2jcw Citations

A structure-based mechanism for copper-zinc superoxide dismutase.

Biochemistry 38 2167-78 (1999)
Related entries: 1yaz, 1b4t, 1f1g, 1f1d, 1f1a, 1f18, 1b4l

Cited: 71 times
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A reaction cycle is proposed for the mechanism of copper-zinc superoxide dismutase (CuZnSOD) that involves inner sphere electron transfer from superoxide to Cu(II) in one portion of the cycle and outer sphere electron transfer from Cu(I) to superoxide in the other portion of the cycle. This mechanism is based on three yeast CuZnSOD structures determined by X-ray crystallography together with many other observations. The new structures reported here are (1) wild type under 15 atm of oxygen pressure, (2) wild type in the presence of azide, and (3) the His48Cys mutant. Final R-values for the three structures are respectively 20.0%, 17.3%, and 20.9%. Comparison of these three new structures to the wild-type yeast Cu(I)ZnSOD model, which has a broken imidazolate bridge, reveals the following: (i) The protein backbones (the "SOD rack") remain essentially unchanged. (ii) A pressure of 15 atm of oxygen causes a displacement of the copper ion 0.37 A from its Cu(I) position in the trigonal plane formed by His46, His48, and His120. The displacement is perpendicular to this plane and toward the NE2 atom of His63 and is accompanied by elongated copper electron density in the direction of the displacement suggestive of two copper positions in the crystal. The copper geometry remains three coordinate, but the His48-Cu bond distance increases by 0.18 A. (iii) Azide binding also causes a displacement of the copper toward His63 such that it moves 1.28 A from the wild-type Cu(I) position, but unlike the effect of 15 atm of oxygen, there is no two-state character. The geometry becomes five-coordinate square pyramidal, and the His63 imidazolate bridge re-forms. The His48-Cu distance increases by 0.70 A, suggesting that His48 becomes an axial ligand. (iv) The His63 imidazole ring tilts upon 15 atm of oxygen treatment and azide binding. Its NE2 atom moves toward the trigonal plane by 0.28 and 0.66 A, respectively, in these structures. (v) The replacement of His48 by Cys, which does not bind copper, results in a five-coordinate square pyramidal, bridge-intact copper geometry with a novel chloride ligand. Combining results from these and other CuZnSOD crystal structures, we offer the outlines of a structure-based cyclic mechanism.

Articles - 2jcw mentioned but not cited (2)

  1. Prediction of catalytic residues using Support Vector Machine with selected protein sequence and structural properties. Petrova NV, Wu CH. BMC Bioinformatics 7 312 (2006)
  2. Structural, Functional, and Immunogenic Insights on Cu,Zn Superoxide Dismutase Pathogenic Virulence Factors from Neisseria meningitidis and Brucella abortus. Pratt AJ, DiDonato M, Shin DS, Cabelli DE, Bruns CK, Belzer CA, Gorringe AR, Langford PR, Tabatabai LB, Kroll JS, Tainer JA, Getzoff ED. J. Bacteriol. 197 3834-3847 (2015)

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  1. Activation of dioxygen by copper metalloproteins and insights from model complexes. Quist DA, Diaz DE, Liu JJ, Karlin KD. J. Biol. Inorg. Chem. 22 253-288 (2017)
  2. Superoxide Dismutases in Pancreatic Cancer. Wilkes JG, Alexander MS, Cullen JJ. Antioxidants (Basel) 6 (2017)
  3. Synthetic fluorescent probes for studying copper in biological systems. Cotruvo JA, Aron AT, Ramos-Torres KM, Chang CJ. Chem Soc Rev 44 4400-4414 (2015)
  4. Strategies to optimize photosensitizers for photodynamic inactivation of bacteria. Tim M. J. Photochem. Photobiol. B, Biol. 150 2-10 (2015)
  5. Questions regarding the predictive value of one evolved complex adaptive system for a second: exemplified by the SOD1 mouse. Greek R, Hansen LA. Prog. Biophys. Mol. Biol. 113 231-253 (2013)
  6. The redox proteome. Go YM, Jones DP. J. Biol. Chem. 288 26512-26520 (2013)
  7. Superoxide dismutases: ancient enzymes and new insights. Miller AF. FEBS Lett. 586 585-595 (2012)
  8. The structural biochemistry of the superoxide dismutases. Perry JJ, Shin DS, Getzoff ED, Tainer JA. Biochim. Biophys. Acta 1804 245-262 (2010)
  9. Structure, folding, and misfolding of Cu,Zn superoxide dismutase in amyotrophic lateral sclerosis. Rakhit R, Chakrabartty A. Biochim. Biophys. Acta 1762 1025-1037 (2006)
  10. Copper-zinc superoxide dismutase and amyotrophic lateral sclerosis. Valentine JS, Doucette PA, Zittin Potter S. Annu. Rev. Biochem. 74 563-593 (2005)

