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Inhibitor coordination interactions in the binuclear manganese cluster of arginase.

Cama E, Pethe S, Boucher JL, Han S, Emig FA, Ash DE, Viola RE, Mansuy D, Christianson DW
Biochemistry 43 8987-99 (2004)
Related entries: 1t4r, 1t4s, 1t4t, 1t5g

Cited: 28 times
EuropePMC logo PMID: 15248756

Abstract

Arginase is a manganese metalloenzyme that catalyzes the hydrolysis of L-arginine to form L-ornithine and urea. The structure and stability of the binuclear manganese cluster are critical for catalytic activity as it activates the catalytic nucleophile, metal-bridging hydroxide ion, and stabilizes the tetrahedral intermediate and its flanking states. Here, we report X-ray structures of a series of inhibitors bound to the active site of arginase, and each inhibitor exploits a different mode of coordination with the Mn(2+)(2) cluster. Specifically, we have studied the binding of fluoride ion (F(-); an uncompetitive inhibitor) and L-arginine, L-valine, dinor-N(omega)-hydroxy-L-arginine, descarboxy-nor-N(omega)-hydroxy-L-arginine, and dehydro-2(S)-amino-6-boronohexanoic acid. Some inhibitors, such as fluoride ion, dinor-N(omega)-hydroxy-L-arginine, and dehydro-2(S)-amino-6-boronohexanoic acid, cause the net addition of one ligand to the Mn(2+)(2) cluster. Other inhibitors, such as descarboxy-nor-N(omega)-hydroxy-L-arginine, simply displace the metal-bridging hydroxide ion of the native enzyme and do not cause any net change in the metal coordination polyhedra. The highest affinity inhibitors displace the metal-bridging hydroxide ion (and sometimes occupy a Mn(2+)(A) site found vacant in the native enzyme) and maintain a conserved array of hydrogen bonds with their alpha-amino and -carboxylate groups.

Reviews citing this publication (7)

  1. Targeting Metalloenzymes for Therapeutic Intervention. Chen AY, Adamek RN, Dick BL, Credille CV, Morrison CN, Cohen SM. Chem Rev 119 1323-1455 (2019)
  2. The versatility of boron in biological target engagement. Diaz DB, Yudin AK. Nat Chem 9 731-742 (2017)
  3. Arginase Inhibitors: A Rational Approach Over One Century. Pudlo M, Demougeot C, Girard-Thernier C. Med Res Rev 37 475-513 (2017)
  4. Development of novel arginase inhibitors for therapy of endothelial dysfunction. Steppan J, Nyhan D, Berkowitz DE. Front Immunol 4 278 (2013)
  5. Arginase as a Potential Biomarker of Disease Progression: A Molecular Imaging Perspective. S Clemente G, van Waarde A, F Antunes I, Dömling A, H Elsinga P. Int J Mol Sci 21 E5291 (2020)
  6. Will morphing boron-based inhibitors beat the β-lactamases? Krajnc A, Lang PA, Panduwawala TD, Brem J, Schofield CJ. Curr Opin Chem Biol 50 101-110 (2019)
  7. Arginine depriving enzymes: applications as emerging therapeutics in cancer treatment. Kumari N, Bansal S. Cancer Chemother Pharmacol 88 565-594 (2021)

Articles citing this publication (21)

