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MetaCyc Pathway: reductive acetyl coenzyme A pathway
Inferred from experiment

Pathway diagram: reductive acetyl coenzyme A pathway

If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.

Synonyms: Wood pathway, acetate synthesis, acetyl-CoA pathway, carbon monoxide dehydrogenase pathway, carbon fixation, CO2 fixation, Ljungdahl-Wood pathway, Wood-Ljungdahl pathway, reductive acetyl CoA pathway

Superclasses: Degradation/Utilization/AssimilationC1 Compounds Utilization and AssimilationCO2 FixationAutotrophic CO2 Fixation

Some taxa known to possess this pathway include : Acetitomaculum ruminis, Acetobacterium carbinolicum, Acetobacterium woodii, Blautia producta, Clostridium formicaceticum, Eubacterium limosum, Methanothermobacter thermautotrophicus, Moorella thermoacetica, Moorella thermoautotrophica, Sporomusa malonica, Sporomusa termitida, Syntrophococcus sucromutans, [Butyribacterium] methylotrophicum

Expected Taxonomic Range: Archaea, Bacteria

This pathway describes autotrophic production of acetyl-CoA from two CO2 molecules. The pathway has been documented in several types of organisms, including homoacetogenic bacteria and methanogenic archaea [Jansen82, Stupperich83]. Homoacetogenic bacteria are strict anaerobes that can synthesize acetate from H2 and CO2 [Diekert94, Ljungdahl86].

Two key enzymes in this pathway activate CO2. One enzyme is NADP-dependent formate dehydrogenase, which reduces CO2 to formate, and the second is carbon monoxide dehydrogenase, which reduces CO2 to carbon monoxide.

The formate formed by NADP-dependent formate dehydrogenase is incorporated into tetrahydropteroyl mono-L-glutamate, and goes through a series of rearrangements resulting in the formation of a methyl group, in the form of N5-methyl-tetrahydropteroyl mono-L-glutamate. This methyl group then reacts with the CO formed by carbon monoxide dehydrogenase, producing acetyl-CoA, which is then used for carbohydrate synthesis in methanogens (see gluconeogenesis II (Methanobacterium thermoautotrophicum)) or converted to acetate in acetogenic bacteria (see Acetate Formation).

The pathway ends with the formation of acetate from acetyl-CoA via acetyl phosphate in an ATP-generating reaction (see acetate formation from acetyl-CoA I). Since all of the ATP that is formed by EC, acetate kinase is consumed by EC, formate—tetrahydrofolate ligase, growth with H2 and CO2 is only possible if the pathway is coupled to electron-transport phosphorylation. Of the redox reactions involved only the reduction of 5,10-methylenetetrahydropteroyl mono-L-glutamate to N5-methyl-tetrahydropteroyl mono-L-glutamate (E0' = -200 mV) [Wohlfarth91] with H2 (E0' = -414 mV) is exergonic enough to be coupled with energy conservation [Hugenholtz90, Buckel13].

In Clostridium formicaceticum the MetVF proteins interact with ferredoxin [Clark84]. Cell extracts of Acetobacterium woodii show methylene-H4F reductase activity with NADH [Buchenau01], and the metFV genes that encode methylene-H4F reductase in that organism are clustered with rnfC2 gene, which encodes an NADH dehydrogenase. In Moorella thermoacetica the MetVF proteins form a complex with HdrCBA and MvhD proteins, suggesting some sort of electron bifurcation [Mock14]. Thus, it seems that different acetogens, although all of them use the Wood-Ljungdahl pathway of CO2 reduction to acetic acid, have evolved different ways to directly or indirectly conserve the energy associated with methylene-H4F reduction [Mock14].

This pathway operates in the opposite direction in sulfate reducing bacteria, where electrons originating from organic molecules are shuttled via acetyl-CoA to NADH, oxidizing acetyl-CoA to CO2 [Rabus06].

Superpathways: Methanobacterium thermoautotrophicum biosynthetic metabolism, gluconeogenesis II (Methanobacterium thermoautotrophicum)

Created 21-Oct-1999 by Pellegrini-Toole A, Marine Biological Laboratory
Revised 08-Mar-2007 by Caspi R, SRI International
Revised 12-Aug-2014 by Caspi R, SRI International


Buchenau01: Buchenau B. (2001). "Are there tetrahydrofolate specific enzymes in methanogenic archaea and tetrahydromethanopterin specific enzymes in acetogenic bacteria?." Diploma thesis. Philipps University, Marburg, Germany.

