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Formate dehydrogenase N, transmembrane
Identifiers
SymbolForm-deh_trans
PfamPF09163
InterProIPR015246
SCOP21kqf / SCOPe / SUPFAM
OPM superfamily3
OPM protein1kqf
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary
PDB1kqfB:246-289 1kqgB:246-289

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 1.2.1.2) or to a cytochrome in formate:ferricytochrome-b1 oxidoreductase (EC 1.2.2.1).[1]

Function

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NAD-dependent formate dehydrogenases are important in methylotrophic yeast and bacteria and are vital in the catabolism of C1 compounds such as methanol.[2] The cytochrome-dependent enzymes are more important in anaerobic metabolism in prokaryotes.[3] 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.[4][5]

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

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One of the enzymes in the oxidoreductase family that sometimes employ tungsten (bacterial formate dehydrogenase H) is known to use a selenium-molybdenum version of molybdopterin.[6]

Transmembrane domain

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The transmembrane domain of the beta subunit of formate dehydrogenase consists of a single transmembrane helix. This domain acts as a transmembrane anchor, allowing the conduction of electrons within the protein.[7]

***Mr. Senfai's Sandbox (prior to incorporation into current stub article)

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Formate dehydrogenase (FDH) is a key enzyme in formate metabolism in bacteria.[8] It belongs to the superfamily of D-specific 2-hydroxy acid dehydrogenases.[9] These heterogeneous enzymes catalyze the reversible 2-electron oxidation of formate to carbon dioxide, as shown in the following equation:[8][10]

CO2 + 2e- + H+ ⇌ HCOO- , Eo' = -420 mV.

The most common FDH in anaerobic microorganisms is an enzyme containing molybdenum- (Mo) or tungsten- (W) cofactor. They are involved in several pathways for prokaryotic energy metabolism, catalyzing the electron transfer to and from various electron acceptors and donors. The enzyme's ability to reduce carbon dioxide is of great interest for carbon sequestration and for the production of formic acid as a safe and stable form of hydrogen fuel.[8][10][11]

Classes of FDH

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Formate dehydrogenase can be divided into two major classes: metal-independent and metal-containing. The assigned class is based on their metal content, structure, and catalytic strategies.[8][11]

The metal-independent FDH class comprises the NAD+-dependent FDH belonging to the 2-oxyacid family of D-specific dehydrogenases. These enzymes can be found in aerobic bacteria, yeasts, plants, and fungi. They have no metal ions or redox cofactors, and as such, their formate oxidation to CO2 has been suggested to involve a direct hydride transfer from formate to NAD+. This is performed by a protein that positions the formate and NAD+ in close proximity to one another, followed by NAD+ acquiring a bipolar form during the transition state of the reaction. This change in conformation leads to increased electrophilicity of NAD+, thereby facilitating the rate-limiting hydride transfer step.[11]

The metal-containing FDH class comprises prokaryotic FDH belonging to the W and Mo-containing enzymes' families. This class is composed of complex proteins holding different redox cofactors, and whose active site holds either a W or Mo atom that mediates the transfer of protons and electrons in formate oxidation. These enzymes use NAD+ only as the terminal electron acceptor (co-substrate).[11]

Families of enzymes containing Mo and W

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Molybdenum is most often found in the active site of enzymes in a mononuclear form. It is coordinated by the cis-dithiolene group of one to two pyranopterin cofactor molecules, as well as by sulfur, oxygen, or selenium atoms. The coordination of the atom classifies the molybdoenzymes into three big families: xanthine oxidase, sulfite oxidase, and dimethylsulfoxide reductase (DMSOR) families. The DMSOR family is the largest family and comprises prokaryotic enzymes of different structures and functions such as DMSOR itself and Mo-FDH. The DMSOR family of enzymes hold a trigonal prismatic core in their oxidized forms.[11]

Tungsten, like molybdenum, is also found in the active site of enzymes in a mononuclear form. It is coordinated by the cis-dithiolene group of two molecules of the same pyranopterin cofactor found on molybdoenzymes. The coordination sphere of tungsten is completed with oxygen and/or sulfur atoms from amino acid residue side chains or from terminal groups, and is held in a trigonal prismatic geometry similar to the DMSOR family of enzymes. Tungstoenzymes can be grouped into a single family that comprises all the tungsten-pyranopterin-containing enzymes, including aldehyde:ferredoxin oxidoreductases and W-FDH.[11]

