Skip to main content

Nitric oxide generation from heme/copper assembly mediated nitrite reductase activity

Abstract

Nitric oxide (NO) as a cellular signaling molecule and vasodilator regulates a range of physiological and pathological processes. Nitrite (NO2 ) is recycled in vivo to generate nitric oxide, particularly in physiologic hypoxia and ischemia. The cytochrome c oxidase binuclear heme a 3/CuB active site is one entity known to be responsible for conversion of cellular nitrite to nitric oxide. We recently reported that a partially reduced heme/copper assembly reduces nitrite ion, producing nitric oxide; the heme serves as the reductant and the cupric ion provides a Lewis acid interaction with nitrite, facilitating nitrite (N–O) bond cleavage (Hematian et al., J. Am. Chem. Soc. 134:18912–18915, 2012). To further investigate this nitrite reductase chemistry, copper(II)–nitrito complexes with tridentate and tetradentate ligands were used in this study, where either O,O′-bidentate or O-unidentate modes of nitrite binding to the cupric center are present. To study the role of the reducing ability of the ferrous heme center, two different tetraarylporphyrinate–iron(II) complexes, one with electron-donating para-methoxy peripheral substituents and the other with electron-withdrawing 2,6-difluorophenyl substituents, were used. The results show that differing modes of nitrite coordination to the copper(II) ion lead to differing kinetic behavior. Here, also, the ferrous heme is in all cases the source of the reducing equivalent required to convert nitrite to nitric oxide, but the reduction ability of the heme center does not play a key role in the observed overall reaction rate. On the basis of our observations, reaction mechanisms are proposed and discussed in terms of heme/copper heterobinuclear structures.

This is a preview of subscription content, access via your institution.

Fig. 1
Scheme 1
Fig. 2
Scheme 2
Fig. 3
Scheme 3
Fig. 4
Fig. 5
Scheme 4
Fig. 6
Scheme 5

Notes

  1. 1.

    In further control experiments, combinations of reduced complexes, (F8)FeII/[(AN)CuI]+, (TMPP)FeII/[(tmpa)CuI(MeCN)]+, and (TMPP)FeII/[(AN)CuI]+, were studied. We observed slow reactivity toward nitrite ion, hours compared with minutes for the FeII/CuII–nitrite “parent” reactions, and the final solutions appeared to be a mixtures of the complexes.

References

  1. 1.

    Schopfer MP, Wang J, Karlin KD (2010) Inorg Chem 49:6267–6282

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  2. 2.

    Tavares P, Pereira AS, Moura JJG, Moura I (2006) J Inorg Biochem 100:2087–2100

    CAS  PubMed  Article  Google Scholar 

  3. 3.

    Zumft WG (1997) Microbiol Mol Biol Rev 61:533–616

    CAS  PubMed Central  PubMed  Google Scholar 

  4. 4.

    Poole RK (2005) Biochem Soc Trans 33:176–180

    CAS  PubMed  Article  Google Scholar 

  5. 5.

    Samouilov A, Kuppusamy P, Zweier JL (1998) Arch Biochem Biophys 357:1–7

    CAS  PubMed  Article  Google Scholar 

  6. 6.

    Dezfulian C, Raat N, Shiva S, Gladwin MT (2007) Cardiovasc Res 75:327–338

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  7. 7.

    Lundberg JO, Gladwin MT, Ahluwalia A, Benjamin N, Bryan NS, Butler A, Cabrales P, Fago A, Feelisch M, Ford PC, Freeman BA, Frenneaux M, Friedman J, Kelm M, Kevil CG, Kim-Shapiro DB, Kozlov AV, Lancaster JR, Lefer DJ, McColl K, McCurry K, Patel RP, Petersson J, Rassaf T, Reutov VP, Richter-Addo GB, Schechter A, Shiva S, Tsuchiya K, van Faassen EE, Webb AJ, Zuckerbraun BS, Zweier JL, Weitzberg E (2009) Nat Chem Biol 5:865–869

    CAS  PubMed  Article  Google Scholar 

  8. 8.

    van Faassen EE, Bahrami S, Feelisch M, Hogg N, Kelm M, Kim-Shapiro DB, Kozlov AV, Li H, Lundberg JO, Mason R, Nohl H, Rassaf T, Samouilov A, Slama-Schwok A, Shiva S, Vanin AF, Weitzberg E, Zweier J, Gladwin MT (2009) Med Res Rev 29:683–741

    PubMed Central  PubMed  Article  Google Scholar 

  9. 9.