Buckel13: Buckel W, Thauer RK (2013). "Energy conservation via electron bifurcating ferredoxin reduction and proton/Na(+) translocating ferredoxin oxidation." Biochim Biophys Acta 1827(2);94-113. PMID: 22800682

Clark84: Clark JE, Ljungdahl LG (1984). "Purification and properties of 5,10-methylenetetrahydrofolate reductase, an iron-sulfur flavoprotein from Clostridium formicoaceticum." J Biol Chem 259(17);10845-9. PMID: 6381490

Diekert94: Diekert G, Wohlfarth G (1994). "Metabolism of homocetogens." Antonie Van Leeuwenhoek 1994;66(1-3);209-21. PMID: 7747932

Hugenholtz90: Hugenholtz J, Ljungdahl LG (1990). "Metabolism and energy generation in homoacetogenic clostridia." FEMS Microbiol Rev 7(3-4);383-9. PMID: 2094291

Jansen82: Jansen, K., Stupperich, E., Fuchs, G. (1982). "Carbohydrate synthesis from acetyl CoA in the autotroph Methanobacterium thermoautotrophicum." Archives of Microbiology 132(4): 355-364.

Ljungdahl86: Ljungdahl LG (1986). "The autotrophic pathway of acetate synthesis in acetogenic bacteria." Annu Rev Microbiol 1986;40;415-50. PMID: 3096193

Mock14: Mock J, Wang S, Huang H, Kahnt J, Thauer RK (2014). "Evidence for a Hexaheteromeric Methylenetetrahydrofolate Reductase in Moorella thermoacetica." J Bacteriol. PMID: 25002540

Rabus06: Rabus, R., Hansen, T. A., Widdel, F. (2006). "Dissimilatory Sulfate- and Sulfur-Reducing Prokaryotes." Prokaryotes 2:659-768.

Stupperich83: Stupperich E, Hammel KE, Fuchs G, Thauer RK (1983). "Carbon monoxide fixation into the carboxyl group of acetyl coenzyme A during autotrophic growth of Methanobacterium." FEBS Lett 152(1);21-3. PMID: 6840273

Wohlfarth91: Wohlfarth G, Diekert G (1991). "Thermodynamics of methylenetetrahydrofolate reduction to methyltetrahydrofolate and its implications for the energy metabolism of homoacetogenic bacteria." Archives of Microbiology 155(4);NIL-NIL.

Other References Related to Enzymes, Genes, Subpathways, and Substrates of this Pathway

Andreesen74: Andreesen JR, Ljungdahl LG (1974). "Nicotinamide adenine dinucleotide phosphate-dependent formate dehydrogenase from Clostridium thermoaceticum: purification and properties." J Bacteriol 1974;120(1);6-14. PMID: 4154039

BRENDA14: BRENDA team (2014). Imported from BRENDA version existing on Aug 2014.

Chen97: Chen L, Chan SY, Cossins EA (1997). "Distribution of Folate Derivatives and Enzymes for Synthesis of 10-Formyltetrahydrofolate in Cytosolic and Mitochondrial Fractions of Pea Leaves." Plant Physiol 115(1);299-309. PMID: 12223808

Chen99: Chen L, Nargang FE, Cossins EA, (1999) "Isolation and sequencing of a plant cDNA encoding a bifunctional methylenetetrahydrofolate dehydrogenase:methenyltetrahydrofolate cyclohydrolase protein." Pteridines (1999), 10, 171-177.

Cheung97: Cheung E, D'Ari L, Rabinowitz JC, Dyer DH, Huang JY, Stoddard BL (1997). "Purification, crystallization, and preliminary x-ray studies of a bifunctional 5,10-methenyl/methylene-tetrahydrofolate cyclohydrolase/dehydrogenase from Escherichia coli." Proteins 27(2);322-4. PMID: 9061797

Curthoys72: Curthoys NP, Scott JM, Rabinowitz JC (1972). "Folate coenzymes of Clostridium acidi-urici. The isolation of (l)-5,10-methenyltetrahydropteroyltriglutamate, its conversion to (l)-tetrahydropteroyltriglutamate and (l)-10-( 14 C)formyltetrahydropteroyltriglutamate, and the synthesis of (l)-10-formyl-(6,7- 3 H 2 )tetrahydropteroyltriglutamate and (l)-(6,7- 3 H 2 )tetrahydropteroyltriglutamate." J Biol Chem 247(7);1959-64. PMID: 5016637