Articles citing this publication (59)

  1. Metal ions in biological catalysis: from enzyme databases to general principles. Andreini C, Bertini I, Cavallaro G, Holliday GL, Thornton JM. J. Biol. Inorg. Chem. 13 1205-1218 (2008)
  2. Crystal structure of nickel-containing superoxide dismutase reveals another type of active site. Wuerges J, Lee JW, Yim YI, Yim HS, Kang SO, Djinovic Carugo K. Proc. Natl. Acad. Sci. U.S.A. 101 8569-8574 (2004)
  3. The structure of holo and metal-deficient wild-type human Cu, Zn superoxide dismutase and its relevance to familial amyotrophic lateral sclerosis. Strange RW, Antonyuk S, Hough MA, Doucette PA, Rodriguez JA, Hart PJ, Hayward LJ, Valentine JS, Hasnain SS. J. Mol. Biol. 328 877-891 (2003)
  4. Structural characterization of zinc-deficient human superoxide dismutase and implications for ALS. Roberts BR, Tainer JA, Getzoff ED, Malencik DA, Anderson SR, Bomben VC, Meyers KR, Karplus PA, Beckman JS. J. Mol. Biol. 373 877-890 (2007)
  5. Convergent evolution of enzyme active sites is not a rare phenomenon. Gherardini PF, Wass MN, Helmer-Citterich M, Sternberg MJ. J. Mol. Biol. 372 817-845 (2007)
  6. Superoxide dismutase: an emerging target for cancer therapeutics. Hileman EA, Achanta G, Huang P. Expert Opin. Ther. Targets 5 697-710 (2001)
  7. Superoxide dismutase from the eukaryotic thermophile Alvinella pompejana: structures, stability, mechanism, and insights into amyotrophic lateral sclerosis. Shin DS, Didonato M, Barondeau DP, Hura GL, Hitomi C, Berglund JA, Getzoff ED, Cary SC, Tainer JA. J. Mol. Biol. 385 1534-1555 (2009)
  8. Catalysing new reactions during evolution: economy of residues and mechanism. Bartlett GJ, Borkakoti N, Thornton JM. J. Mol. Biol. 331 829-860 (2003)
  9. Effects of cadmium on structure and enzymatic activity of Cu,Zn-SOD and oxidative status in neural cells. Huang YH, Shih CM, Huang CJ, Lin CM, Chou CM, Tsai ML, Liu TP, Chiu JF, Chen CT. J. Cell. Biochem. 98 577-589 (2006)
  10. SIRT5 desuccinylates and activates SOD1 to eliminate ROS. Lin ZF, Xu HB, Wang JY, Lin Q, Ruan Z, Liu FB, Jin W, Huang HH, Chen X. Biochem. Biophys. Res. Commun. 441 191-195 (2013)
  11. Mechanism and thermodynamics of guanidinium chloride-induced denaturation of ALS-associated mutant Cu,Zn superoxide dismutases. Rumfeldt JA, Stathopulos PB, Chakrabarrty A, Lepock JR, Meiering EM. J. Mol. Biol. 355 106-123 (2006)
  12. The structure of human extracellular copper-zinc superoxide dismutase at 1.7 A resolution: insights into heparin and collagen binding. Antonyuk SV, Strange RW, Marklund SL, Hasnain SS. J. Mol. Biol. 388 310-326 (2009)
  13. Functional and crystallographic characterization of Salmonella typhimurium Cu,Zn superoxide dismutase coded by the sodCI virulence gene. Pesce A, Battistoni A, Stroppolo ME, Polizio F, Nardini M, Kroll JS, Langford PR, O'Neill P, Sette M, Desideri A, Bolognesi M. J. Mol. Biol. 302 465-478 (2000)
  14. Structure of fully reduced bovine copper zinc superoxide dismutase at 1.15 A. Hough MA, Hasnain SS. Structure 11 937-946 (2003)
  15. Denaturational stress induces formation of zinc-deficient monomers of Cu,Zn superoxide dismutase: implications for pathogenesis in amyotrophic lateral sclerosis. Mulligan VK, Kerman A, Ho S, Chakrabartty A. J. Mol. Biol. 383 424-436 (2008)
