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 DiglesActivity
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Cited In
- Polymorphisms in genes related to one-carbon metabolism are not related to pancreatic cancer in PanScan and PanC4 (2014).
- Human Monocytes Exposed to SARS-CoV-2 Display Features of Innate Immune Memory Producing High Levels of CXCL10 upon Restimulation (2023).
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Organisms
Homo sapiensCommunities
CPTAC MicronutrientsAnnotations
Pathway Ontology
folate mediated one-carbon metabolic pathway| 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 | |
| CHDH | GeneProduct | uniprot:Q8NE62 | |
| MTR | GeneProduct | ncbigene:4548 | |
| MTHFR | GeneProduct | ncbigene:4524 | |
| 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) |
| SHMT1 | GeneProduct | ncbigene:6470 | |
| TYMS | GeneProduct | ncbigene:7298 | KEGG database: One carbon pool by folate - Homo sapiens (human) |
| GART | GeneProduct | ncbigene:2618 | |
| SHMT2 | GeneProduct | ncbigene:6472 | 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 | |
| AHCY | GeneProduct | ncbigene:191 | KEGG Database Methionine metabolism - Homo sapiens (human) |
| TCN II | GeneProduct | ncbigene:6948 |
References
- 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
- 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
- Structure-based perspectives on B12-dependent enzymes. Ludwig ML, Matthews RG. Annu Rev Biochem. 1997;66:269–313. PubMed Europe PMC Scholia
- S-Adenosylmethionine. Lu SC. Int J Biochem Cell Biol. 2000 Apr;32(4):391–5. PubMed Europe PMC Scholia
- 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
- Glutathione-homocystine transhydrogenase. RACKER E. J Biol Chem. 1955 Dec;217(2):867–74. PubMed Europe PMC Scholia
- 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
- 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