Disorders of folate metabolism and transport (WP4259)

Homo sapiens

Folates play an essential role in one-carbon methyl transfer reactions, mediating several biological processes (e.g. DNA synthesis, epigentics by methylation, embryonic central nervous system development, cata-/anabolism of amino acids, and anabolism of thymidines, purines, and neurotransmitters. The biologically active folic acid derivative is 5,6,7,8-tetrahydrofolate (THF). Dietary folate is absorbed in the intestine, and stored in the liver for few months. [rephrased from chapter 10 of Blau et al, ISBN 3642403360 (978-3642403361)]. For more detail on MTHFR deficiency, please visit [https://www.wikipathways.org/index.php/Pathway:WP4288].
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Jesse Vercoulen , Egon Willighagen , Andra Waagmeester , Denise Slenter , Kristina Hanspers , Irene Hemel , Josien Landman , Friederike Ehrhart , Eric Weitz , and Finterly Hu

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Homo sapiens


Diseases Inherited Metabolic Disorders (IMD) Pathways Rare Diseases


Pathway Ontology: folate metabolic pathway disease pathway methylenetetrahydrofolate reductase deficiency pathway

Disease Ontology: vitamin B12 deficiency vitamin metabolic disorder cerebral folate receptor alpha deficiency glutamate formiminotransferase deficiency megaloblastic anemia

Cell Type Ontology: central nervous system neuron


Label Type Compact Identifier Comment
SAM Metabolite chebi:67040
serine Metabolite chebi:17822
THF Metabolite chebi:20506
5-Methyl-THF Metabolite chebi:15641
NH4+ Metabolite chebi:28938
L-glutamic acid Metabolite chebi:16015
SAH Metabolite chebi:16680
CO2 Metabolite chebi:16526
glycine Metabolite chebi:15428
N-formimidoyl-L-glutamate Metabolite chebi:58928 Based on Rhea, the side metabolite is not Histidine
Homocysteine Metabolite chebi:17230
DHF Metabolite chebi:15633 AKA 7,8-DHF
Methionine Metabolite chebi:16643
Folic acid Metabolite chebi:27470
5,10-Methylene-THF Metabolite chebi:1989
Vitamin B12 Metabolite chebi:30411
5-formimino-THF Metabolite chebi:15639
5,10-Methenyl-THF Metabolite chebi:15638
GAR Metabolite chebi:18349
Formyl-GAR Metabolite chebi:18272
AICAR Metabolite chebi:2030
FAICAR Metabolite chebi:18381
10-Formyl-THF Metabolite chebi:15637
5-Formyl-THF Metabolite chebi:15640
dTMP Metabolite chebi:17013
dUMP Metabolite chebi:17622
Folic acid Metabolite chebi:27470
THF Metabolite chebi:20506
5-Methyl-THF Metabolite chebi:15641
qDHF Metabolite inchikey:AIZSNLNTIFEHJG-KIYNQFGBSA-N AKA quinoid DHF; SMILES: Nc1-n=C2NCC(CNc3ccc(cc3)C(=O)N[[email protected]@H](CCC(O)=O)C(O)=O)N=c2C(=O)N=1
7.8-dihydropterin Metabolite chebi:64277 Reference [PMID:30587505] does not provide info on stereochemistry
iminium ion Metabolite chebi:35286
formaldehyde Metabolite chebi:1684
MTHFD1 Protein uniprot:P11586 Found based on EC code for MTHFCH, information in UniProt describes this reaction.
QDPR Protein uniprot:P09417
MTHFD1 Protein uniprot:P11586
SHMT1 Protein uniprot:P34896
GARTF Protein uniprot:C9JKQ7
MTHFS Protein ensembl:ENSG00000136371
MTHFCH Protein eccode: MTHFCH: methenyl-THF cyclohydrolase
SLC46A1 Protein uniprot:Q96NT5 AKA PCFT
FOLR1 Protein uniprot:P15328 AKA Folate receptor alpha
AICART Protein uniprot:P31939 AKA ATIC, PURH
TS Protein uniprot:P04818 AKA TYMS
ALDH1L1 Protein uniprot:O75891 AKA FTHFD, cytosolic
MS Protein uniprot:Q99707
SHMT Protein uniprot:P34897 AKA SHMT2; Rhea and UniProt confirm the '2' addition, whereas the Blau book chapter only mentions SHMT.
FTCD Protein uniprot:O95954 AKA FITHFCH
DHFR Protein uniprot:B0YJ76
MTHFR Protein uniprot:P42898
MTHFD1 Protein uniprot:P11586
SHMT1 Protein uniprot:P34896
SLC19A1 Protein uniprot:P41440 AKA Folate receptor alpha
ALDH1L2 Protein uniprot:Q3SY69 AKA FTHFD, mitochondrial
MTHFD2 Protein uniprot:P13995 Found based on EC code for MTHFCH, information in UniProt describes this reaction.
MTHFD2L Protein uniprot:Q9H903 Found based on EC code for MTHFCH, information in UniProt describes this reaction.


  1. Blau N, Duran M, Gibson KM, Dionisi-Vici C. Physician’s Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases [Internet]. Springer; 2014. 867 p. Available from: https://books.google.com/books/about/Physician_s_Guide_to_the_Diagnosis_Treat.html?hl=&id=wJRBnwEACAAJ OpenLibrary Worldcat
  2. Toward a better understanding of folate metabolism in health and disease. Zheng Y, Cantley LC. J Exp Med. 2019 Feb 4;216(2):253–66. PubMed Europe PMC Scholia