MTHFR deficiency (WP4288)
Homo sapiens
There are currently three hypothesis for demyelination in the Central Nervous System (CNS) of methylenetetrahydrofolate reductase (MTHFR) deficient patients. These three possible mechanisms are: inadequate methionine synthesis, a deficiency of S-adenosylmethionine or accumulation of toxic intermediates from the elevated levels of homocysteine. This pathway includes all three of these possible mechanisms. This pathway was inspired by Chapter 10 of the book of Blau(ISBN 3642403360 (978-3642403361)) and the paper by Prasad et al. (2011, https://www.ncbi.nlm.nih.gov/pubmed/21778025). For an overview of disorders related to folate metabolism and transport, please see [https://www.wikipathways.org/index.php/Pathway:WP4259].
Authors
Jesse Vercoulen , Denise Slenter , Egon Willighagen , Kristina Hanspers , Irene Hemel , Josien Landman , Friederike Ehrhart , and Eric WeitzActivity
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Organisms
Homo sapiensCommunities
Diseases Inherited Metabolic Disorders (IMD) Pathways Rare DiseasesAnnotations
Pathway Ontology
hyperhomocysteinemia pathway disease pathway methylenetetrahydrofolate reductase deficiency pathway folate metabolic pathway S-adenosylmethionine homeostasis pathwayCell Type Ontology
oligodendrocyteDisease Ontology
inherited metabolic disorder| Label | Type | Compact URI | Comment |
|---|---|---|---|
| Choline | Metabolite | chebi:15354 | Methionine Hypothesis |
| SAM | Metabolite | chebi:67040 | SAMdef Hypothesis |
| Homocysteine thiolactone | Metabolite | hmdb:HMDB0002287 | Toxic Hypothesis |
| Phosphatidylcholine | Metabolite | chebi:49183 | Methionine Hypothesis |
| [Myelin basic protein]-N-methylarginine | Metabolite | chebi:10167 | SAMdef Hypothesis |
| Dimethylglycine | Metabolite | chebi:17724 | |
| Homocysteine | Metabolite | chebi:58199 | |
| [Myelin basic protein]-arginine | Metabolite | chebi:10166 | SAMdef Hypothesis |
| Phosphocholine | Metabolite | chebi:295975 | Methionine Hypothesis |
| Ca2+ | Metabolite | chebi:29108 | Toxic Hypothesis |
| Ceramide | Metabolite | chebi:17761 | Methionine Hypothesis |
| Methionine | Metabolite | chebi:57844 | |
| CDP-choline | Metabolite | chebi:58779 | Methionine Hypothesis |
| Betaine aldehyde | Metabolite | chebi:15710 | Methionine Hypothesis |
| betaine | Metabolite | chebi:17750 | |
| 5,10-Methylene-THF | Metabolite | chebi:1989 | |
| DAG | Metabolite | chebi:18035 | Methionine Hypothesis |
| Sphingomyelin | Metabolite | chebi:64583 | Methionine Hypothesis |
| 5-Methyl-THF | Metabolite | chebi:15641 | |
| SAH | Metabolite | chebi:16680 | SAMdef Hypothesis |
| Phosphatidylethanolamine | Metabolite | chebi:16038 | Methionine Hypothesis |
| Reactive oxygen species | Metabolite | wikidata:Q424361 | Toxic Hypothesis |
| Betaine | Metabolite | chebi:17750 | Methionine Hypothesis |
| Choline | Metabolite | chebi:15354 | Methionine Hypothesis |
| SAM | Metabolite | chebi:67040 | Methionine Hypothesis |
| SAM | Metabolite | chebi:67040 | Methionine Hypothesis |
| SAM | Metabolite | chebi:67040 | Methionine Hypothesis |
| Homocysteine | Metabolite | chebi:17230 | Toxic Hypothesis |
| Homocysteine | Metabolite | chebi:17230 | Toxic Hypothesis |
| Ca2+ | Metabolite | chebi:29108 | Toxic Hypothesis |
| Homocysteine | Metabolite | chebi:17230 | Toxic Hypothesis |
| Ca2+ | Metabolite | chebi:29108 | Toxic Hypothesis |
