Formate dehydrogenases are a set of enzymes that catalyse the oxidation of formate to carbon dioxide, donating the electrons to a second substrate, such as NAD⁺ in formate:NAD+ oxidoreductase (EC 1.17.1.9) or to a cytochrome in formate:ferricytochrome-b1 oxidoreductase (EC 1.2.2.1). This family of enzymes has attracted attention as inspiration or guidance on methods for the carbon dioxide fixation, relevant to global warming.

Function

NAD-dependent formate dehydrogenases are important in methylotrophic yeast and bacteria, being vital in the catabolism of C1 compounds such as methanol. The cytochrome-dependent enzymes are more important in anaerobic metabolism in prokaryotes. For example, in E. coli, the formate:ferricytochrome-b1 oxidoreductase is an intrinsic membrane protein with two subunits and is involved in anaerobic nitrate respiration.

NAD-dependent reaction

Formate + NAD⁺ ⇌ CO₂ + NADH + H⁺

Cytochrome-dependent reaction

Formate + 2 ferricytochrome b1 ⇌ CO₂ + 2 ferrocytochrome b1 + 2 H⁺

Molybdopterin, molybdenum and selenium dependence

The metal-dependent Fdh's feature Mo or W at their active sites. These active sites resemble the motif seen in DMSO reductase, with two molybdopterin cofactors bound to Mo/W in a bidentate fashion. The fifth and sixth ligands are sulfide and either cysteinate or selenocysteinate.

The mechanism of action appears to involve 2e redox of the metal centers, induced by hydride transfer from formate and release of carbon dioxide:

S=M^VI(Scys)(SR)₄ + HCO−2 ⇌ HS−M^IV(Scys)(SR)₄ + CO₂

S=M^VI(Secys)(SR)₄ + HCO−2 ⇌ HS−M^IV(Secys)(SR)₄ + CO₂

In this scheme, (SR)₄ represents the four thiolate-like ligands provided by the two dithiolene cofactors, the molybdopterins. The dithiolene and cysteinyl/selenocysteinyl ligands are redox-innocent. In terms of the molecular details, the mechanism remains uncertain, despite numerous investigations. Most mechanisms assume that formate does not coordinate to Mo/W, in contrast to typical Mo/W oxo-transferases (e.g., [[dmso reductase). A popular mechanistic proposal entails transfer of H^- from formate to the Mo/W^VI=S group.

Formate Dehydrogenase (PDB 1KQF, 1.6 A resolution, from E. coli); overall view of the electron transport chain showing the [Fe4S4] clusters in the periplasmic alpha and beta subunits, and the cytoplasmic gamma subunit showing the Fe(heme b)P and the Fe-(heme b)C menoquinone binding site where an HQNO ligand is bound close the Fe(heme b)C. Atom colours: Fe = orange, S = yellow, C = grey, O = red, N = blue.

Transmembrane domain

Formate dehydrogenase consists of two transmembrane domains; three α-helices of the β-subunit and four transmembrane helices from the gamma-subunit.

The β-subunit of formate dehydrogenase is present in the periplasm with a single transmembrane α-helix spanning the membrane by anchoring the β-subunit to the inner-membrane surface. The β-subunit has two subdomains, where each subdomain has two [4Fe-4S] ferredoxin clusters. The judicious alignment of the [4Fe-4S] clusters in a chain through the subunit have low separation distances, which allow rapid electron flow through [4Fe-4S]-1, [4Fe-4S]-4, [4Fe-4S]-2, and [4Fe-4S]-3 to the periplasmic heme b in the γ-subunit. The electron flow is then directed across the membrane to a cytoplasmic heme b in the γ-subunit .

The γ-subunit of formate dehydrogenase is a membrane-bound cytochrome b consisting of four transmembrane helices and two heme b groups which produce a four-helix bundle which aids in heme binding. The heme b cofactors bound to the gamma subunit allow for the hopping of electrons through the subunit. The transmembrane helices maintain both heme b groups, while only three provide the heme ligands thereby anchoring Fe-heme. The periplasmic heme b group accepts electrons from [4Fe-4S]-3 clusters of the β-subunit’s periplasmic domain. The cytoplasmic heme b group accepts electrons from the periplasmic heme b group, where electron flow is then directed towards the menaquinone (vitamin K) reduction site, present in the transmembrane domain of the gamma subunit. The menaquinone reduction site in the γ-subunit, accepts electrons through the binding of a histidine ligand of the cytoplasmic heme b.

