Acetyl-coenzyme A synthase: the case for a Nip0-based mechanism of catalysis

  • Paul A. LindahlEmail author


Acetyl-CoA synthase (also known as carbon monoxide dehydrogenase) is a bifunctional Ni-Fe-S-containing enzyme that catalyzes the reversible reduction of CO2 to CO and the synthesis of acetyl-coenzyme A from CO, CoA, and a methyl group donated by a corrinoid iron-sulfur protein. The active site for the latter reaction, called the A-cluster, consists of an Fe4S4 cubane bridged to the proximal Ni site (Nip), which is bridged in turn to the so-called distal Ni site. In this review, evidence is presented that Nip achieves a zero-valent state at low potentials and during catalysis. Nip appears to be the metal to which CO and methyl groups bind and then react to form an acetyl-Nip intermediate. Methyl group binding requires reductive activation, where two electrons reduce some site on the A-cluster. The coordination environment of the distal Ni suggests that it could not be stabilized in redox states lower than 2+. The rate at which the [Fe4S4]2+ cubane is reduced is far slower than that at which reductive activation occurs, suggesting that the cubane is not the site of reduction. An intriguing possibility is that Nip2+ might be reduced to the zero-valent state. Reinforcing this idea are Ni-organometallic complexes in which the Ni exhibits analogous reactivity properties when reduced to the zero-valent state. A zero-valent Ni stabilized exclusively with biological ligands would be remarkable and unprecedented in biology.


Carbon monoxide dehydrogenase Nickel(0) Zero-valent nickel 



Many of the developments described here could not have been made without the efforts of Juan C. Fontecilla-Camps and his group in Grenoble. Discussions with Marcetta Y. Darensbourg and Michael B. Hall were critical in developing the Ni0 hypothesis. The author thanks his co-workers at Texas A&M who worked on problems related to this hypothesis over the past decade or so, including Woonsup Shin, David P. Barondeau, Xiangshi Tan, and Matthew R. Bramlett. Thanks are also due to Mark Gerstein and co-workers (Yale University) for preparing the movie of the α subunit conformations. This project is supported by the National Institutes of Health (GM46441).

Supplementary material

acs1.mpeg (1.3 mb)
acs1.mpeg (1.3 MB)


