FeMoco (FeMo cofactor) is the primary cofactor of nitrogenase. Nitrogenase is the enzyme that catalyzes the conversion of atmospheric nitrogen molecules N2 into ammonia (NH3) through the process known as nitrogen fixation. Containing iron and molybdenum, the cofactor is called FeMoco. Its stoichiometry is Fe7MoS9C.

FeMoco cluster
Structure of the FeMo cofactor showing the sites of binding to nitrogenase. The amino acids cysteine (Cys) and histidine (His) are indicated.


The FeMo cofactor is a cluster with composition Fe7MoS9C. Fe is the chemical symbol for the element iron (ferrum), and Mo is the symbol for molybdenum. This large cluster can be viewed as two subunits composed of one Fe4S3 (iron(III) sulfide) cluster and one MoFe3S3 cluster. The two clusters are linked by three sulfide ligands. The unique iron (Fe) is anchored to the protein by a cysteine. It is also bound to three sulfides, resulting in tetrahedral molecular geometry. The additional six Fe centers in the cluster are each bonded to three sulfides. These six internal Fe centers define a trigonal prismatic arrangement around a central carbide center. The molybdenum is attached to three sulfides and is anchored to the protein by the imidazole group of a histidine residue. Also bound to Mo is a bidentate homocitrate cofactor, leading to octahedral geometry.[1] Crystallographic analysis of the MoFe protein initially proposed the geometry of FeMoco, which was confirmed by extended X-ray absorption fine-structure (EXAFS) studies.[2][3] Distances for Fe-S, Fe-Fe and Fe-Mo distances were determined to be 2.32, 2.64, and 2.73 Å respectively.[3]

Electronic properties of FeMoco

According to the analysis by electron paramagnetic resonance spectroscopy, the resting state of the FeMo cofactor has a spin state of S=3/2. Upon one-electron reduction, the cofactor becomes EPR silent. Understanding the process in which an electron is transferred in the protein adduct shows a more precise kinetic model of the FeMo cofactor.[4] Density functional theory calculations have suggested that the formal oxidation state is MoIV-2FeII-5FeIII-C4−-H+, but the "true" oxidation states have not been confirmed experimentally.[5]


Biosynthesis of FeMoco is a complicated process that requires several Nif gene products, specifically those of nifS, nifQ, nifB, nifE, nifN, nifV, nifH, nifD, and nifK (expressed as the proteins NifS, NifU, etc.). FeMoco assembly is proposed to be initiated by NifS and NifU which mobilize Fe and sulfide into small Fe-S fragments. These fragments are transferred to the NifB scaffold and arranged into a Fe7MoS9C cluster before transfer to the NifEN protein (encoded by nifE and nifN) and rearranged before delivery to the MoFe protein.[6] Several other factors participate in the biosynthesis. For example, NifV is the homocitrate synthase that supplies homocitrate to FeMoco. NifV, a protein factor, is proposed to be involved in the storage and/or mobilization of Mo. Fe protein is the electron donor for MoFe protein6. These biosynthetic factors have been elucidated and characterized with the exact functions and sequence confirmed by biochemical, spectroscopic, and structural analyses.


Isolation of the FeMo cofactor from nitrogenase is done through centrifugal sedimentation of nitrogenase into the MoFe protein and the Fe protein. The FeMo cofactor is extracted by treating the MoFe protein with acids. The first extraction is done with N,N-dimethylformamide and the second by a mixture of N-methylformamide and Na2HPO4 before final sedimentation by centrifugation.[7]

Identity of the core atom in the cofactor

The three proteins that play a direct role in the M-cluster synthesis are NifH, NifEN, and NifB. The NifB protein is responsible for the assembly of the Fe-S core of the cofactor; a process that involves stitching together two [4Fe-4S] clusters. NifB belongs to the SAM (S-adenosyl-L-methionine) enzyme superfamily. During the biosynthesis of the FeMo cofactor, NifB and its SAM cofactor are directly involved in the insertion of a carbon atom at the center of the Fe-S complex. An equivalent of SAM donates a methyl group, which becomes the interstitial carbide of the M-cluster. The methyl group of SAM is mobilized by radical removal of an H by a 5’-deoxyadenosine radical (5’-dA·). Presumably, a transient –CH2· radical is formed that is subsequently incorporated into the metal cluster forming a Fe6-carbide species. The interstitial carbon remains associated with the FeMo cofactor after insertion into the nitrogenase,[8] The central carbon atom has been confirmed by 13C labeling with detection by pulsed EPR spectroscopy.[9] In addition to EPR spectroscopy, X-ray diffractometry was used to verify that there was a central atom in the middle of the FeMo cofactor and x-ray emission spectroscopic studies showed that central atom was carbon due to the 2p→1s carbon-iron transition.[10] The use of X-ray crystallography showed that while the FeMo cofactor is not in its catalytic form, the carbon keeps the structure rigid which helps describe the reactivity of nitrogenase.