  1. 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)
  2. Crystal structures of a purple acid phosphatase, representing different steps of this enzyme's catalytic cycle. Schenk G, Elliott TW, Leung E, Carrington LE, Mitić N, Gahan LR, Guddat LW. BMC Struct Biol 8 6 (2008)
  3. Human tartrate-resistant acid phosphatase becomes an effective ATPase upon proteolytic activation. Mitić N, Valizadeh M, Leung EW, de Jersey J, Hamilton S, Hume DA, Cassady AI, Schenk G. Arch Biochem Biophys 439 154-164 (2005)
  4. Crystal structure of arginase from Plasmodium falciparum and implications for L-arginine depletion in malarial infection . Dowling DP, Ilies M, Olszewski KL, Portugal S, Mota MM, Llinás M, Christianson DW. Biochemistry 49 5600-5608 (2010)
  5. Fluoride inhibition of Sporosarcina pasteurii urease: structure and thermodynamics. Benini S, Cianci M, Mazzei L, Ciurli S. J Biol Inorg Chem 19 1243-1261 (2014)
  6. Molecular transition-metal phosphonates. Chandrasekhar V, Senapati T, Dey A, Hossain S. Dalton Trans 40 5394-5418 (2011)
  7. Comparative investigation of the reaction mechanisms of the organophosphate-degrading phosphotriesterases from Agrobacterium radiobacter (OpdA) and Pseudomonas diminuta (OPH). Pedroso MM, Ely F, Mitić N, Carpenter MC, Gahan LR, Wilcox DE, Larrabee JL, Ollis DL, Schenk G. J Biol Inorg Chem 19 1263-1275 (2014)
  8. Molecular modeling of Helicobacter pylori arginase and the inhibitor coordination interactions. Azizian H, Bahrami H, Pasalar P, Amanlou M. J Mol Graph Model 28 626-635 (2010)
  9. Mutational analysis of substrate recognition by human arginase type I--agmatinase activity of the N130D variant. Alarcón R, Orellana MS, Neira B, Uribe E, García JR, Carvajal N. FEBS J 273 5625-5631 (2006)
  10. Inhibition of rat liver and kidney arginase by cadmium ion. Tormanen CD. J Enzyme Inhib Med Chem 21 119-123 (2006)
  11. 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)
  12. A new arginase enzymatic reactor: development and application for the research of plant-derived inhibitors. André C, Herlem G, Gharbi T, Guillaume YC. J Pharm Biomed Anal 55 48-53 (2011)
  13. Comparative pharmacokinetics of N(ω)-hydroxy-nor-L-arginine, an arginase inhibitor, after single-dose intravenous, intraperitoneal and intratracheal administration to brown Norway rats. Havlinova Z, Babicova A, Hroch M, Chladek J. Xenobiotica 43 886-894 (2013)
  14. Impact of substrate protonation and tautomerization states on interactions with the active site of arginase I. Nagagarajan S, Xue F, MacKerell AD. J Chem Inf Model 53 452-460 (2013)
  15. Insight on the interaction of an agmatinase-like protein with Mn(2+) activator ions. Quiñones M, Cofre J, Benítez J, García D, Romero N, González A, Carvajal N, García M, López V, Schenk G, Uribe E. J Inorg Biochem 145 65-69 (2015)
  16. Mammalian agmatinases constitute unusual members in the family of Mn2+-dependent ureahydrolases. Romero N, Benítez J, Garcia D, González A, Bennun L, García-Robles MA, López V, Wilson LA, Schenk G, Carvajal N, Uribe E. J Inorg Biochem 166 122-125 (2017)
  17. The inhibitory effect of various indolyl amino acid derivatives on arginase activity in macrophages. Hrabák A, Bajor T, Mészáros G. Amino Acids 34 293-300 (2008)
  18. Ligand displacement for fixing manganese: relevance to cellular metal ion transport and synthesis of polymeric coordination complexes. Sanchez-Ballester NM, Shrestha LK, Elsegood MR, Schmitt W, Ariga K, Anson CE, Hill JP, Powell AK. Dalton Trans 42 2779-2785 (2013)
  19. Aminoalcohol-Induced Activation of Organophosphorus Hydrolase (OPH) towards Diisopropylfluorophosphate (DFP). Li D, Zhang Y, Song H, Lu L, Liu D, Yuan Y. PLoS One 12 e0169937 (2017)
  20. In silico design and in vitro assessment of anti-Helicobacter pylori compounds as potential small-molecule arginase inhibitors. Fiori-Duarte AT, de Oliveira Guarnieri JP, de Oliveira Borlot JRP, Lancellotti M, Rodrigues RP, Kitagawa RR, Kawano DF. Mol Divers 26 3365-3378 (2022)
  21. In-silico studies to recognize repurposing therapeutics toward arginase-I inhibitors as a potential onco-immunomodulators. Zaki MEA, Al-Hussain SA, Al-Mutairi AA, Samad A, Ghosh A, Chaudhari S, Khatale PN, Ajmire P, Jawarkar RD. Front Pharmacol 14 1129997 (2023)


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