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Chemical Compound Review

iron-molybdenum cofactor     azanide;3-carboxy-3-hydroxy- hexanedioate;...

Synonyms: FeMoco, FeMo-co, CPD-41, Fe-Mo cofactor, CHEBI:30409, ...
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Disease relevance of Homocitrate

  • The biosynthesis of the FeMo cofactor (FeMoco) of Azotobacter vinelandii nitrogenase presumably starts with the production of its Fe/S core by NifB (the nifB gene product) [1].
  • Crystallographic analysis of the MoFe protein of nitrogenase from a nifV mutant of Klebsiella pneumoniae identifies citrate as a ligand to the molybdenum of iron molybdenum cofactor (FeMoco) [2].
  • The uppermost species comigrates with the apoMoFe protein produced by a K. pneumoniae mutant unable to synthesize FeMoco (UN106) and by Escherichia coli harboring the plasmids pVL222+pVL15 (nifHDKTYUSWZM+A) [3].
  • Acidified extracts of Plectonema induced in Mo-containing medium contained the Fe-Mo cofactor required to activate extracts of the Azotobacter mutant UW45 in vitro, but they did not activate extracts of Mo-starved Plectonema [4].
  • The nifQ gene, involved in early stages of iron-molybdenum cofactor (FeMo-co) biosynthesis, was identified downstream of the nifB and nifF genes of Enterobacter agglomerans [5].

Psychiatry related information on Homocitrate

  • Determination of ligand binding constants for the iron-molybdenum cofactor of nitrogenase: monomers, multimers, and cooperative behavior [6].
  • These changes corresponded with those in the intensity of the S=3/2 EPR signal of the FeMoco centres of Kp1 and were consistent with the transient reduction of the FeMoco centre of Kp1 to an EPR-silent form, followed by restoration of the signal at longer reaction times [7].

High impact information on Homocitrate

  • A exhibits an S = (1/2) EPR signal from the active-site iron-molybdenum cofactor (FeMo-co) to which are bound at least two hydrides/protons [8].
  • The iron-molybdenum cofactor (FeMoco) of the nitrogenase MoFe protein is a highly complex metallocluster that provides the catalytically essential site for biological nitrogen fixation [9].
  • A facile scheme by which FeMoco and alternative, non-molybdenum-containing nitrogenase cofactors are constructed from this common precursor is presented that has important implications for the biosynthesis and biomimetic chemical synthesis of FeMoco [9].
  • By using GroEL-containing extracts from a DeltanifHDK strain of A. vinelandii CA12 along with FeMoco, Fe protein, and MgATP, we were able to supply all required proteins and/or factors and obtained a fully active reconstituted E146D nifH MoFe protein [10].
  • The metal cluster active site of this enzyme, the iron-molybdenum cofactor (FeMoco), can be studied either while bound within the MoFe protein component of nitrogenase or after it has been extracted into N-methylformamide [11].

Chemical compound and disease context of Homocitrate


Biological context of Homocitrate

  • These results provide quantitative details about an exchangeable thiol/selenol binding site on FeMoco in its isolated, solution state and establish an Fe atom as the site of this reaction [11].
  • In vitro synthesis of the iron-molybdenum cofactor (FeMo-co) of dinitrogenase using homocitrate and its analogs allows the formation of modified forms of FeMo-co that show altered substrate specificities (N2, acetylene, cyanide, or proton reduction) of nitrogenase [reduced ferredoxin:dinitrogen oxidoreductase (ATP-hydrolyzing), EC] [15].
  • The reaction showed saturation kinetics when Kp1 was titrated with increasing amounts of Kp2 and, at saturation, the amount of H2 formed was stoichiometric with the FeMoco content of Kp1 [16].
  • However, we report here that during the preparation of the MgADP-AlF4 K. pneumoniae complex under argon, H2 was evolved in amounts corresponding to one half of the FeMoco content of the Kp1 (FeMoco is the likely catalytic site of nitrogenase with a composition Mo:Fe7:S9:homocitrate) [16].
  • The relationship between ATP hydrolysis and substrate-reducing activity, the EPR spectra of the S = 3/2 spin state of the iron-molybdenum cofactor (FeMoco) and the pH profile of acetylene-reduction activities of the three fractions did not differ significantly from those exhibited by wild-type Kp1 [17].