Binding of substrates

The location of substrate attachment to the complex has yet to be elucidated. It is believed that the Fe atoms closest to the interstitial carbon participate in substrate activation, but the terminal molybdenum is also a candidate for nitrogen fixation.[11]


  1. ^ G.J. Leigh. Ch. 5 Structure and Spectroscopic Properties of Metallo-sulfur Clusters Nitrogen Fixation at the Millennium. Elsevier Science B. V., Amsterdam, 2002. 209-210. ISBN 9780444509659.
  2. ^ Kim, J; Rees, DC (1992). "Structural models for the metal centers in the nitrogenase molybdenum-iron protein". Science. 257: 1677–82. Bibcode:1992Sci...257.1677K. doi:10.1126/science.1529354.
  3. ^ a b Roat-Malone, R.M. Ch.6 MoFe Protein Structure. Bioinorganic Chemistry. John Wiley & Sons, Inc., Hoboken, New Jersey, 2002. 253-254. ISBN 9780471265337.
  4. ^ Burgess, B. K.; Lowe, D. J. (1996). "Mechanism of Molybdeum Nitrogenase". Chem. Rev. 96: 2983–3011. doi:10.1021/cr950055x.
  5. ^ Harris, T.V.; Szilagyi, R.K. (2011). "Comparative Assessment of the Composition and Charge State of Nitrogenase FeMo-Cofactor". Inorg Chem. 50: 4811–4824. doi:10.1021/ic102446n. PMC 3105220.
  6. ^ Hu, Y. Ribbe (2011). "Biosynthesis of Nitrogenase FeMoco". Coord Chem Rev. 255: 1218–1224. doi:10.1016/j.ccr.2010.11.018. PMC 3077758.
  7. ^ Burgess, C. F.; Jacobs, D. B.; Stiefel, E. I. "Large Scale Purification of High Activity Azotobacter Vinelandii Nitrogenase". Biochimica et Biophysica Acta. 1980 (614): 196–209. doi:10.1016/0005-2744(80)90180-1.
  8. ^ Boal, A. K.; Rosenzweig, A. C. (2012). "A Radical Route for Nitrogenase Carbide Insertion". Science. 337: 1617–1618. Bibcode:2012Sci...337.1617B. doi:10.1126/science.1229088.
  9. ^ Ramaswamy, S (2011). "One Atom Makes All the Difference". Science. 334: 914–915. Bibcode:2011Sci...334..914R. doi:10.1126/science.1215283.
  10. ^ Einsle, O (2014). "Nitrogenase FeMo Cofactor: an Atomic Structure in Three Simple Steps". J. Biol. Inorg. Chem. 19: 737–745. doi:10.1007/s00775-014-1116-7.2.
  11. ^ Hallmen, P. P.; Kästner, J. "N2 Binding to the FeMo-Cofactor of Nitrogenase. Z. Anorg. Allg. Chem. 2014. doi:10.1002/zaac.201400114
Azotobacter vinelandii

Azotobacter vinelandii is Gram-negative diazotroph that can fix nitrogen while grown aerobically. It is a genetically tractable system that is used to study nitrogen fixation. These bacteria are easily cultured and grown.

A. vinelandii is a free-living N2 fixer known to produce many phytohormones and vitamins in soils. It produces fluorescent pyoverdine pigments.The nitrogenase holoenzyme of A. vinelandii has been characterised by X-ray crystallography in both ADP tetrafluoroaluminate-bound and MgATP-bound states. The enzyme possesses molybdenum iron-sulfido cluster cofactors (FeMoco) as active sites, each bearing two pseudocubic iron-sulfido structures.

