One-carbon metabolism (Homo sapiens)

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3Deoxythymidine monophosphateDNA repair pathwaysDeoxyuridine monophosphateDNA 5-methylcytosineDNAMTHFD2Alcohol5,10-Methenyl Tetrahydrofolate5-Formyl TetrahydrofolateATICMTRMethylcobalaminB12MAT1AALDH1L1FTCDRiboflavinVitamin B2MTHFRTYMSMTHFD1CholineGRX1SHMT2BetaineSHMT1FolateAHCYTetrahydrofolateMTHFSTCN IIGART10-Formyl TetrahydrofolateFOLH1FTCDSerineMTHFD1MTHFD1PolyglutamateDNMT3bPyridoxal 5'-phosphateVitamin B6DNMT3aGARTMTFMTMTHFD1LS-adenosylhomocysteineAMTMIsmatch repairBHMTMTHFD1LDHFRDNMT1Thymidylate synthesisMTHFD2ZnAMTHomocystineCHDH5-Methyl Tetrahydrofolate5-Formimino TetrahydrofolateMTRRPolyamine synthesisMethionineMTHFD1LS-AdenosylmethionineDihydrofolateVitamin B9DHFRGlycineDHFRHomocysteineMAT2BKIAA0828Cobalamin5,10-Methylene TetrahydrofolateNon-homologous end joining554, 555552555551, 6, 78555555555555555555


This one-carbon metabolism pathway is centered around folate. Folate has two key carbon-carbon double bonds. Saturating one of them yields dihydrofolate (DHF) and adding an additional molecule of hydrogen across the second yields tetrahydrofolate (THF). Folates serve as donors of single carbons in any one of three oxidation states: 5-methyl-THF (CH3THF; reduced), 5,10 methylene-THF (CH2THF; intermediate) and 10-formyl-THF (CHOTHF; oxidized). The single carbon donor CH3THF is used to convert homocysteine into methionine which can then be used to methylate DNA, the donor CH2THF is used (along with a molecule of hydrogen at the site of one of the double bonds) to convert dUMP (deoxyuridylate) into dTMP (thymidylate) and the donor CHOTHF is used to set up ring closure reactions in de novo purine synthesis. CH3THF is the primary methyl-group donor for processes such as DNA methylation reactions. Purines are used both in RNA synthesis and in DNA synthesis and dTMP is synthesized srtictly for DNA synthesis, be it for DNA repair or DNA replication.

The folate pathway is central to any study related to DNA methylation, dTMP synthesis or purine synthesis.

Differential methylation (e.g. hypermethylation of tumor suppressors) as well as disturbances in nucleotide synthesis and repair, are associated with several forms of cancer. There are also indications that hypermethylation is involved in the progression of adenomas to cancer.

The pathway is also illustrative of the role of a number of B vitamins, including vitamin B12 (cobalamine) which is important for the sythesis of folate (vitamin B9) and of methionine.

Proteins on this pathway have targeted assays available via the CPTAC Assay Portal

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  1. Papov VV, Gravina SA, Mieyal JJ, Biemann K; ''The primary structure and properties of thioltransferase (glutaredoxin) from human red blood cells.''; Protein Sci, 1994 PubMed Europe PMC Scholia
  2. Waditee R, Tanaka Y, Aoki K, Hibino T, Jikuya H, Takano J, Takabe T; ''Isolation and functional characterization of N-methyltransferases that catalyze betaine synthesis from glycine in a halotolerant photosynthetic organism Aphanothece halophytica.''; J Biol Chem, 2003 PubMed Europe PMC Scholia
  3. Lu SC; ''S-Adenosylmethionine.''; Int J Biochem Cell Biol, 2000 PubMed Europe PMC Scholia
  4. Ludwig ML, Matthews RG; ''Structure-based perspectives on B12-dependent enzymes.''; Annu Rev Biochem, 1997 PubMed Europe PMC Scholia
  5. Hazra A, Wu K, Kraft P, Fuchs CS, Giovannucci EL, Hunter DJ; ''Twenty-four non-synonymous polymorphisms in the one-carbon metabolic pathway and riskof colorectal adenoma in the Nurses' Health Study.''; Carcinogenesis, 2007 PubMed Europe PMC Scholia
  6. Kim HY; ''Glutaredoxin serves as a reductant for methionine sulfoxide reductases with or without resolving cysteine.''; Acta Biochim Biophys Sin (Shanghai), 2012 PubMed Europe PMC Scholia
  7. RACKER E; ''Glutathione-homocystine transhydrogenase.''; J Biol Chem, 1955 PubMed Europe PMC Scholia
  8. Boch J, Kempf B, Schmid R, Bremer E; ''Synthesis of the osmoprotectant glycine betaine in Bacillus subtilis: characterization of the gbsAB genes.''; J Bacteriol, 1996 PubMed Europe PMC Scholia