Associations of Homocitrate with other chemical compounds


Gene context of Homocitrate

  • Isolation of an iron-molybdenum cofactor from nitrogenase [22].
  • Dinitrogenase, the enzyme capable of catalyzing the reduction of N2, is a heterotetramer (alpha 2 beta 2) and contains the iron-molybdenum cofactor (FeMo-co) at the active site of the enzyme [23].
  • Likewise, the Delta nifZ Delta nifB MoFe protein has the same composition as the Delta nifZ MoFe protein except for the absence of FeMoco, an effect caused by the deletion of the nifB gene [24].
  • The largest negative Delta E of -333 kJ/mol is for the FeMoco with a N(3-) in the center (the isolated form) and an intermediate in the proposed mechanism [25].
  • There is an apparent dependence on the charge density of the anion employed for elution of FeMoco bound to DEAE-cellulose, such that Cl- greater than Br- much greater than I-, PF6- is the order of effectiveness of the Bu4N+ salts of these anions.(ABSTRACT TRUNCATED AT 250 WORDS)[26]

Analytical, diagnostic and therapeutic context of Homocitrate


  1. Identification of a nitrogenase FeMo cofactor precursor on NifEN complex. Hu, Y., Fay, A.W., Ribbe, M.W. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  2. Crystallographic analysis of the MoFe protein of nitrogenase from a nifV mutant of Klebsiella pneumoniae identifies citrate as a ligand to the molybdenum of iron molybdenum cofactor (FeMoco). Mayer, S.M., Gormal, C.A., Smith, B.E., Lawson, D.M. J. Biol. Chem. (2002) [Pubmed]
  3. Electrophoretic studies on the assembly of the nitrogenase molybdenum-iron protein from the Klebsiella pneumoniae nifD and nifK gene products. White, T.C., Harris, G.S., Orme-Johnson, W.H. J. Biol. Chem. (1992) [Pubmed]
  4. Molybdenum independence of nitrogenase component synthesis in the non-heterocystous cyanobacterium Plectonema. Nagatani, H.H., Haselkorn, R. J. Bacteriol. (1978) [Pubmed]
  5. Structure of the nifQ gene from Enterobacter agglomerans 333 and its overexpression in Escherichia coli. Siddavattam, D., Singh, M., Klingmüller, W. Mol. Gen. Genet. (1993) [Pubmed]
  6. Determination of ligand binding constants for the iron-molybdenum cofactor of nitrogenase: monomers, multimers, and cooperative behavior. Frank, P., Angove, H.C., Burgess, B.K., Hodgson, K.O. J. Biol. Inorg. Chem. (2001) [Pubmed]
  7. Long-range interactions between the Fe protein binding sites of the MoFe protein of nitrogenase. Maritano, S., Fairhurst, S.A., Eady, R.R. J. Biol. Inorg. Chem. (2001) [Pubmed]
  8. Inaugural Article: Connecting nitrogenase intermediates with the kinetic scheme for N2 reduction by a relaxation protocol and identification of the N2 binding state. Lukoyanov, D., Barney, B.M., Dean, D.R., Seefeldt, L.C., Hoffman, B.M. Proc. Natl. Acad. Sci. U.S.A. (2007) [Pubmed]
  9. Structural insights into a protein-bound iron-molybdenum cofactor precursor. Corbett, M.C., Hu, Y., Fay, A.W., Ribbe, M.W., Hedman, B., Hodgson, K.O. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  10. The chaperone GroEL is required for the final assembly of the molybdenum-iron protein of nitrogenase. Ribbe, M.W., Burgess, B.K. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  11. Selenol binds to iron in nitrogenase iron-molybdenum cofactor: an extended x-ray absorption fine structure study. Conradson, S.D., Burgess, B.K., Newton, W.E., Di Cicco, A., Filipponi, A., Wu, Z.Y., Natoli, C.R., Hedman, B., Hodgson, K.O. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  12. Genes required for formation of the apoMoFe protein of Klebsiella pneumoniae nitrogenase in Escherichia coli. Harris, G.S., White, T.C., Flory, J.E., Orme-Johnson, W.H. J. Biol. Chem. (1990) [Pubmed]