    Fukuto JM, Carrington SJ, Tantillo DJ, Harrison JG, Ignarro LJ, Freeman BA, Chen A, Wink DA (2012) Chem Res Toxicol 25:769–793

    CAS  PubMed  Article  Google Scholar 

  10. 10.

    Kozlov AV, Staniek K, Nohl H (1999) FEBS Lett 454:127–130

    CAS  PubMed  Article  Google Scholar 

  11. 11.

    Crane BR (2008) Biochem Soc Trans 036:1149–1154

    CAS  Article  Google Scholar 

  12. 12.

    Zhu Y, Silverman RB (2008) Biochemistry 47:2231–2243

    CAS  PubMed  Article  Google Scholar 

  13. 13.

    Gladwin MT, Schechter AN, Kim-Shapiro DB, Patel RP, Hogg N, Shiva S, Cannon RO, Kelm M, Wink DA, Espey MG, Oldfield EH, Pluta RM, Freeman BA, Lancaster JR, Feelisch M, Lundberg JO (2005) Nat Chem Biol 1:308–314

    CAS  PubMed  Article  Google Scholar 

  14. 14.

    Gladwin MT, Shiva S (2009) Circ Res 104:1136–1138

    CAS  PubMed  Article  Google Scholar 

  15. 15.

    Zweier JL, Samouilov A, Kuppusamy P (1999) Biochim Biophys Acta 1411:250–262

    CAS  PubMed  Article  Google Scholar 

  16. 16.

    Cosby K, Partovi KS, Crawford JH, Patel RP, Reiter CD, Martyr S, Yang BK, Waclawiw MA, Zalos G, Xu XL, Huang KT, Shields H, Kim-Shapiro DB, Schechter AN, Cannon RO, Gladwin MT (2003) Nat Med 9:1498–1505

    CAS  PubMed  Article  Google Scholar 

  17. 17.

    Shiva S, Huang Z, Grubina R, Sun JH, Ringwood LA, MacArthur PH, Xu XL, Murphy E, Darley-Usmar VM, Gladwin MT (2007) Circ Res 100:654–661

    CAS  PubMed  Article  Google Scholar 

  18. 18.

    Shiva S, Rassaf T, Patel RP, Gladwin MT (2011) Cardiovasc Res 89:566–573

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  19. 19.

    Rassaf T, Flogel U, Drexhage C, Hendgen-Cotta U, Kelm M, Schrader J (2007) Circ Res 100:1749–1754

    CAS  PubMed  Article  Google Scholar 

  20. 20.

    Totzeck M, Hendgen-Cotta UB, Luedike P, Berenbrink M, Klare JP, Steinhoff HJ, Semmler D, Shiva S, Williams D, Kipar A, Gladwin MT, Schrader J, Kelm M, Cossins AR, Rassaf T (2012) Circulation 126:325–334

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  21. 21.

    Tiso M, Js Tejero, Basu S, Azarov I, Wang X, Simplaceanu V, Frizzell S, Jayaraman T, Geary L, Shapiro C, Ho C, Shiva S, Kim-Shapiro DB, Gladwin MT (2011) J Biol Chem 286:18277–18289

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  22. 22.

    Basu S, Azarova NA, Font MD, King SB, Hogg N, Gladwin MT, Shiva S, Kim-Shapiro DB (2008) J Biol Chem 283:32590–32597

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  23. 23.

    Gladwin MT (2005) Nat Chem Biol 1:245–246

    CAS  PubMed  Article  Google Scholar 

  24. 24.

    Lundberg JO, Weitzberg E, Gladwin MT (2008) Nat Rev Drug Discov 7:156–167

    CAS  PubMed  Article  Google Scholar 

  25. 25.

    de Mel A, Murad F, Seifalian AM (2011) Chem Rev 111:5742–5767

    PubMed  Article  Google Scholar 

  26. 26.

    Babcock GT, Wikström M (1992) Nature 356:301–309

    CAS  PubMed  Article  Google Scholar 

  27. 27.

    Ferguson-Miller S, Babcock GT (1996) Chem Rev 96:2889–2908

    CAS  PubMed  Article  Google Scholar 

  28. 28.

