One-carbon metabolism (WP241)

Homo sapiens

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 [https://assays.cancer.gov/available_assays?wp_id=WP241 CPTAC Assay Portal]

Authors

Michiel Adriaens , Frank , Thomas Kelder , Txr24 , Egoyenechea , Chris Evelo , Alex Pico , Kristina Hanspers , Egon Willighagen , Jeff , Marianthi Kalafati , Garima Thakur , Denise Slenter , Friederike Ehrhart , Eric Weitz , and Daniela Digles

Activity

last edited

Discuss this pathway

Check for ongoing discussions or start your own.

Cited In

Are you planning to include this pathway in your next publication? See How to Cite and add a link here to your paper once it's online.

Organisms

Homo sapiens

Communities

CPTAC Micronutrients

Annotations

Pathway Ontology

folate mediated one-carbon metabolic pathway

Participants

Label Type Compact URI Comment
Deoxyuridine monophosphate Metabolite pubchem.compound:65063
Deoxythymidine monophosphate Metabolite pubchem.compound:9700
Tetrahydrofolate Metabolite cas:135-16-0
5-Methyl Tetrahydrofolate Metabolite cas:134-35-0
Alcohol Metabolite pubchem.compound:702
Betaine Metabolite cas:107-43-7
glycine Metabolite hmdb:HMDB0000123
5-Formyl Tetrahydrofolate Metabolite cas:135-16-0
Zn Metabolite hmdb:HMDB0015532
RiboflavinVitamin B2 Metabolite hmdb:HMDB0000244
10-Formyl Tetrahydrofolate Metabolite cas:2800-34-2
5,10-Methenyl Tetrahydrofolate Metabolite cas:7444-29-3
Choline Metabolite cas:62-49-7
5-Formimino Tetrahydrofolate Metabolite cas:135-16-0
Folate Metabolite cas:59-30-3
DihydrofolateVitamin B9 Metabolite cas:4033-27-6
5,10-Methylene Tetrahydrofolate Metabolite chebi:12071
Methionine Metabolite cas:63-68-3
S-adenosylhomocysteine Metabolite cas:979-92-0
S-Adenosylmethionine Metabolite cas:29908-03-0
Cobalamin Metabolite hmdb:HMDB0002174
serine Metabolite pubchem.compound:617
MethylcobalaminB12 Metabolite hmdb:HMDB0002274
Homocystine Metabolite chebi:17485
Pyridoxal 5'-phosphateVitamin B6 Metabolite hmdb:HMDB0001491
Homocysteine Metabolite hmdb:HMDB0000742
Polyglutamate Metabolite cas:25513-46-6
MAT1A GeneProduct ncbigene:4143 KEGG Database Methionine metabolism - Homo sapiens (human)
BHMT GeneProduct ncbigene:635
GRX1 GeneProduct ncbigene:2745
MTHFS GeneProduct ncbigene:10588 KEGG database: One carbon pool by folate - Homo sapiens (human)
DHFR GeneProduct ncbigene:1719 KEGG database: One carbon pool by folate - Homo sapiens (human)
MTHFD2 GeneProduct ncbigene:10797 KEGG database: One carbon pool by folate - Homo sapiens (human)
MTHFD1 GeneProduct ncbigene:4522
MTHFD1L GeneProduct ncbigene:25902 KEGG database: One carbon pool by folate - Homo sapiens (human)
FOLH1 GeneProduct ncbigene:2346
MTFMT GeneProduct ncbigene:123263 KEGG database: One carbon pool by folate - Homo sapiens (human)
DNMT1 GeneProduct ncbigene:1786
MTHFD1 GeneProduct ncbigene:4522
CHDH GeneProduct uniprot:Q8NE62
MTR GeneProduct ncbigene:4548
MTHFR GeneProduct ncbigene:4524
MTHFD1L GeneProduct ncbigene:25902 KEGG database: One carbon pool by folate - Homo sapiens (human)
FTCD GeneProduct ncbigene:10841 KEGG database: One carbon pool by folate - Homo sapiens (human)
DNMT3b GeneProduct ncbigene:1789 KEGG database: Methionine metabolism - Homo sapiens (human)
KIAA0828 GeneProduct ncbigene:23382 KEGG Database Methionine metabolism - Homo sapiens (human)
ALDH1L1 GeneProduct ncbigene:10840
AMT GeneProduct ncbigene:275 KEGG database: One carbon pool by folate - Homo sapiens (human)
MTRR GeneProduct ncbigene:4552
MAT2B GeneProduct ncbigene:27430 KEGG Database Methionine metabolism - Homo sapiens (human)
FTCD GeneProduct ncbigene:10841 KEGG database: One carbon pool by folate - Homo sapiens (human)
SHMT1 GeneProduct ncbigene:6470
AMT GeneProduct ncbigene:275 KEGG database: One carbon pool by folate - Homo sapiens (human)
TYMS GeneProduct ncbigene:7298 KEGG database: One carbon pool by folate - Homo sapiens (human)
MTHFD1 GeneProduct ncbigene:4522
GART GeneProduct ncbigene:2618
SHMT2 GeneProduct ncbigene:6472 KEGG database: One carbon pool by folate - Homo sapiens (human)
MTHFD1L GeneProduct ncbigene:25902 KEGG database: One carbon pool by folate - Homo sapiens (human)
DNMT3a GeneProduct ncbigene:1788 KEGG Database Methionine metabolism - Homo sapiens (human)
ATIC GeneProduct ncbigene:471
MTHFD2 GeneProduct ncbigene:10797 KEGG database: One carbon pool by folate - Homo sapiens (human)
AHCY GeneProduct ncbigene:191 KEGG Database Methionine metabolism - Homo sapiens (human)
TCN II GeneProduct ncbigene:6948
GART GeneProduct ncbigene:2618
DHFR GeneProduct ncbigene:1719 KEGG database: One carbon pool by folate - Homo sapiens (human)
DHFR GeneProduct ncbigene:1719 KEGG database: One carbon pool by folate - Homo sapiens (human)