Bioinorganic chemistry

Bioinorganic chemistry is a field that examines the role of metals in biology. Bioinorganic chemistry includes the study of both natural phenomena such as the behavior of metalloproteins as well as artificially introduced metals, including those that are non-essential, in medicine and toxicology. Many biological processes such as respiration depend upon molecules that fall within the realm of inorganic chemistry. The discipline also includes the study of inorganic models or mimics that imitate the behaviour of metalloproteins.As a mix of biochemistry and inorganic chemistry, bioinorganic chemistry is important in elucidating the implications of electron-transfer proteins, substrate bindings and activation, atom and group transfer chemistry as well as metal properties in biological chemistry.

Bioorganometallic chemistry

Bioorganometallic chemistry is the study of biologically active molecules that contain carbon directly bonded to metals or metalloids. This area straddles the fields of organometallic chemistry, biochemistry, and medicine. It is subset of bioinorganic chemistry (and can be viewed as exogenous biometal uses for molecular biology in such context; i.e. "inorganic" mediums for "organic" uses and processes). Naturally occurring bioorganometallics include enzymes and sensor proteins. Also within this realm is the development of new drugs and imaging agents as well as the principles relevant to the toxicology or organometallic compounds.


Carbon (from Latin: carbo "coal") is a chemical element with symbol C and atomic number 6. It is nonmetallic and tetravalent—making four electrons available to form covalent chemical bonds. It belongs to group 14 of the periodic table. Three isotopes occur naturally, 12C and 13C being stable, while 14C is a radionuclide, decaying with a half-life of about 5,730 years. Carbon is one of the few elements known since antiquity.Carbon is the 15th most abundant element in the Earth's crust, and the fourth most abundant element in the universe by mass after hydrogen, helium, and oxygen. Carbon's abundance, its unique diversity of organic compounds, and its unusual ability to form polymers at the temperatures commonly encountered on Earth enables this element to serve as a common element of all known life. It is the second most abundant element in the human body by mass (about 18.5%) after oxygen.The atoms of carbon can bond together in different ways, termed allotropes of carbon. The best known are graphite, diamond, and amorphous carbon. The physical properties of carbon vary widely with the allotropic form. For example, graphite is opaque and black while diamond is highly transparent. Graphite is soft enough to form a streak on paper (hence its name, from the Greek verb "γράφειν" which means "to write"), while diamond is the hardest naturally occurring material known. Graphite is a good electrical conductor while diamond has a low electrical conductivity. Under normal conditions, diamond, carbon nanotubes, and graphene have the highest thermal conductivities of all known materials. All carbon allotropes are solids under normal conditions, with graphite being the most thermodynamically stable form at standard temperature and pressure. They are chemically resistant and require high temperature to react even with oxygen.

The most common oxidation state of carbon in inorganic compounds is +4, while +2 is found in carbon monoxide and transition metal carbonyl complexes. The largest sources of inorganic carbon are limestones, dolomites and carbon dioxide, but significant quantities occur in organic deposits of coal, peat, oil, and methane clathrates. Carbon forms a vast number of compounds, more than any other element, with almost ten million compounds described to date, and yet that number is but a fraction of the number of theoretically possible compounds under standard conditions. For this reason, carbon has often been referred to as the "king of the elements".

Iron–sulfur protein

Iron–sulfur proteins are proteins characterized by the presence of iron–sulfur clusters containing sulfide-linked di-, tri-, and tetrairon centers in variable oxidation states. Iron–sulfur clusters are found in a variety of metalloproteins, such as the ferredoxins, as well as NADH dehydrogenase, hydrogenases, coenzyme Q – cytochrome c reductase, succinate – coenzyme Q reductase and nitrogenase. Iron–sulfur clusters are best known for their role in the oxidation-reduction reactions of mitochondrial electron transport. Both Complex I and Complex II of oxidative phosphorylation have multiple Fe–S clusters. They have many other functions including catalysis as illustrated by aconitase, generation of radicals as illustrated by SAM-dependent enzymes, and as sulfur donors in the biosynthesis of lipoic acid and biotin. Additionally, some Fe–S proteins regulate gene expression. Fe–S proteins are vulnerable to attack by biogenic nitric oxide, forming dinitrosyl iron complexes. In most Fe–S proteins, the terminal ligands on Fe are thiolate, but exceptions exist.The prevalence of these proteins on the metabolic pathways of most organisms leads some scientists to theorize that iron–sulfur compounds had a significant role in the origin of life in the iron–sulfur world theory.