    Kim E, Chufán EE, Kamaraj K, Karlin KD (2004) Chem Rev 104:1077–1133

    CAS  PubMed  Article  Google Scholar 

  29. 29.

    Poyton RO, Ball KA (2011) Discov Med 57:154–159

    Google Scholar 

  30. 30.

    Shiva S (2013) Redox Biol 1:40–44

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  31. 31.

    Castello PR, David PS, McClure T, Crook Z, Poyton RO (2006) Cell Metab 3:277–287

    CAS  PubMed  Article  Google Scholar 

  32. 32.

    Gupta KJ, Stoimenova M, Kaiser WM (2005) J Exp Bot 56:2601–2609

    CAS  PubMed  Article  Google Scholar 

  33. 33.

    Castello PR, Woo DK, Ball K, Wojcik J, Liu L, Poyton RO (2008) Proc Natl Acad Sci USA 105:8203–8208

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  34. 34.

    Poyton RO, Castello PR, Ball KA, Woo DK, Pan N (2009) Ann N Y Acad Sci 1177:48–56

    CAS  PubMed  Article  Google Scholar 

  35. 35.

    Gupta KJ, Igamberdiev AU (2011) Mitochondrion 11:537–543

    CAS  PubMed  Article  Google Scholar 

  36. 36.

    Hematian S, Siegler MA, Karlin KD (2012) J Am Chem Soc 134:18912–18915

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  37. 37.

    Kopf M-A, Neuhold Y-M, Zuberbühler AD, Karlin KD (1999) Inorg Chem 38:3093–3102

    CAS  Article  Google Scholar 

  38. 38.

    Ghiladi RA, Kretzer RM, Guzei I, Rheingold AL, Neuhold Y-M, Hatwell KR, Zuberbühler AD, Karlin KD (2001) Inorg Chem 40:5754–5767

    CAS  PubMed  Article  Google Scholar 

  39. 39.

    Torres J, Sharpe MA, Rosquist A, Cooper CE, Wilson MT (2000) FEBS Lett 475:263–266

    CAS  PubMed  Article  Google Scholar 

  40. 40.

    Ford PC, Lorkovic IM (2002) Chem Rev 102:993–1017

    CAS  PubMed  Article  Google Scholar 

  41. 41.

    Wang J, Schopfer MP, Sarjeant AAN, Karlin KD (2009) J Am Chem Soc 131:450–451

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  42. 42.

    Schopfer MP, Mondal B, Lee D-H, Sarjeant AAN, Karlin KD (2009) J Am Chem Soc 131:11304–11305

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  43. 43.

    Liang H-C, Zhang CX, Henson MJ, Sommer RD, Hatwell KR, Kaderli S, Zuberbuehler AD, Rheingold AL, Solomon EI, Karlin KD (2002) J Am Chem Soc 124:4170–4171

    CAS  PubMed  Article  Google Scholar 

  44. 44.

    Park GY, Deepalatha S, Puiu SC, Lee D-H, Mondal B, Narducci Sarjeant AA, del Rio D, Pau MYM, Solomon EI, Karlin KD (2009) J Biol Inorg Chem 14:1301–1311

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  45. 45.

    Vogel KM, Kozlowski PM, Zgierski MZ, Spiro TG (1999) J Am Chem Soc 121:9915–9921

    CAS  Article  Google Scholar 

  46. 46.

    Sheldrick GM (2008) Acta Crystallogr Sect A 64:112–122

    CAS  Article  Google Scholar 

  47. 47.

    Yang L, Powell DR, Houser RP (2007) Dalton Trans 955–964

  48. 48.

    Mukhopadhyay U, Bernal I, Massoud SS, Mautner FA (2004) Inorg Chim Acta 357:3673–3682

    CAS  Article  Google Scholar 

  49. 49.

    Nakamoto K (1997) Infrared and Raman spectra of inorganic and coordination compounds, 5th edn. Wiley Interscience, New York, pp 48–53

    Google Scholar 

  50. 50.

    Quant Hatcher L, Karlin KD (2004) J Biol Inorg Chem 9:669–683

    Google Scholar 

  51. 51.

    Hatcher LQ, Karlin KD (2006) Adv Inorg Chem 58:131–184

    CAS  Article  Google Scholar 

  52. 52.