  13. Nitrogenase from Klebsiella pneumoniae. An e.p.r. signal observed during enzyme turnover under ethylene is associated with the iron-molybdenum cofactor. Hawkes, T.R., Lowe, D.J., Smith, B.E. Biochem. J. (1983) [Pubmed]
  14. N2O reduction and HD formation by nitrogenase from a nifV mutant of Klebsiella pneumoniae. Liang, J., Burris, R.H. J. Bacteriol. (1989) [Pubmed]
  15. Diastereomer-dependent substrate reduction properties of a dinitrogenase containing 1-fluorohomocitrate in the iron-molybdenum cofactor. Madden, M.S., Kindon, N.D., Ludden, P.W., Shah, V.K. Proc. Natl. Acad. Sci. U.S.A. (1990) [Pubmed]
  16. MgATP-independent hydrogen evolution catalysed by nitrogenase: an explanation for the missing electron(s) in the MgADP-AlF4 transition-state complex. Yousafzai, F.K., Eady, R.R. Biochem. J. (1999) [Pubmed]
  17. Isolation and characterization of nitrogenase MoFe protein from the mutant strain pHK17 of Klebsiella pneumoniae in which the two bridging cysteine residues of the P-clusters are replaced by the non-coordinating amino acid alanine. Yousafzai, F.K., Buck, M., Smith, B.E. Biochem. J. (1996) [Pubmed]
  18. In vitro synthesis of the iron-molybdenum cofactor of nitrogenase. Shah, V.K., Imperial, J., Ugalde, R.A., Ludden, P.W., Brill, W.J. Proc. Natl. Acad. Sci. U.S.A. (1986) [Pubmed]
  19. Small-angle x-ray scattering studies of the iron-molybdenum cofactor from Azotobacter vinelandii nitrogenase. Eliezer, D., Frank, P., Gillis, N., Newton, W.E., Doniach, S., Hodgson, K.O. J. Biol. Chem. (1993) [Pubmed]
  20. Cloning and mutational analysis of the gamma gene from Azotobacter vinelandii defines a new family of proteins capable of metallocluster binding and protein stabilization. Rubio, L.M., Rangaraj, P., Homer, M.J., Roberts, G.P., Ludden, P.W. J. Biol. Chem. (2002) [Pubmed]
  21. Iron-molybdenum cofactor insertion into the Apo-MoFe protein of nitrogenase involves the iron protein-MgATP complex. Robinson, A.C., Chun, T.W., Li, J.G., Burgess, B.K. J. Biol. Chem. (1989) [Pubmed]
  22. Isolation of an iron-molybdenum cofactor from nitrogenase. Shah, V.K., Brill, W.J. Proc. Natl. Acad. Sci. U.S.A. (1977) [Pubmed]
  23. Characterization of the gamma protein and its involvement in the metallocluster assembly and maturation of dinitrogenase from Azotobacter vinelandii. Homer, M.J., Dean, D.R., Roberts, G.P. J. Biol. Chem. (1995) [Pubmed]
  24. Characterization of Azotobacter vinelandii nifZ deletion strains. Indication of stepwise MoFe protein assembly. Hu, Y., Fay, A.W., Dos Santos, P.C., Naderi, F., Ribbe, M.W. J. Biol. Chem. (2004) [Pubmed]
  25. Density functional theory calculations and exploration of a possible mechanism of N2 reduction by nitrogenase. Huniar, U., Ahlrichs, R., Coucouvanis, D. J. Am. Chem. Soc. (2004) [Pubmed]
  26. A new method for extraction of iron-molybdenum cofactor (FeMoco) from nitrogenase adsorbed to DEAE-cellulose. 1. Effects of anions, cations, and preextraction treatments. McLean, P.A., Wink, D.A., Chapman, S.K., Hickman, A.B., McKillop, D.M., Orme-Johnson, W.H. Biochemistry (1989) [Pubmed]
  27. Electron-paramagnetic-resonance and magnetic-circular-dichroism studies of the binding of cyanide and thiols to the thiols to the iron-molybdenum cofactor from Klebsiella pneumoniae nitrogenase. Richards, A.J., Lowe, D.J., Richards, R.L., Thomson, A.J., Smith, B.E. Biochem. J. (1994) [Pubmed]
  28. Mössbauer spectroscopy applied to the oxidized and semi-reduced states of the iron-molybdenum cofactor of nitrogenase. Newton, W.E., Gheller, S.F., Sands, R.H., Dunham, W.R. Biochem. Biophys. Res. Commun. (1989) [Pubmed]
  29. Purification and spectroscopic characteristics in N-methylformamide of the Azotobacter vinelandii Fe-Mo cofactor. Frank, P., Gheller, S.F., Newton, W.E., Hodgson, K.O. Biochem. Biophys. Res. Commun. (1989) [Pubmed]
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