Molybdenum is a chemical element with symbol Mo and atomic number 42. The name is from Neo-Latin molybdaenum, from Ancient Greek Μόλυβδος molybdos, meaning lead, since its ores were confused with lead ores. Molybdenum minerals have been known throughout history, but the element was discovered (in the sense of differentiating it as a new entity from the mineral salts of other metals) in 1778 by Carl Wilhelm Scheele. The metal was first isolated in 1781 by Peter Jacob Hjelm.Molybdenum does not occur naturally as a free metal on Earth; it is found only in various oxidation states in minerals. The free element, a silvery metal with a gray cast, has the sixth-highest melting point of any element. It readily forms hard, stable carbides in alloys, and for this reason most of world production of the element (about 80%) is used in steel alloys, including high-strength alloys and superalloys.

Most molybdenum compounds have low solubility in water, but when molybdenum-bearing minerals contact oxygen and water, the resulting molybdate ion MoO2−4 is quite soluble. Industrially, molybdenum compounds (about 14% of world production of the element) are used in high-pressure and high-temperature applications as pigments and catalysts.

Molybdenum-bearing enzymes are by far the most common bacterial catalysts for breaking the chemical bond in atmospheric molecular nitrogen in the process of biological nitrogen fixation. At least 50 molybdenum enzymes are now known in bacteria, plants, and animals, although only bacterial and cyanobacterial enzymes are involved in nitrogen fixation. These nitrogenases contain molybdenum in a form different from other molybdenum enzymes, which all contain fully oxidized molybdenum in a molybdenum cofactor. These various molybdenum cofactor enzymes are vital to the organisms, and molybdenum is an essential element for life in all higher eukaryote organisms, though not in all bacteria.

Molybdenum cofactor

Molybdenum cofactor has two meanings, which are sometimes used interchangeably:

Molybdopterin, the organophosphate-dithiolate ligand that binds Mo and W in most molybdenum-containing and tungsten-containing proteins. It contains no molybdenum.

FeMoco, the metal cluster in nitrogenases that contains Fe, Mo, and S.

Nitrogen fixation

Nitrogen fixation is a process by which nitrogen in the air is converted into ammonia (NH3) or related nitrogenous compounds. Atmospheric nitrogen, is molecular dinitrogen (N2), a relatively nonreactive molecule that is metabolically useless to all but a few microorganisms. Biological nitrogen fixation converts N2 into ammonia, which is metabolized by most organisms.

Nitrogen fixation is essential to life because fixed inorganic nitrogen compounds are required for the biosynthesis of all nitrogen-containing organic compounds, such as amino acids and proteins, nucleoside triphosphates and nucleic acids. As part of the nitrogen cycle, it is essential for agriculture and the manufacture of fertilizer. It is also, indirectly, relevant to the manufacture of all chemical compounds that contain nitrogen, which includes explosives, most pharmaceuticals, and dyes.

Nitrogen fixation is carried out naturally in the soil by a wide range of microorganisms termed diazotrophs that include bacteria such as Azotobacter, and archaea. Some nitrogen-fixing bacteria have symbiotic relationships with some plant groups, especially legumes. Looser non-symbiotic relationships between diazotrophs and plants are often referred to as associative, as seen in nitrogen fixation on rice roots. Nitrogen fixation also occurs between some termites and fungi. It also occurs naturally in the air by means of NOx production by lightning.All biological nitrogen fixation is effected by enzymes called nitrogenases. These enzymes contain iron, often with a second metal, usually molybdenum but sometimes vanadium.

Quantum threshold theorem

In quantum computing, the (quantum) threshold theorem (or quantum fault-tolerance theorem), proved by Michael Ben-Or and Dorit Aharonov (along with other groups), states that a quantum computer with a physical error rate below a certain threshold can, through application of quantum error correction schemes, suppress the logical error rate to arbitrarily low levels. Current estimates put the threshold for the surface code on the order of 1%, though estimates range widely and are difficult to calculate due to the exponential difficulty of simulating large quantum systems. At a 0.1% probability of a depolarizing error, the surface code would require approximately 1,000-10,000 physical qubits per logical data qubit, though more pathological error types could change this figure drastically.

According to leading quantum information theorist Scott Aaronson:"The entire content of the Threshold Theorem is that you're correcting errors faster than they're created. That's the whole point, and the whole non-trivial thing that the theorem shows. That's the problem it solves."

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