  1. 1.
    Lindahl PA (2002) Biochemistry 41:2097–2105CrossRefPubMedGoogle Scholar
  2. 2.
    Wood HG, Ljungdahl LG (1991) In: Shively JM, Barton LL (eds) Variations in autotrophic life. Academic Press, New York, pp 201–250Google Scholar
  3. 3.
    Lindahl PA, Chang B (2001) Origins Life Evol Biosphere 31:403–434CrossRefGoogle Scholar
  4. 4.
    Doukov TI, Iverson TM, Seravalli J, Ragsdale SW, Drennan CL (2002) Science 298:567–572CrossRefPubMedGoogle Scholar
  5. 5.
    Darnault C, Volbeda A, Kim EJ, Legrand P, Vernede X, Lindahl PA, Fontecilla-Camps JC (2003) Nat Struct Biol 10:271–279CrossRefPubMedGoogle Scholar
  6. 6.
    Svetlitchnyi V, Dobbek H, Meyer-Klaucke W, Meins T, Thiele B, Römer P, Huber R, Meyer O (2004) Proc Natl Acad Sci USA 101:446–451CrossRefPubMedGoogle Scholar
  7. 7.
    Echols N, Milburn D, Gerstein M (2003) Nucleic Acids Res 31:478–482CrossRefPubMedGoogle Scholar
  8. 8.
    Krebs WG, Gerstein M (2000) Nucleic Acids Res 28:1665–1675CrossRefPubMedGoogle Scholar
  9. 9.
    Seravalli J, Gu W, Tam A, Strauss E, Begley TP, Cramer SP, Ragsdale SW (2003) Proc Natl Acad Sci USA 100:3689–3694CrossRefPubMedGoogle Scholar
  10. 10.
    Gencic S, Grahame DA (2003) J Biol Chem 278:6101–6110CrossRefPubMedGoogle Scholar
  11. 11.
    Bramlett MR, Tan X, Lindahl PA (2003) J Am Chem Soc125:9316–9317CrossRefGoogle Scholar
  12. 12.
    Seravalli J, Xiao Y, Gu W, Cramer SP, Antholine WE, Krymov V, Gerfen GJ, Ragsdale SW (2004) Biochemistry 43:3944–3456CrossRefPubMedGoogle Scholar
  13. 13.
    Krüger HJ, Peng G, Holm RH (1991) Inorg Chem 30:734–742Google Scholar
  14. 14.
    Hanss J, Krüger HJ (1998) Angew Chem Int Ed 37:360–363CrossRefGoogle Scholar
  15. 15.
    Marlin DS, Mascharak PK (2000) Chem Soc Rev 29:69–74CrossRefGoogle Scholar
  16. 16.
    Harrop TC, Olmstead MM, Mascharak PK (2002) Inorg Chim Acta 338:189–195CrossRefGoogle Scholar
  17. 17.
    Loke HK, Bennett B, Lindahl PA (2000) Proc Natl Acad Sci USA 97:12530–12535CrossRefPubMedGoogle Scholar
  18. 18.
    Loke HK, Tan X, Lindahl PA (2002) J Am Chem Soc 124:8667–8672CrossRefPubMedGoogle Scholar
  19. 19.
    Lindahl PA, Ragsdale SW, Münck E (1990) J Biol Chem 265:3880–3888PubMedGoogle Scholar
  20. 20.
    Xia J, Hu Z, Popescu C, Lindahl PA, Münck E (1997) J Am Chem Soc 119:8301–8312CrossRefGoogle Scholar
  21. 21.
    Fan CL, Gorst CM, Ragsdale SW, Hoffman BM (1991) Biochemistry 30:431–435PubMedGoogle Scholar
  22. 22.
    Shin W, Lindahl PA (1992) Biochemistry 31:12870–12875PubMedGoogle Scholar
  23. 23.
    Russell WK, Stålhandske CMV, Xia J, Scott RA, Lindahl PA (1998) J Am Chem Soc 120:7502–7510CrossRefGoogle Scholar
  24. 24.
    Lindahl PA, Münck E, Ragsdale SW (1990) J Biol Chem 265:3873–3879PubMedGoogle Scholar
  25. 25.
    Shin W, Lindahl PA (1992) J Am Chem Soc 114:9718–9719Google Scholar
  26. 26.
    Shin W, Anderson ME, Lindahl PA (1993) J Am Chem Soc 115:5522–5526Google Scholar
  27. 27.
    Schenker RP, Brunold TC (2003) J Am Chem Soc 125:13962–13963CrossRefPubMedGoogle Scholar
  28. 28.
    Stavropoulos P, Muetterties MC, Carrie M, Holm RH (1991) J Am Chem Soc 113:8485–8491Google Scholar
  29. 29.
    Stoppioni P, Dapporto P, Sacconi L (1978) Inorg Chem 17:718–725Google Scholar
  30. 30.
    Pezacka E, Wood HG (1988) J Biol Chem 263:16000–16006PubMedGoogle Scholar
  31. 31.
    Lu WP, Harder SR, Ragsdale SW (1990) J Biol Chem 265:3124–3133PubMedGoogle Scholar
  32. 32.
    Barondeau DP, Lindahl PA (1997) J Am Chem Soc 119:3959–3970CrossRefGoogle Scholar
  33. 33.
    Tan X, Sewell C, Yang Q, Lindahl PA (2003) J Am Chem Soc 125:318–319CrossRefPubMedGoogle Scholar
  34. 34.
    Kumar M, Qiu D, Spiro TG, Ragsdale SW (1995) Science 270:628–630PubMedGoogle Scholar
  35. 35.
    Lebertz H, Simon H, Courtney LF, Benkovic SJ, Zydowsky LD, Lee K, Floss HG (1987) J Am Chem Soc 109:3173–3174Google Scholar
  36. 36.
    Tan X, Sewell C, Lindahl PA (2002) J Am Chem Soc 124:6277–6284CrossRefPubMedGoogle Scholar
  37. 37.
    Webster CE, Darensbourg MY, Lindahl PA, Hall MB (2004) J Am Chem Soc 126:3410–3411CrossRefPubMedGoogle Scholar
  38. 38.
    Hsiao Y-M, Chojnacki SS, Hinton P, Reibenspies JH, Darensbourg MY (1993) Organometallics 12:870–875Google Scholar
  39. 39.
    Wang Q, Blake AJ, Davies ES, McInnes EJL, Wilson C, Schröder M (2003) Chem Commun 24:3012–3013CrossRefGoogle Scholar
  40. 40.
    Musie G, Farmer PJ, Tuntulani T, Reibenspies JH, Darensbourg MY (1996) Inorg Chem 35:2176–2183CrossRefPubMedGoogle Scholar
  41. 41.
    Linck RC, Spahn CW, Rauchfuss TB, Wilson SR (2003) J Am Chem Soc 125:8700–8701CrossRefPubMedGoogle Scholar
  42. 42.
    Krishnan R, Riordan CG (2004) J Am Chem Soc 126:4484–4485CrossRefPubMedGoogle Scholar
  43. 43.
    Tolman CA, Seidel WC, Gosser LW (1974) J Am Chem Soc 96:53–60Google Scholar
  44. 44.
    Daniele S, Martelli M, Bontempelli G (1991) Inorg Chim Acta 179:105–111CrossRefGoogle Scholar

Copyright information

© SBIC 2004

Authors and Affiliations

  1. 1.Departments of Chemistry and of Biochemistry and BiophysicsTexas A&M UniversityCollege StationUSA

Personalised recommendations