The enzymes of all families catalyze the transfer of an oxygen atom from water to the product, or from the substrate to water. A net exchange of two electrons is implied in which the Mo or W cycles between Mo4+ and Mo6+ or W4+ and W6+. The electrons derived from or those needed to carry out the catalysis are intramolecularly transferred from the electron donor, or to the electron acceptor, via different redox centres such as iron-sulfur (Fe-S) clusters, flavins, and haems.[11]

In prokaryotic FDHs, every biochemical pathway they're involved in requires specific enzymatic machinery. These heterogeneous proteins have membrane-bound enzymes that are docked at the membrane and interact with membrane-associated electron acceptors. There are also cytoplasmatic and periplasmatic enzymes that need an appropriate interface to use ferredoxins, cytochromes, NAD, or coenzyme F420 as electron acceptors. As a result, FDHs display diverse redox centres, as well as complex quaternary structures and subunit compositions.[11]

Spectroscopic properties of Mo-FDH and W-FDH

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FDHs have been explored using several spectroscopic methods, particularly X-ray absorption spectroscopy XAS and electron paramagnetic resonance (EPR) spectroscopy.[10][11] Studies on oxidized E. coli FDH-H and the D. desulfuricans enzyme by molybdenum K-edge XAS and X-ray crystallography points towards a molybdenum centre containing a hydroxyl group, coordinated to a selenocysteine. However, selenium K-edge data obtained with dithionite-reduced FDH-H points towards an Se-S bond. EPR studies on the molybdenum centre of the formate-reduced E. coli FDH-H revealed an anisotropic, nearly axial Mo5+, suggesting a square-pyramidal geometry for the reduced Mo species. A high hyperfine coupling constant could be observed with 77Se-labelled enzyme suggesting a coordination of the selenocysteine directly to the Mo. All of the spectroscopic data suggests a global coordination, with an apical selenium atom from the selenocysteine at the top of the pyramid, coordinated by four sulfur atoms of the two pyranopterin guanosine dinucleotide (PGD) cofactor molecules at the bottom. EPR spectroscopy has also demonstrated the incorporation of either molybdenum or tungsten in D. alaskensis FDH, one of the few examples where an enzyme of the Mo/W-bis PGD family can retain activity even after the incorporation of both metal atoms.[11]

Mechanism for formate handling in Mo-FDH and W-FDH

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FDH-catalyzed oxidation of formate occurs at the enzyme's Mo or W centre. FDH has to abstract one proton and two electrons from formate in order to form carbon dioxide. Different reaction mechanisms for formate oxidation have been proposed. Overall, the mechanism is believed to be similar in both Mo-FDH and W-FDH, as molybdenum and tungsten both share very similar chemical properties.[11]

The first proposed mechanism assumes the coordination of an Mo atom by a hydroxyl group, rather than a terminal sulfur atom. In this mechanistic approach, the conserved histidine and arginine roles would be to facilitate formate binding, and the histidine residue would act as the final proton acceptor. The Mo terminal sulfo ligand would have no active role in formate oxidation.[8][11]

The second proposed mechanistic model involves the selenocysteine dissociating from the molybdenum via sulfur-shift. In this approach, the conserved and positively charged arginine has a key role in driving the formate anion into the active site, as well as subsequent binding to the Mo at the correct position. The arginine would also play a role in product release. The conserved histidine would facilitate the formate proton abstraction by the selenocysteine by lowering the activation energy for the selenocysteine dissociation via formation of a hydrogen bond with the selenol anion.[8][11]

The third mechanistic model proposed involves the formate oxidation occurring via the initial hydride transfer from formate to the Mo atom, resulting in the formation of an Mo-H intermediate followed by a proton transfer from Mo to the selenocysteine. In this proposal, the Mo centre is given a key role in mediating the proton transfer from formate to the selenocysteine.[8][11]

FDH-catalyzed CO2 reduction

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FDH-catalyzed formate oxidation is a reversible reaction and several FDHs are able to catalyze the reduction of CO2 either in vivo or in vitro. W-FDHs are suggested to be more efficient at reducing CO2 than their Mo-FDH counterparts due to the lower reduction potential of W4+ compared to that of Mo4+.[11]

Applications and future work

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FDH is widely accepted as a model enzyme in the study of the hydride ion transfer mechanism in the active centre of dehydrogenases. The reaction catalyzed by the enzyme has no proton transfer steps, implying a substrate with a relatively simple structure.[9]