References

  1. The primary structure and properties of thioltransferase (glutaredoxin) from human red blood cells. Papov VV, Gravina SA, Mieyal JJ, Biemann K. Protein Sci. 1994 Mar;3(3):428–34. PubMed Europe PMC Scholia
  2. Synthesis of the osmoprotectant glycine betaine in Bacillus subtilis: characterization of the gbsAB genes. Boch J, Kempf B, Schmid R, Bremer E. J Bacteriol. 1996 Sep;178(17):5121–9. PubMed Europe PMC Scholia
  3. Structure-based perspectives on B12-dependent enzymes. Ludwig ML, Matthews RG. Annu Rev Biochem. 1997;66:269–313. PubMed Europe PMC Scholia
  4. S-Adenosylmethionine. Lu SC. Int J Biochem Cell Biol. 2000 Apr;32(4):391–5. PubMed Europe PMC Scholia
  5. Isolation and functional characterization of N-methyltransferases that catalyze betaine synthesis from glycine in a halotolerant photosynthetic organism Aphanothece halophytica. Waditee R, Tanaka Y, Aoki K, Hibino T, Jikuya H, Takano J, et al. J Biol Chem. 2003 Feb 14;278(7):4932–42. PubMed Europe PMC Scholia
  6. Glutathione-homocystine transhydrogenase. RACKER E. J Biol Chem. 1955 Dec;217(2):867–74. PubMed Europe PMC Scholia
  7. Twenty-four non-synonymous polymorphisms in the one-carbon metabolic pathway and risk of colorectal adenoma in the Nurses’ Health Study. Hazra A, Wu K, Kraft P, Fuchs CS, Giovannucci EL, Hunter DJ. Carcinogenesis. 2007 Jul;28(7):1510–9. PubMed Europe PMC Scholia
  8. Glutaredoxin serves as a reductant for methionine sulfoxide reductases with or without resolving cysteine. Kim HY. Acta Biochim Biophys Sin (Shanghai). 2012 Jul;44(7):623–7. PubMed Europe PMC Scholia