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128724view02:20, 21 February 2024EweitzStandardize case
126998view12:13, 17 July 2023DdiglesAdded SAM to polyamine synthesis as suggested by KestUrba here:
120901view14:02, 29 January 2022EgonwReplaced an old HMDB identifier with the current one
116573view11:04, 8 May 2021EweitzModified title
113976view06:45, 14 December 2020EgonwThree more clickable pathways
110208view11:40, 24 April 2020Fehrhartadded link to Thymidylate synthesis via the pyrimidine pathway
107128view14:20, 17 September 2019MaintBotChEBI identifier normalization
106574view21:21, 6 September 2019KhanspersModified description
106172view12:06, 16 August 2019MaintBotHMDB identifier normalization
105504view05:57, 8 August 2019KhanspersModified description
101824view08:32, 12 November 2018EgonwReplaced an old Uniprot data source with the new one.
98057view06:50, 13 July 2018Fehrhartlayout
97559view15:19, 24 May 2018DeSlRemoved licence number
97558view15:18, 24 May 2018DeSlConnected lines.
97557view15:12, 24 May 2018DeSlChanged KEGG GENE ID to Uniprot
89671view08:13, 24 September 2016EgonwReplaced the CAS for polyglutamate with the ChEBI ID for this metabolite.
85415view11:27, 14 May 2016EgonwMore clean up.
85414view11:04, 14 May 2016EgonwCleaned up two multi-entity reactions.
85413view10:20, 14 May 2016EgonwClean up and mim annotation of catalyses.
85105view11:10, 14 April 2016Garima.thakurAddition of Homocystine
83818view22:16, 11 December 2015AlexanderPicoMerged Emma Beswick's edits from duplicate effort
82712view09:56, 23 October 2015EgonwCleaned up the layout a bit.
82255view11:49, 17 September 2015MirellaKalafatiPeriodical save, work in progress
82228view09:45, 16 September 2015MirellaKalafatiCholine conversion to betaine (by choline dehydrogenase aka CHDH)
82227view09:36, 16 September 2015MirellaKalafatiPeriodical save, work in progress
82226view09:06, 16 September 2015MirellaKalafatiPeriodical save, work in progress
82225view08:55, 16 September 2015MirellaKalafatiPeriodical save, work in progress
82224view08:35, 16 September 2015MirellaKalafatiPeriodical save, work in progress
80389view19:29, 12 June 2015AlexanderPicoReverted to version '23:01, 27 May 2015' by AlexanderPico
80249view08:16, 28 May 2015IamlovePeriodical save, work in progress
80244view06:01, 28 May 2015KhanspersReverted to version '15:46, 2 April 2015' by Khanspers
80150view18:45, 14 May 2015KhanspersAdded mir29 family targeting and associated lit ref
79667view15:46, 2 April 2015EveloChanged "monoglutamate" label to Folate
78552view10:30, 7 January 2015MaintBotadded missing graphIds
68025view08:18, 29 June 2013EgonwAdded a missing metabolite identifiers.
68024view08:08, 29 June 2013EgonwConverted two labels into Metabolite DataNodes.
65710view13:11, 11 June 2013EgonwConverted three labels to metabolite DataNodes.
61699view23:32, 16 April 2013MaintBotupdated data node type "Unkown" to "GeneProduct" for annotated genes
49064view08:35, 4 July 2012Eveloimproved homocysteine annotatopn
45325view20:12, 7 October 2011KhanspersOntology Term : 'folate mediated one-carbon metabolic pathway' added !
41078view23:20, 1 March 2011MaintBotRemoved redundant pathway information and comments
38794view06:48, 24 September 2010Thomaslinked to dna repair pathways
36799view12:04, 4 May 2010EveloMTHFR Riboflavin complex
36797view11:56, 4 May 2010EveloModified description
36795view11:38, 4 May 2010EveloAdded MTR reference
36794view11:29, 4 May 2010EveloModified description
36793view11:12, 4 May 2010EveloAdded more vitamins as metabolites, multiline labels
36792view10:28, 4 May 2010EveloAdded vitamin names to metabolite labels
36779view09:04, 4 May 2010Eveloadded connection
36699view12:09, 16 April 2010MichielMinor edits