The FDH enzyme's ability to reduce CO2 is of great interest for the sequestration of carbon and the production of formic acid as a safe and stable form of hydrogen fuel, increasing biotechnological interest in FDHs tremendously. These enzymes have advantages over chemical catalysts due to being specific and yielding only one product, formate, and of working as homogeneous catalysts.[8][10][11] There is an issue of long-term stability of the FDH enzyme as well as slow reaction rates that would need to be addressed for future commercial applications. Furthermore, the dioxygen sensitivity of FDH is a major bottleneck in the advancement of FDHs for use in biotechnological applications.[8][11]

A future goal is to produce formate from CO2 and protons through the use of bacterial FDHs.[8]

FDHs can be used as biocatalysts for the regeneration of NADH in enzymatic syntheses of optically active compounds with dehydrogenases, but at a steep cost. This cost can be decreased by increasing the operational stability of FDH, improving its kinetic properties, and by decreasing the price of its production and storage.[9]

Further data collection on the structure of FDHs and of different mutant FDHs will aid in explaining how fine differences in the structures of closely related FDH enzymes influence their stability, as well as their kinetic and regulatory properties.[9]

See also

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References

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  1. ^ Ferry JG (1990). "Formate dehydrogenase". FEMS Microbiol. Rev. 7 (3–4): 377–82. doi:10.1111/j.1574-6968.1990.tb04940.x. PMID 2094290.
  2. ^ Popov VO, Lamzin VS (1994). "NAD(+)-dependent formate dehydrogenase". Biochem. J. 301 (3): 625–43. doi:10.1042/bj3010625. PMC 1137035. PMID 8053888.
  3. ^ Jormakka M, Byrne B, Iwata S (2003). "Formate dehydrogenase--a versatile enzyme in changing environments". Curr. Opin. Struct. Biol. 13 (4): 418–23. doi:10.1016/S0959-440X(03)00098-8. PMID 12948771.
  4. ^ Graham A, Boxer DH (1981). "The organization of formate dehydrogenase in the cytoplasmic membrane of Escherichia coli". Biochem. J. 195 (3): 627–37. doi:10.1042/bj1950627. PMC 1162934. PMID 7032506.
  5. ^ Ruiz-Herrera J, DeMoss JA (1969). "Nitrate reductase complex of Escherichia coli K-12: participation of specific formate dehydrogenase and cytochrome b1 components in nitrate reduction". J. Bacteriol. 99 (3): 720–9. doi:10.1128/JB.99.3.720-729.1969. PMC 250087. PMID 4905536.
  6. ^ Khangulov SV, Gladyshev VN, Dismukes GC, Stadtman TC (1998). "Selenium-Containing Formate Dehydrogenase H from Escherichia coli: A Molybdopterin Enzyme That Catalyzes Formate Oxidation without Oxygen Transfer". Biochemistry. 37 (10): 3518–3528. doi:10.1021/bi972177k. PMID 9521673.
  7. ^ Jormakka M, Törnroth S, Byrne B, Iwata S (2002). "Molecular basis of proton motive force generation: structure of formate dehydrogenase-N". Science. 295 (5561): 1863–1868. doi:10.1126/science.1068186. PMID 11884747. S2CID 30645871.
  8. ^ a b c d e f g h i j Hartmann, Tobias; Schwanhold, Nadine; Leimkühler, Silke (December 2014). "Assembly and catalysis of molybdenum or tungsten-containing formate dehydrogenases from bacteria". Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics. 1854 (9): 1090–1100. doi:10.1016/j.bbapap.2014.12.006. PMID 25514355.
  9. ^ a b c d Tishkov, VI; Popov, VO (November 2004). "Catalytic mechanism and application of formate dehydrogenase". Biochemistry. Biokhimiia. 69 (11): 1252–67. doi:10.1007/s10541-005-0071-x. PMID 15627379. S2CID 24790696.
  10. ^ a b c d Gonzalez, Pablo J.; Rivas, Maria G.; Mota, Cristiano S.; Brondino, Carlos D.; Moura, Isabel; Moura, José J.G. (January 2013). "Periplasmic nitrate reductases and formate dehydrogenases: Biological control of the chemical properties of Mo and W for fine tuning of reactivity, substrate specificity and metabolic role". Coordination Chemistry Reviews. 257 (2): 315–331. doi:10.1016/j.ccr.2012.05.020.
  11. ^ a b c d e f g h i j k l m n o p q Maia, Luisa B.; Moura, José J. G.; Moura, Isabel (5 December 2014). "Molybdenum and tungsten-dependent formate dehydrogenases". JBIC Journal of Biological Inorganic Chemistry. 20 (2): 287–309. doi:10.1007/s00775-014-1218-2. PMID 25476858. S2CID 16590962.
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Category:Cellular respiration Category:Metabolism Category:EC 1.2.2 Category:EC 1.2.1


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