiol., 2013, 63, 1121-1129.
[http://dx.doi.org/10.1007/s13213-012-0569-6]
[17]
Sharma, A.; Bala, K.; Husain, I. Preliminary evaluation of arginine deiminase activity of indigenous bacterial strains for suitable chemotherapeutic applications. Biocatal. Agric. Biotechnol., 2017, 12, 66-77.
[http://dx.doi.org/10.1016/j.bcab.2017.09.001]
[18]
El-Sayed, A.S.; Hassan, M.N.; Nada, H.M. Purification, immobilization, and biochemical characterization of l-arginine deiminase from thermophilic Aspergillus fumigatus KJ434941: Anticancer activity in vitro. Biotechnol. Prog., 2015, 31(2), 396-405.
[http://dx.doi.org/10.1002/btpr.2045] [PMID: 25582958]
[19]
Shirai, H.; Mokrab, Y.; Mizuguchi, K. The guanidino-group modifying enzymes: Structural basis for their diversity and commonality. Proteins, 2006, 64(4), 1010-1023.
[http://dx.doi.org/10.1002/prot.20863] [PMID: 16779844]
[20]
Kundu, M.; Thomas, J.; Fialho, A.; Kwan, J.; Moreira, L.; Mahfouz, M.; Das Gupta, T.; Chakrabarty, A. The anticancer activity of the N-terminal CARD-like domain of Arginine Deiminase (ADI) from Pseudomonas aeruginosa. Lett. Drug Des. Discov., 2009, 6(6), 403-412.
[http://dx.doi.org/10.2174/157018009789057580]
[21]
Zarei, M.; Nezafat, N.; Morowvat, M.H.; Ektefaie, M.; Ghasemi, Y. In silico analysis of different signal peptides for secretory production of arginine deiminase in Escherichia coli. Recent Pat. Biotechnol., 2018, 13(3), 217-227.
[http://dx.doi.org/10.2174/1872208313666190101114602] [PMID: 30621572]
[22]
Boeckmann, B.; Bairoch, A.; Apweiler, R.; Blatter, M-C.; Estreicher, A.; Gasteiger, E.; Martin, M.J.; Michoud, K.; O’Donovan, C.; Phan, I.; Pilbout, S.; Schneider, M. The SWISS-PROT protein knowledgebase and its supplement TrEMBL in 2003. Nucleic Acids Res., 2003, 31(1), 365-370.
[http://dx.doi.org/10.1093/nar/gkg095] [PMID: 12520024]
[23]
Zimmermann, L.; Stephens, A.; Nam, S.Z.; Rau, D.; Kübler, J.; Lozajic, M.; Gabler, F.; Söding, J.; Lupas, A.N.; Alva, V. A completely reimplemented MPI bioinformatics toolkit with a new HHpred server at its core. J. Mol. Biol., 2018, 430(15), 2237-2243.
[http://dx.doi.org/10.1016/j.jmb.2017.12.007] [PMID: 29258817]
[24]
Pattengale, N.D.; Alipour, M.; Bininda-Emonds, O.R.; Moret, B.M.; Stamatakis, A. How many bootstrap replicates are necessary? J. Comput. Biol., 2010, 17(3), 337-354.
[http://dx.doi.org/10.1089/cmb.2009.0179] [PMID: 20377449]
[25]
Frickey, T.; Lupas, A. CLANS: A Java application for visualizing protein families based on pairwise similarity. Bioinformatics, 2004, 20(18), 3702-3704.
[http://dx.doi.org/10.1093/bioinformatics/bth444] [PMID: 15284097]
[26]
Pearson, W.R. Selecting the right similarity‐scoring matrix. Curr. Protoc. Bioinformatics, 2013, 43(1), 1-9.
[http://dx.doi.org/10.1002/0471250953.bi0305s43]
[27]
Gasteiger, E.; Hoogland, C.; Gattiker, A.; Wilkins, M.R.; Appel, R.D.; Bairoch, A. Protein identification and analysis tools on the ExPASy server. The Proteomics Protocols Handbook; Springer, 2005, pp. 571-607.
[http://dx.doi.org/10.1385/1-59259-890-0:571]
[28]
Gasteiger, E.; Hoogland, C.; Gattiker, A.; Duvaud, S.; Wilkins, M.R.; Appel, R.D.; Bairoch, A. Protein identification and analysis tools on the ExPASy server; Humana Press, 2005, pp. 571-607.
[http://dx.doi.org/10.1385/1-59259-890-0:571]
[29]
Kyte, J.; Doolittle, R.F. A simple method for displaying the hydropathic character of a protein. J. Mol. Biol., 1982, 157(1), 105-132.