Menaquinone binding site alongside proposed water proton pathway

Additional reading

Ferry JG (1990). "Formate dehydrogenase". FEMS Microbiol. Rev. 7 (3–4): 377–82. doi:10.1111/j.1574-6968.1990.tb04940.x. PMID 2094290.

Metabolism: Citric acid cycle enzymes

Cycle

Citrate synthase
Aconitase
Isocitrate dehydrogenase
Oxoglutarate dehydrogenase
Succinyl CoA synthetase

Succinate dehydrogenase (SDHA)
Fumarase
Malate dehydrogenase and ETC

Anaplerotic

to acetyl-CoA	Pyruvate dehydrogenase complex (E1, E2, E3) (regulated by Pyruvate dehydrogenase kinase and Pyruvate dehydrogenase phosphatase)
to α-ketoglutaric acid	Glutamate dehydrogenase
to succinyl-CoA	Methylmalonyl-CoA mutase
to oxaloacetic acid	Pyruvate carboxylase Aspartate transaminase

Mitochondrial
electron transport chain/
oxidative phosphorylation

Primary	Complex I/NADH dehydrogenase Complex II/Succinate dehydrogenase Coenzyme Q₁₀ (CoQ10) Complex III/Coenzyme Q - cytochrome c reductase Cytochrome c Complex IV/Cytochrome c oxidase Coenzyme Q₁₀ synthesis: COQ2 COQ3 COQ4 COQ5 COQ6 COQ7 COQ9 COQ10A COQ10B PDSS1 PDSS2
Other	Alternative oxidase Electron-transferring-flavoprotein dehydrogenase

Metabolism, catabolism, anabolism

General

Metabolic pathway
Metabolic network
Primary nutritional groups

Energy
metabolism

Aerobic respiration	Glycolysis → Pyruvate decarboxylation → Citric acid cycle → Oxidative phosphorylation (electron transport chain + ATP synthase)
Anaerobic respiration	Electron acceptors other than oxygen
Fermentation	Glycolysis → Substrate-level phosphorylation ABE Ethanol Lactic acid

Specific
paths

Protein metabolism

Carbohydrate metabolism
(carbohydrate catabolism
and anabolism)

Human

Glycolysis ⇄ Gluconeogenesis
Glycogenolysis ⇄ Glycogenesis
Pentose phosphate pathway Fructolysis Galactolysis
Glycosylation N-linked O-linked

Nonhuman

Photosynthesis Anoxygenic photosynthesis Chemosynthesis Carbon fixation
Xylose metabolism Radiotrophism

Lipid metabolism
(lipolysis, lipogenesis)

Fatty acid metabolism	Fatty acid degradation (Beta oxidation) Fatty acid synthesis
Other	Steroid metabolism Sphingolipid metabolism Eicosanoid metabolism Ketosis Reverse cholesterol transport

Amino acid

Amino acid synthesis
Urea cycle

Nucleotide
metabolism

Purine metabolism
Nucleotide salvage
Pyrimidine metabolism

Other

v t e Aldehyde/oxo oxidoreductases (EC 1.2)
1.2.1: NAD or NADP	Aldehyde dehydrogenase Acetaldehyde dehydrogenase Long-chain-aldehyde dehydrogenase Mycothiol-dependent formaldehyde dehydrogenase
1.2.2: cytochrome	Formate dehydrogenase (cytochrome)
1.2.3: oxygen	Aldehyde oxidase
1.2.4: disulfide	Oxoglutarate dehydrogenase complex Pyruvate dehydrogenase Branched-chain alpha-keto acid dehydrogenase complex BCKDHA BCKDHB DBT DLD
1.2.7: iron–sulfur protein	Pyruvate synthase

v t e Enzymes
Activity	Active site Binding site Catalytic triad Oxyanion hole Enzyme promiscuity Diffusion-limited enzyme Coenzyme Cofactor Enzyme catalysis
Regulation	Allosteric regulation Cooperativity Enzyme inhibitor Enzyme activator
Classification	EC number Enzyme superfamily Enzyme family List of enzymes
Kinetics	Enzyme kinetics Eadie–Hofstee diagram Hanes–Woolf plot Lineweaver–Burk plot Michaelis–Menten kinetics
Types	EC1 Oxidoreductases (list) EC2 Transferases (list) EC3 Hydrolases (list) EC4 Lyases (list) EC5 Isomerases (list) EC6 Ligases (list) EC7 Translocases (list)

Formate dehydrogenase

Function

Molybdopterin, molybdenum and selenium dependence

Transmembrane domain

See also

Additional reading

External links