  16. Interaction of Cu(2+) with His-Val-His and of Zn(2+) with His-Val-Gly-Asp, two peptides surrounding metal ions in Cu,Zn-superoxide dismutase enzyme. Myari A, Malandrinos G, Deligiannakis Y, Plakatouras JC, Hadjiliadis N, Nagy Z, Sòvágó I. J. Inorg. Biochem. 85 253-261 (2001)
  17. Candida albicans SOD5 represents the prototype of an unprecedented class of Cu-only superoxide dismutases required for pathogen defense. Gleason JE, Galaleldeen A, Peterson RL, Taylor AB, Holloway SP, Waninger-Saroni J, Cormack BP, Cabelli DE, Hart PJ, Culotta VC. Proc. Natl. Acad. Sci. U.S.A. 111 5866-5871 (2014)
  18. Metal deficiency increases aberrant hydrophobicity of mutant superoxide dismutases that cause amyotrophic lateral sclerosis. Tiwari A, Liba A, Sohn SH, Seetharaman SV, Bilsel O, Matthews CR, Hart PJ, Valentine JS, Hayward LJ. J. Biol. Chem. 284 27746-27758 (2009)
  19. An inquiry into protein structure and genetic disease: introducing undergraduates to bioinformatics in a large introductory course. Bednarski AE, Elgin SC, Pakrasi HB. Cell Biol Educ 4 207-220 (2005)
  20. Cu,Zn superoxide dismutase structure from a microbial pathogen establishes a class with a conserved dimer interface. Forest KT, Langford PR, Kroll JS, Getzoff ED. J. Mol. Biol. 296 145-153 (2000)
  21. Molecular characterization of two superoxide dismutases from Hydra vulgaris. Dash B, Metz R, Huebner HJ, Porter W, Phillips TD. Gene 387 93-108 (2007)
  22. Electrochemistry of immobilized CuZnSOD and FeSOD and their interaction with superoxide radicals. Ge B, Scheller FW, Lisdat F. Biosens Bioelectron 18 295-302 (2003)
  23. Single mutation induces a metal-dependent subunit association in dimeric Cu,Zn superoxide dismutase. D'Orazio M, Battistoni A, Stroppolo ME, Desideri A. Biochem. Biophys. Res. Commun. 272 81-83 (2000)
  24. Stepwise vs. concerted pathways in scandium ion-coupled electron transfer from superoxide ion to p-benzoquinone derivatives. Kawashima T, Ohkubo K, Fukuzumi S. Phys Chem Chem Phys 13 3344-3352 (2011)
  25. Temperature downshift induces antioxidant response in fungi isolated from Antarctica. Gocheva YG, Tosi S, Krumova ET, Slokoska LS, Miteva JG, Vassilev SV, Angelova MB. Extremophiles 13 273-281 (2009)
  26. Single mutations at the subunit interface modulate copper reactivity in Photobacterium leiognathi Cu,Zn superoxide dismutase. Stroppolo ME, Pesce A, D'Orazio M, O'Neill P, Bordo D, Rosano C, Milani M, Battistoni A, Bolognesi M, Desideri A. J. Mol. Biol. 308 555-563 (2001)
  27. Cell response of Antarctic and temperate strains of Penicillium spp. to different growth temperature. Gocheva YG, Krumova ET, Slokoska LS, Miteva JG, Vassilev SV, Angelova MB. Mycol. Res. 110 1347-1354 (2006)
  28. Structural and functional analysis of glycosylated Cu/Zn-superoxide dismutase from the fungal strain Humicola lutea 103. Dolashka-Angelova P, Stevanovic S, Dolashki A, Angelova M, Serkedjieva J, Krumova E, Pashova S, Zacharieva S, Voelter W. Biochem. Biophys. Res. Commun. 317 1006-1016 (2004)
  29. Post-translational modification of Cu/Zn superoxide dismutase under anaerobic conditions. Leitch JM, Li CX, Baron JA, Matthews LM, Cao X, Hart PJ, Culotta VC. Biochemistry 51 677-685 (2012)
  30. Structures of mouse SOD1 and human/mouse SOD1 chimeras. Seetharaman SV, Taylor AB, Holloway S, Hart PJ. Arch. Biochem. Biophys. 503 183-190 (2010)