[http://dx.doi.org/10.1016/0022-2836(82)90515-0] [PMID: 7108955]
[30]
Ikai, A. Thermostability and aliphatic index of globular proteins. J. Biochem., 1980, 88(6), 1895-1898.
[PMID: 7462208]
[31]
Apweiler, R.; Bairoch, A.; Wu, C.H.; Barker, W.C.; Boeckmann, B.; Ferro, S.; Gasteiger, E.; Huang, H.; Lopez, R.; Magrane, M. UniProt: The universal protein knowledgebase. Nucleic Acids Res.,, 2004, 32(suppl_1), D115-D119.
[http://dx.doi.org/ 10.1093/nar/gkh131]
[32]
Doytchinova, I.A.; Flower, D.R. VaxiJen: A server for prediction of protective antigens, tumour antigens and subunit vaccines. BMC Bioinformatics, 2007, 8(1), 4.
[http://dx.doi.org/10.1186/1471-2105-8-4] [PMID: 17207271]
[33]
Kolaskar, A.S.; Tongaonkar, P.C. A semi-empirical method for prediction of antigenic determinants on protein antigens. FEBS Lett., 1990, 276(1-2), 172-174.
[http://dx.doi.org/10.1016/0014-5793(90)80535-Q] [PMID: 1702393]
[34]
Berman, H.M.; Westbrook, J.; Feng, Z.; Gilliland, G.; Bhat, T.N.; Weissig, H.; Shindyalov, I.N.; Bourne, P.E. The protein data bank. Nucleic Acids Res., 2000, 28(1), 235-242.
[http://dx.doi.org/10.1093/nar/28.1.235] [PMID: 10592235]
[35]
Berman, H.M.; Westbrook, J.D.; Gabanyi, M.J.; Tao, W.; Shah, R.; Kouranov, A.; Schwede, T.; Arnold, K.; Kiefer, F.; Bordoli, L.; Kopp, J.; Podvinec, M.; Adams, P.D.; Carter, L.G.; Minor, W.; Nair, R.; La Baer, J. The protein structure initiative structural genomics knowledgebase. Nucleic Acids Res., 2009, 37(Database issue), D365-D368.
[http://dx.doi.org/10.1093/nar/gkn790] [PMID: 19010965]
[36]
Smialowski, P.; Doose, G.; Torkler, P.; Kaufmann, S.; Frishman, D. PROSO II--a new method for protein solubility prediction. FEBS J., 2012, 279(12), 2192-2200.
[http://dx.doi.org/10.1111/j.1742-4658.2012.08603.x] [PMID: 22536855]
[37]
Hebditch, M.; Carballo-Amador, M.A.; Charonis, S.; Curtis, R.; Warwicker, J. Protein-Sol: A web tool for predicting protein solubility from sequence. Bioinformatics, 2017, 33(19), 3098-3100.
[http://dx.doi.org/10.1093/bioinformatics/btx345] [PMID: 28575391]
[38]
Das, K.; Butler, G.H.; Kwiatkowski, V.; Clark, A.D. Jr.; Yadav, P.; Arnold, E. Crystal structures of arginine deiminase with covalent reaction intermediates; implications for catalytic mechanism. Structure, 2004, 12(4), 657-667.
[http://dx.doi.org/10.1016/j.str.2004.02.017] [PMID: 15062088]
[39]
Piovesan, D.; Minervini, G.; Tosatto, S.C. The RING 2.0 web server for high quality residue interaction networks. Nucleic Acids Res., 2016, 44(W1)W367-74
[http://dx.doi.org/10.1093/nar/gkw315] [PMID: 27198219]
[40]
Shannon, P.; Markiel, A.; Ozier, O.; Baliga, N.S.; Wang, J.T.; Ramage, D.; Amin, N.; Schwikowski, B.; Ideker, T. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res., 2003, 13(11), 2498-2504.
[http://dx.doi.org/10.1101/gr.1239303] [PMID: 14597658]
[41]
Pace, C.N.; Grimsley, G.R.; Scholtz, J.M. Protein ionizable groups: pK values and their contribution to protein stability and solubility. J. Biol. Chem., 2009, 284(20), 13285-13289.
[http://dx.doi.org/10.1074/jbc.R800080200] [PMID: 19164280]
[42]
Misawa, S.; Aoshima, M.; Takaku, H.; Matsumoto, M.; Hayashi, H. High-level expression of Mycoplasma arginine deiminase in Escherichia coli and its efficient renaturation as an anti-tumor enzyme. J. Biotechnol., 1994, 36(2), 145-155.
[http://dx.doi.org/10.1016/0168-1656(94)90050-7] [http://dx.doi.org/ 7765234]


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VOLUME: 17
ISSUE: 2
Year: 2020
Page: [132 - 146]
Pages: 15
DOI: 10.2174/1570164616666190619111852
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