External references


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NameTypeDatabase referenceComment
10-Formyl TetrahydrofolateMetabolite2800-34-2 (CAS)
5,10-Methenyl TetrahydrofolateMetabolite7444-29-3 (CAS)
5,10-Methylene TetrahydrofolateMetaboliteCHEBI:12071 (ChEBI)
5-Formimino TetrahydrofolateMetabolite135-16-0 (CAS)
5-Formyl TetrahydrofolateMetabolite135-16-0 (CAS)
5-Methyl TetrahydrofolateMetabolite134-35-0 (CAS)
AHCYGeneProduct191 (Entrez Gene) KEGG Database Methionine metabolism - Homo sapiens (human)
ALDH1L1GeneProduct10840 (Entrez Gene)
AMTGeneProduct275 (Entrez Gene) KEGG database: One carbon pool by folate - Homo sapiens (human)
ATICGeneProduct471 (Entrez Gene)
AlcoholMetabolite702 (PubChem-compound)
BHMTGeneProduct635 (Entrez Gene)
BetaineMetabolite107-43-7 (CAS)
CHDHGeneProductQ8NE62 (Uniprot-TrEMBL)
CholineMetabolite62-49-7 (CAS)
CobalaminMetaboliteHMDB0002174 (HMDB)
DHFRGeneProduct1719 (Entrez Gene) KEGG database: One carbon pool by folate - Homo sapiens (human)
DNMT1GeneProduct1786 (Entrez Gene)
DNMT3aGeneProduct1788 (Entrez Gene) KEGG Database Methionine metabolism - Homo sapiens (human)
DNMT3bGeneProduct1789 (Entrez Gene) KEGG database: Methionine metabolism - Homo sapiens (human)
Deoxythymidine monophosphateMetabolite9700 (PubChem-compound)
Deoxyuridine monophosphateMetabolite65063 (PubChem-compound)
Dihydrofolate Vitamin B9Metabolite4033-27-6 (CAS)
FOLH1GeneProduct2346 (Entrez Gene)
FTCDGeneProduct10841 (Entrez Gene) KEGG database: One carbon pool by folate - Homo sapiens (human)
FolateMetabolite59-30-3 (CAS)
GARTGeneProduct2618 (Entrez Gene)
GRX1GeneProduct2745 (Entrez Gene)
GlycineMetaboliteHMDB0000123 (HMDB)
HomocysteineMetaboliteHMDB0000742 (HMDB)
HomocystineMetaboliteCHEBI:17485 (ChEBI)
KIAA0828GeneProduct23382 (Entrez Gene) KEGG Database Methionine metabolism - Homo sapiens (human)
MAT1AGeneProduct4143 (Entrez Gene) KEGG Database Methionine metabolism - Homo sapiens (human)
MAT2BGeneProduct27430 (Entrez Gene) KEGG Database Methionine metabolism - Homo sapiens (human)
MIsmatch repairPathwayWP531 (WikiPathways)
MTFMTGeneProduct123263 (Entrez Gene) KEGG database: One carbon pool by folate - Homo sapiens (human)
MTHFD1GeneProduct4522 (Entrez Gene)
MTHFD1LGeneProduct25902 (Entrez Gene) KEGG database: One carbon pool by folate - Homo sapiens (human)
MTHFD2GeneProduct10797 (Entrez Gene) KEGG database: One carbon pool by folate - Homo sapiens (human)
MTHFRGeneProduct4524 (Entrez Gene)
MTHFSGeneProduct10588 (Entrez Gene) KEGG database: One carbon pool by folate - Homo sapiens (human)
MTRGeneProduct4548 (Entrez Gene)
MTRRGeneProduct4552 (Entrez Gene)
MethionineMetabolite63-68-3 (CAS)
Methylcobalamin B12MetaboliteHMDB0002274 (HMDB)
Non-homologous end joiningPathwayWP438 (WikiPathways)
Polyamine synthesisPathwayWikidata: Q21123704
PolyglutamateMetabolite25513-46-6 (CAS)
Pyridoxal 5'-phosphate Vitamin B6MetaboliteHMDB0001491 (HMDB)
Riboflavin Vitamin B2MetaboliteHMDB0000244 (HMDB)
S-AdenosylmethionineMetabolite29908-03-0 (CAS)
S-adenosylhomocysteineMetabolite979-92-0 (CAS)
SHMT1GeneProduct6470 (Entrez Gene)
SHMT2GeneProduct6472 (Entrez Gene) KEGG database: One carbon pool by folate - Homo sapiens (human)
SerineMetabolite617 (PubChem-compound)
TCN IIGeneProduct6948 (Entrez Gene)
TYMSGeneProduct7298 (Entrez Gene) KEGG database: One carbon pool by folate - Homo sapiens (human)
TetrahydrofolateMetabolite135-16-0 (CAS)
Thymidylate synthesisPathwayWP4225 (WikiPathways)
ZnMetaboliteHMDB0015532 (HMDB)

Annotated Interactions

No annotated interactions

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