  31. Characterization of the superoxide dismutase SOD1 gene of Kluyveromyces marxianus L3 and improved production of SOD activity. Raimondi S, Uccelletti D, Matteuzzi D, Pagnoni UM, Rossi M, Palleschi C. Appl. Microbiol. Biotechnol. 77 1269-1277 (2008)
  32. SOD1, a new Kluyveromyces lactis helper gene for heterologous protein secretion. Raimondi S, Zanni E, Talora C, Rossi M, Palleschi C, Uccelletti D. Appl. Environ. Microbiol. 74 7130-7137 (2008)
  33. Structural evidence for a copper-bound carbonate intermediate in the peroxidase and dismutase activities of superoxide dismutase. Strange RW, Hough MA, Antonyuk SV, Hasnain SS. PLoS ONE 7 e44811 (2012)
  34. Spectroscopic and computational investigation of three Cys-to-Ser mutants of nickel superoxide dismutase: insight into the roles played by the Cys2 and Cys6 active-site residues. Johnson OE, Ryan KC, Maroney MJ, Brunold TC. J. Biol. Inorg. Chem. 15 777-793 (2010)
  35. Molecular orbital study of complexes of zinc(II) with sulphide, thiomethanolate, thiomethanol, dimethylthioether, thiophenolate, formiate, acetate, carbonate, hydrogen carbonate, iminomethane and imidazole. Relationships with structural and catalytic zinc in some metallo-enzymes. Cini R. J. Biomol. Struct. Dyn. 16 1225-1237 (1999)
  36. Structural and functional studies of monomeric mutant of Cu-Zn superoxide dismutase without Arg 143. Banci L, Bertini I, Del Conte R, Viezzoli MS. Biospectroscopy 5 S33-41 (1999)
  37. Polarizable molecular mechanics studies of Cu(I)/Zn(II) superoxide dismutase: bimetallic binding site and structured waters. Gresh N, El Hage K, Perahia D, Piquemal JP, Berthomieu C, Berthomieu D. J Comput Chem 35 2096-2106 (2014)
  38. Dietary zinc intake is inversely associated to metabolic syndrome in male but not in female urban adolescents. Suarez-Ortegón MF, Ordoñez-Betancourth JE, Aguilar-de Plata C. Am. J. Hum. Biol. 25 550-554 (2013)
  39. Molecular cloning, characterization and predicted structure of a putative copper-zinc SOD from the camel, Camelus dromedarius. Ataya FS, Fouad D, Al-Olayan E, Malik A. Int J Mol Sci 13 879-900 (2012)
  40. Coordination of semiquinone and superoxide radical anions to the zinc ion in SOD model complexes that act as the key step in disproportionation of the radical anions. Ohtsu H, Fukuzumi S. Chemistry 7 4947-4953 (2001)
  41. The Essential Role of a Zn(II) Ion in the Disproportionation of Semiquinone Radical Anion by an Imidazolate-Bridged Cu(II)-Zn(II) Model of Superoxide Dismutase We are grateful to Mituo Ohama, Graduate School of Science, Osaka University, for recording resonance Raman spectra. This work was partially supported by a Grant-in-Aid for Scientific Research Priority Area (No. 11228205) from the Ministry of Education, Science, Sports and Culture, Japan. Ohtsu H, Fukuzumi S. Angew. Chem. Int. Ed. Engl. 39 4537-4539 (2000)
  42. The Phylogeny and Active Site Design of Eukaryotic Copper-only Superoxide Dismutases. Peterson RL, Galaleldeen A, Villarreal J, Taylor AB, Cabelli DE, Hart PJ, Culotta VC. J. Biol. Chem. 291 20911-20923 (2016)
  43. Electron transfer mechanism of catalytic superoxide dismutation via Cu(ii/i) complexes: evidence of cupric-superoxo/-hydroperoxo species. Maji RC, Das PP, Mishra S, Bhandari A, Maji M, Patra AK. Dalton Trans 45 11898-11910 (2016)
  44. Structure of Cu/Zn superoxide dismutase from the heavy-metal-tolerant yeast Cryptococcus liquefaciens strain N6. Teh AH, Kanamasa S, Kajiwara S, Kumasaka T. Biochem. Biophys. Res. Commun. 374 475-478 (2008)