DAri91: D'Ari L, Rabinowitz JC (1991). "Purification, characterization, cloning, and amino acid sequence of the bifunctional enzyme 5,10-methylenetetrahydrofolate dehydrogenase/5,10-methenyltetrahydrofolate cyclohydrolase from Escherichia coli." J Biol Chem 1991;266(35);23953-8. PMID: 1748668

Dev78a: Dev IK, Harvey RJ (1978). "A complex of N5,N10-methylenetetrahydrofolate dehydrogenase and N5,N10-methenyltetrahydrofolate cyclohydrolase in Escherichia coli. Purification, subunit structure, and allosteric inhibition by N10-formyltetrahydrofolate." J Biol Chem 1978;253(12);4245-53. PMID: 350870

Drake81: Drake HL, Hu SI, Wood HG (1981). "Purification of five components from Clostridium thermoaceticum which catalyze synthesis of acetate from pyruvate and methyltetrahydrofolate. Properties of phosphotransacetylase." J Biol Chem 1981;256(21);11137-44. PMID: 7287757

Goenrich02: Goenrich M, Bursy J, Hubner E, Linder D, Schwartz AC, Vorholt JA (2002). "Purification and characterization of the methylene tetrahydromethanopterin dehydrogenase MtdB and the methylene tetrahydrofolate dehydrogenase FolD from Hyphomicrobium zavarzinii ZV580." Arch Microbiol 177(4);299-303. PMID: 11889483

Guenther99: Guenther BD, Sheppard CA, Tran P, Rozen R, Matthews RG, Ludwig ML (1999). "The structure and properties of methylenetetrahydrofolate reductase from Escherichia coli suggest how folate ameliorates human hyperhomocysteinemia." Nat Struct Biol 6(4);359-65. PMID: 10201405

Himes62: Himes, RH, Rabinowitz, JC (1962). "Formyltetrahydrofolate synthetase. II. Characteristics of the enzyme and the enzymic reaction." J Biol Chem 237;2903-14. PMID: 13907490

Himmelreich96: Himmelreich R, Hilbert H, Plagens H, Pirkl E, Li BC, Herrmann R (1996). "Complete sequence analysis of the genome of the bacterium Mycoplasma pneumoniae." Nucleic Acids Res 1996;24(22);4420-49. PMID: 8948633

Hum91: Hum DW, MacKenzie RE (1991). "Expression of active domains of a human folate-dependent trifunctional enzyme in Escherichia coli." Protein Eng 4(4);493-500. PMID: 1881876

Kirk94: Kirk CD, Imeson HC, Zheng LL, Cossins EA (1994). "The affinity of pea cotyledon 10-formyltetrahydrofolate synthetase for polyglutamate substrates." Phytochemistry. 35(2), 291-296.

Kirk95: Kirk CD, Chen L, Imeson HC, Cossins EA, (1995) "A 5,10-methylenetetrahydrofolate dehydrogenase:5,10-methenyltetrahydrofolate cyclohydrolase protein from Pisum sativum." Phytochemistry (1995), 39(6), 1309-1317.

Latendresse13: Latendresse M. (2013). "Computing Gibbs Free Energy of Compounds and Reactions in MetaCyc."

Lee09a: Lee MN, Takawira D, Nikolova AP, Ballou DP, Furtado VC, Phung NL, Still BR, Thorstad MK, Tanner JJ, Trimmer EE (2009). "Functional role for the conformationally mobile phenylalanine 223 in the reaction of methylenetetrahydrofolate reductase from Escherichia coli." Biochemistry 48(32);7673-85. PMID: 19610625

Li03: Li R, Moore M, King J (2003). "Investigating the regulation of one-carbon metabolism in Arabidopsis thaliana." Plant Cell Physiol 44(3);233-41. PMID: 12668769

Ljungdahl70: Ljungdahl L, Brewer JM, Neece SH, Fairwell T (1970). "Purification, stability, and composition of formyltetrahydrofolate synthetase from Clostridium thermoaceticum." J Biol Chem 1970;245(18);4791-7. PMID: 5456151

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Please cite the following article in publications resulting from the use of MetaCyc: Caspi et al, Nucleic Acids Research 42:D459-D471 2014
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