formate dehydrogenase

NAD-dependent formate dehydrogenases are important in methylotrophic yeast and bacteria, being vital in the catabolism of C1 compounds such as methanol.{{cite journal | vauthors = Popov VO, Lamzin VS | title = NAD(+)-dependent formate dehydrogenase | journal = Biochem. J. | volume = 301 | issue = 3 | pages = 625–43 | year = 1994 | doi = 10.1042/bj3010625 | pmid = 8053888 | pmc = 1137035 }} The cytochrome-dependent enzymes are more important in anaerobic metabolism in prokaryotes.{{cite journal | vauthors = Jormakka M, Byrne B, Iwata S | title = Formate dehydrogenase--a versatile enzyme in changing environments | journal = Curr. Opin. Struct. Biol. | volume = 13 | issue = 4 | pages = 418–23 | year = 2003 | pmid = 12948771 | doi = 10.1016/S0959-440X(03)00098-8 }} 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.{{cite journal | vauthors = Graham A, Boxer DH | title = The organization of formate dehydrogenase in the cytoplasmic membrane of Escherichia coli | journal = Biochem. J. | volume = 195 | issue = 3 | pages = 627–37 | year = 1981 | doi = 10.1042/bj1950627 | pmid = 7032506 | pmc = 1162934 }}{{cite journal | vauthors = Ruiz-Herrera J, DeMoss JA | title = Nitrate reductase complex of Escherichia coli K-12: participation of specific formate dehydrogenase and cytochrome b1 components in nitrate reduction | journal = J. Bacteriol. | volume = 99 | issue = 3 | pages = 720–9 | year = 1969 | doi = 10.1128/JB.99.3.720-729.1969 | pmid = 4905536 | pmc = 250087 }}

NAD-dependent reaction

Formate + NAD⁺ {{eqm}} CO₂ + NADH + H⁺

Cytochrome-dependent reaction

Formate + 2 ferricytochrome b1 {{eqm}} CO₂ + 2 ferrocytochrome b1 + 2 H⁺

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.{{cite journal |doi=10.1021/acs.chemrev.1c00914|title=Second and Outer Coordination Sphere Effects in Nitrogenase, Hydrogenase, Formate Dehydrogenase, and CO Dehydrogenase |year=2022 |last1=Stripp |first1=Sven T. |last2=Duffus |first2=Benjamin R. |last3=Fourmond |first3=Vincent |last4=Léger |first4=Christophe |last5=Leimkühler |first5=Silke |last6=Hirota |first6=Shun |last7=Hu |first7=Yilin |last8=Jasniewski |first8=Andrew |last9=Ogata |first9=Hideaki |last10=Ribbe |first10=Markus W. |journal=Chemical Reviews |volume=122 |issue=14 |pages=11900–11973 |pmid=35849738 |pmc=9549741 }}

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

:{{chem2|S\dM^{VI}(Scys)(SR)4 + HCO2- <-> HS\sM^{IV}(Scys)(SR)4 + CO2}}

:{{chem2|S\dM^{VI}(Secys)(SR)4 + HCO2- <-> HS\sM^{IV}(Secys)(SR)4 + CO2}}

In this scheme, {{chem2|(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.{{cite journal |doi=10.3390/molecules27185989|doi-access=free |title=Formate Dehydrogenase Mimics as Catalysts for Carbon Dioxide Reduction |year=2022 |last1=Fogeron |first1=Thibault |last2=Li |first2=Yun |last3=Fontecave |first3=Marc |journal=Molecules |volume=27 |issue=18 |page=5989 |pmid=36144724 |pmc=9506188 }}

File:Formate Dehydrogenase 1kqf overall protein 1 (KC).png

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.{{Cite journal|last=Stiefel|first=Edward|date=2002-03-31|title=Faculty Opinions recommendation of Molecular basis of proton motive force generation: structure of formate dehydrogenase-N.|doi=10.3410/f.1004770.61154 |doi-access=free }}

File:Colored_electron_tunneling_F-DHN.jpg

{{Portal|Biology}}

• Formate dehydrogenase (cytochrome)
• Formate dehydrogenase (cytochrome-c-553)
• Formate dehydrogenase (NADP+)
• Microbial metabolism

• {{cite journal | vauthors = Ferry JG | title = Formate dehydrogenase | journal = FEMS Microbiol. Rev. | volume = 7 | issue = 3–4 | pages = 377–82 | year = 1990 | pmid = 2094290 | doi=10.1111/j.1574-6968.1990.tb04940.x| doi-access = free }}

{{reflist}}

• [http://us.expasy.org/enzyme/1.2.2.1 ENZYME link for EC 1.2.2.1]
• [http://us.expasy.org/enzyme/1.2.1.2 ENZYME link for EC 1.2.1.2]

{{Electron transport chain}}

{{Cellular respiration}}

{{Aldehyde/Oxo oxidoreductases}}

{{Enzymes}}

Category:Cellular respiration

Category:Metabolism

Category:EC 1.2.2

Category:EC 1.2.1