  45. Preparation of a hydroperoxo zinc(II) intermediate. Wada A, Yamaguchi S, Jitsukawa K, Masuda H. Angew. Chem. Int. Ed. Engl. 44 5698-5701 (2005)
  46. A comparison of the mechanism for the reductive half-reaction between pea seedling and other copper amine oxidases (CAOs). Prabhakar R, Siegbahn PE. J Comput Chem 24 1599-1609 (2003)
  47. Investigation of the active site of Escherichia coli Cu,Zn superoxide dismutase reveals the absence of the copper-coordinated water molecule. is the water molecule really necessary for the enzymatic mechanism? Sette M, Bozzi M, Battistoni A, Fasano M, Paci M, Rotilio G. FEBS Lett. 483 21-26 (2000)
  48. Classical hydrogen bonding and stacking of chelate rings in new copper(ii) complexes. Singh YP, Patel RN, Singh Y, Choquesillo-Lazarte D, Butcher RJ. Dalton Trans 46 2803-2820 (2017)
  49. Toxic and essential elements in Nigerian rice and estimation of dietary intake through rice consumption. Adedire CO, Adeyemi JA, Paulelli AC, da Cunha Martins-Junior A, Ileke KD, Segura FR, de Oliveira-Souza VC, Batista BL, Barbosa F. Food Addit Contam Part B Surveill 8 271-276 (2015)
  50. Dynamic features of the subunit interface of Cu,Zn superoxide dismutase as probed by tryptophan phosphorescence. Cioni P, Stroppolo ME, Desideri A, Strambini GB. Arch. Biochem. Biophys. 391 111-118 (2001)
  51. Reaction mechanism of electron transfer from FeII(CN)6(4-) or W(IV)(CN)8(4-) to the cupric ions in human copper, zinc superoxide dismutase. Hirose J, Minakami M, Settu K, Tsukahara K, Ueda J, Ozawa T. Arch. Biochem. Biophys. 383 246-255 (2000)
  52. The role of oxidative stress on the effect of 1,4,7,10,13,16-hexathiacyclooctadecane on copper and zinc toxicity in HepG2 cells. Smet PW, Elskens M, Bolle F, Dierickx PJ. Hum Exp Toxicol 22 89-93 (2003)
  53. Catalytic activities of dismution reactions of Cu(bpy)Br(2) compound and its derivatives as SOD mimics: a theoretical study. Lu Q, Li X, Wang Y, Chen G. J Mol Model 15 1397-1405 (2009)
  54. Profiling the active site of a copper enzyme through its far-infrared fingerprint. Marboutin L, Petitjean H, Xerri B, Vita N, Dupeyrat F, Flament JP, Berthomieu D, Berthomieu C. Angew. Chem. Int. Ed. Engl. 50 8062-8066 (2011)
  55. Superoxide disproportionation driven by zinc complexes with various steric and electrostatic properties. Wada A, Jitsukawa K, Masuda H. Angew. Chem. Int. Ed. Engl. 52 12293-12297 (2013)
  56. Disproportionation of a 2,2-diphenyl-1-picrylhydrazyl radical as a model of reactive oxygen species catalysed by Lewis and/or Brønsted acids. Nakanishi I, Kawashima T, Ohkubo K, Waki T, Uto Y, Kamada T, Ozawa T, Matsumoto K, Fukuzumi S. Chem. Commun. (Camb.) 50 814-816 (2014)
  57. [Effects of antioxidant on reduction of hindlimb muscle atrophy induced by cisplatin in rats]. Kim Ji, Choe MA. J Korean Acad Nurs 44 371-380 (2014)
  58. Dioxygen Activation by a Macrocyclic Copper Complex Leads to a Cu2O2 Core with Unexpected Structure and Reactivity. Garcia-Bosch I, Cowley RE, Díaz DE, Siegler MA, Nam W, Solomon EI, Karlin KD. Chemistry 22 5133-5137 (2016)
  59. S95C substitution in CuZn-SOD of Ipomoea carnea: impact on the structure, function and stability. Mishra P, Satpati S, Baral SK, Dixit A, Sabat SC. Mol Biosyst 12 3017-3031 (2016)

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