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Probing the specificity determinants of amino acid recognition by arginase.

Shishova EY, Di Costanzo L, Emig FA, Ash DE, Christianson DW
Biochemistry 48 121-31 (2009)
Related entries: 3e6v, 3e8q, 3e8z, 3e9b

Cited: 19 times
EuropePMC logo PMID: 19093830

Abstract

Arginase is a binuclear manganese metalloenzyme that serves as a therapeutic target for the treatment of asthma, erectile dysfunction, and atherosclerosis. In order to better understand the molecular basis of inhibitor affinity, we have employed site-directed mutagenesis, enzyme kinetics, and X-ray crystallography to probe the molecular recognition of the amino acid moiety (i.e., the alpha-amino and alpha-carboxylate groups) of substrate l-arginine and inhibitors in the active site of arginase I. Specifically, we focus on (1) a water-mediated hydrogen bond between the substrate alpha-carboxylate and T135, (2) a direct hydrogen bond between the substrate alpha-carboxylate and N130, and (3) a direct charged hydrogen bond between the substrate alpha-amino group and D183. Amino acid substitutions for T135, N130, and D183 generally compromise substrate affinity as reflected by increased K(M) values but have less pronounced effects on catalytic function as reflected by minimal variations of k(cat). As with substrate K(M) values, inhibitor K(d) values increase for binding to enzyme mutants and suggest that the relative contribution of intermolecular interactions to amino acid affinity in the arginase active site is water-mediated hydrogen bond < direct hydrogen bond < direct charged hydrogen bond. Structural comparisons of arginase with the related binuclear manganese metalloenzymes agmatinase and proclavaminic acid amidinohydrolase suggest that the evolution of substrate recognition in the arginase fold occurs by mutation of residues contained in specificity loops flanking the mouth of the active site (especially loops 4 and 5), thereby allowing diverse guanidinium substrates to be accommodated for catalysis.

Articles - 3e6k mentioned but not cited (2)

  1. Probing the specificity determinants of amino acid recognition by arginase. Shishova EY, Di Costanzo L, Emig FA, Ash DE, Christianson DW. Biochemistry 48 121-131 (2009)
  2. Identifying medically relevant xenon protein targets by in silico screening of the structural proteome. Winkler DA, Katz I, Warden A, Thornton AW, Farjot G. Med Gas Res 13 33-38 (2023)


Reviews citing this publication (3)

  1. Manganese and its role in Parkinson's disease: from transport to neuropathology. Aschner M, Erikson KM, Herrero Hernández E, Tjalkens R. Neuromolecular Med 11 252-266 (2009)
  2. Targeting Metalloenzymes for Therapeutic Intervention. Chen AY, Adamek RN, Dick BL, Credille CV, Morrison CN, Cohen SM. Chem Rev 119 1323-1455 (2019)
  3. Arginase Inhibitors: A Rational Approach Over One Century. Pudlo M, Demougeot C, Girard-Thernier C. Med Res Rev 37 475-513 (2017)

Articles citing this publication (14)

  1. Differences in the risk of celiac disease associated with HLA-DQ2.5 or HLA-DQ2.2 are related to sustained gluten antigen presentation. Fallang LE, Bergseng E, Hotta K, Berg-Larsen A, Kim CY, Sollid LM. Nat Immunol 10 1096-1101 (2009)
  2. Inhibition of human arginase I by substrate and product analogues. Di Costanzo L, Ilies M, Thorn KJ, Christianson DW. Arch Biochem Biophys 496 101-108 (2010)
  3. Binding of α,α-disubstituted amino acids to arginase suggests new avenues for inhibitor design. Ilies M, Di Costanzo L, Dowling DP, Thorn KJ, Christianson DW. J Med Chem 54 5432-5443 (2011)
  4. SCHEMA-designed variants of human Arginase I and II reveal sequence elements important to stability and catalysis. Romero PA, Stone E, Lamb C, Chantranupong L, Krause A, Miklos AE, Hughes RA, Fechtel B, Ellington AD, Arnold FH, Georgiou G. ACS Synth Biol 1 221-228 (2012)
  5. Crystal structure of an arginase-like protein from Trypanosoma brucei that evolved without a binuclear manganese cluster. Hai Y, Kerkhoven EJ, Barrett MP, Christianson DW. Biochemistry 54 458-471 (2015)
  6. Crystal structures of Pseudomonas aeruginosa guanidinobutyrase and guanidinopropionase, members of the ureohydrolase superfamily. Lee SJ, Kim DJ, Kim HS, Lee BI, Yoon HJ, Yoon JY, Kim KH, Jang JY, Im HN, An DR, Song JS, Kim HJ, Suh SW. J Struct Biol 175 329-338 (2011)
  7. Expression, purification and characterization of arginase from Helicobacter pylori in its apo form. Zhang J, Zhang X, Wu C, Lu D, Guo G, Mao X, Zhang Y, Wang DC, Li D, Zou Q. PLoS One 6 e26205 (2011)
  8. Crystal structure of Schistosoma mansoni arginase, a potential drug target for the treatment of schistosomiasis. Hai Y, Edwards JE, Van Zandt MC, Hoffmann KF, Christianson DW. Biochemistry 53 4671-4684 (2014)
  9. Crystal structures of complexes with cobalt-reconstituted human arginase I. D'Antonio EL, Christianson DW. Biochemistry 50 8018-8027 (2011)
  10. Butyrylcholinesterase-a potential plasma biomarker in manganese-induced neurobehavioral changes. Anjum A, Biswas S, Rahman M, Rahman A, Siddique AE, Karim Y, Aktar S, Nikkon F, Haque A, Himeno S, Hossain K, Saud ZA. Environ Sci Pollut Res Int 26 6378-6387 (2019)
  11. New Insights into the Determinants of Specificity in Human Type I Arginase: Generation of a Mutant That Is Only Active with Agmatine as Substrate. Orellana MS, Jaña GA, Figueroa M, Martínez-Oyanedel J, Medina FE, Tarifeño-Saldivia E, Gatica M, García-Robles MÁ, Carvajal N, Uribe E. Int J Mol Sci 23 6438 (2022)
  12. Crystallization of an apo form of human arginase: using all the tools in the toolbox simultaneously. Newman J, Pearce L, Lesburg CA, Strickland C, Peat TS. Acta Crystallogr Sect F Struct Biol Cryst Commun 67 90-93 (2011)
  13. Inhibiting Human and Leishmania Arginases Using Cannabis sativa as a Potential Therapy for Cutaneous Leishmaniasis: A Molecular Docking Study. Assouab A, El Filaly H, Akarid K. Trop Med Infect Dis 7 400 (2022)
  14. Structural and Biochemical Insights into Post-Translational Arginine-to-Ornithine Peptide Modifications by an Atypical Arginase. Mordhorst S, Badmann T, Bösch NM, Morinaka BI, Rauch H, Piel J, Groll M, Vagstad AL. ACS Chem Biol 18 528-536 (2023)


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