    Chufan EE, Mondal B, Gandhi T, Kim E, Rubie ND, Moenne-Loccoz P, Karlin KD (2007) Inorg Chem 46:6382–6394

    CAS  PubMed  Article  Google Scholar 

  53. 53.

    Kakuda S, Peterson RL, Ohkubo K, Karlin KD, Fukuzumi S (2013) J Am Chem Soc 135:6513–6522

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  54. 54.

    Das D, Lee Y-M, Ohkubo K, Nam W, Karlin KD, Fukuzumi S (2013) J Am Chem Soc 135:2825–2834

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  55. 55.

    Itoh S (2011) In: Itoh S, Karlin KD (eds) Copper-oxygen chemistry. Wiley, Hoboken, pp 225–282

  56. 56.

    Halime Z, Kieber-Emmons MT, Qayyum MF, Mondal B, Gandhi T, Puiu SC, Chufán EE, Sarjeant AAN, Hodgson KO, Hedman B, Solomon EI, Karlin KD (2010) Inorg Chem 49:3629–3645

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  57. 57.

    Fox S, Nanthakumar A, Wikström M, Karlin KD, Blackburn NJ (1996) J Am Chem Soc 118:24–34

    CAS  Article  Google Scholar 

  58. 58.

    Obias HV, van Strijdonck GPF, Lee D-H, Ralle M, Blackburn NJ, Karlin KD (1998) J Am Chem Soc 120:9696–9697

    CAS  Article  Google Scholar 

  59. 59.

    Wang J, Schopfer MP, Puiu SC, Sarjeant AAN, Karlin KD (2010) Inorg Chem 49:1404–1419

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  60. 60.

    Karlin KD, Nanthakumar A, Fox S, Murthy NN, Ravi N, Huynh BH, Orosz RD, Day EP (1994) J Am Chem Soc 116:4753–4763

    CAS  Article  Google Scholar 

  61. 61.

    Helms JH, Terhaar LW, Hatfield WE, Harris DL, Jayaraj K, Toney GE, Gold A, Mewborn TD, Pemberton JR (1986) Inorg Chem 25:2334–2337

    CAS  Article  Google Scholar 

  62. 62.

    Yi J, Heinecke J, Tan H, Ford PC, Richter-Addo GB (2009) J Am Chem Soc 131:18119–18128

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  63. 63.

    Silaghi-Dumitrescu R (2004) Inorg Chem 43:3715–3718

    CAS  PubMed  Article  Google Scholar 

  64. 64.

    Williams PA, Fulop V, Garman EF, Saunders NFW, Ferguson SJ, Hajdu J (1997) Nature 389:406–412

    CAS  PubMed  Article  Google Scholar 

  65. 65.

    Perissinotti LL, Marti MA, Doctorovich F, Luque FJ, Estrin DA (2008) Biochemistry 47:9793–9802

    CAS  PubMed  Article  Google Scholar 

  66. 66.

    Blomberg LM, Blomberg MRA, Siegbahn PEM (2006) Biochim Biophys Acta 1757:240–252

    CAS  PubMed  Article  Google Scholar 

  67. 67.

    Blomberg LM, Blomberg MRA, Siegbahn PEM (2007) J Biol Inorg Chem 12:79–89

    CAS  PubMed  Article  Google Scholar 

  68. 68.

    Halime Z, Kotani H, Li Y, Fukuzumi S, Karlin KD (2011) Proc Natl Acad Sci USA 108:13990–13994

    CAS  PubMed Central  PubMed  Article  Google Scholar 

Download references

Acknowledgments

We are grateful to the US National Institutes of Health for support of this research (GM60353).

Author information

Affiliations

Authors

Corresponding author

Correspondence to Kenneth D. Karlin.

Additional information

Responsible Editors: Lucia Banci and Claudio Luchinat.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 1135 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Hematian, S., Siegler, M.A. & Karlin, K.D. Nitric oxide generation from heme/copper assembly mediated nitrite reductase activity. J Biol Inorg Chem 19, 515–528 (2014). https://doi.org/10.1007/s00775-013-1081-6

Download citation

Keywords

  • Nitric oxide
  • Model compounds
  • Nitrite reductase
  • Nitrite coordination modes
  • Cytochrome c oxidase