| EHMT1 | GeneProduct | ensembl:ENSG00000181090 | SAMdef Hypothesis |
| MTHFR | GeneProduct | ensembl:ENSG00000177000 | |
| CASP3 | GeneProduct | ensembl:ENSG00000164305 | Toxic Hypothesis |
| DNMT3A | GeneProduct | ensembl:ENSG00000119772 | SAMdef Hypothesis |
| DNMT3B | GeneProduct | ensembl:ENSG00000088305 | SAMdef Hypothesis |
| CASP9 | GeneProduct | ensembl:ENSG00000132906 | Toxic Hypothesis |
| ASMT | GeneProduct | ensembl:ENSG00000196433 | SAMdef Hypothesis |
| EHMT2 | GeneProduct | ensembl:ENSG00000204371 | |
| COMT | GeneProduct | ensembl:ENSG00000093010 | SAMdef Hypothesis |
| DNMT1 | GeneProduct | ensembl:ENSG00000130816 | SAMdef Hypothesis |
| Cytochrome c | Protein | uniprot:G4XXL9 | Toxic Hypothesis |
| NMDA 2D | Protein | uniprot:O15399 | Toxic Hypothesis |
| HNMT | Protein | uniprot:P50135 | |
| NMDA 1 | Protein | uniprot:Q05586 | Toxic Hypothesis |
| NMDA 2A | Protein | uniprot:F5GZ52 | Toxic Hypothesis |
| BHMT | Protein | uniprot:Q93088 | |
| Choline kinase alpha | Protein | uniprot:P35790 | Methionine Hypothesis |
| CHDH | Protein | uniprot:Q8NE62 | Methionine Hypothesis |
| PEMT | Protein | uniprot:Q9UBM1 | Methionine Hypothesis |
| PRMT | Protein | uniprot:B4E0W7 | SAMdef Hypothesis |
| SGMS 1 | Protein | uniprot:D3DWC4 | Methionine Hypothesis |
| MetRS | Protein | uniprot:P56192 | Needs annotationToxic Hypothesis |
| BADH | Protein | uniprot:P49419 | Methionine Hypothesis |
| CHPT-1 | Protein | uniprot:Q8WUD6 | Methionine Hypothesis |
| CCT-alpha | Protein | uniprot:P49585 | Methionine Hypothesis |
| Cytochrome c | Protein | uniprot:G4XXL9 | Toxic Hypothesis |
| EC 2.1.1.79 | Protein | eccode:2.1.1.79 | |
| EC 2.1.1.72 | Protein | eccode:2.1.1.72 |
References
- Elevation in S-adenosylhomocysteine and DNA hypomethylation: potential epigenetic mechanism for homocysteine-related pathology. James SJ, Melnyk S, Pogribna M, Pogribny IP, Caudill MA. J Nutr. 2002 Aug;132(8 Suppl):2361S-2366S. PubMed Europe PMC Scholia
- Betaine homocysteine S-methyltransferase: just a regulator of homocysteine metabolism? Pajares MA, Pérez-Sala D. Cell Mol Life Sci. 2006 Dec;63(23):2792–803. PubMed Europe PMC Scholia
- Phosphatidylcholine and choline homeostasis. Li Z, Vance DE. J Lipid Res. 2008 Jun;49(6):1187–94. PubMed Europe PMC Scholia
- Choline and betaine in health and disease. Ueland PM. J Inherit Metab Dis. 2011 Feb;34(1):3–15. PubMed Europe PMC Scholia
- An overview of sphingolipid metabolism: from synthesis to breakdown. Gault CR, Obeid LM, Hannun YA. Adv Exp Med Biol. 2010;688:1–23. PubMed Europe PMC Scholia
- Methylenetetrahydrofolate reductase (MTHFR) deficiency and infantile epilepsy. Prasad AN, Rupar CA, Prasad C. Brain Dev. 2011 Oct;33(9):758–69. PubMed Europe PMC Scholia
- Novel crosstalk between ERK MAPK and p38 MAPK leads to homocysteine-NMDA receptor-mediated neuronal cell death. Poddar R, Paul S. J Neurochem. 2013 Feb;124(4):558–70. PubMed Europe PMC Scholia
- Hyperhomocysteinemia as a risk factor for the neuronal system disorders. Petras M, Tatarkova Z, Kovalska M, Mokra D, Dobrota D, Lehotsky J, et al. J Physiol Pharmacol. 2014 Feb;65(1):15–23. PubMed Europe PMC Scholia
- The NMDA receptor complex: a multifunctional machine at the glutamatergic synapse. Fan X, Jin WY, Wang YT. Front Cell Neurosci. 2014 Jun 10;8:160. PubMed Europe PMC Scholia
- Conformational status of cytochrome c upon N-homocysteinylation: Implications to cytochrome c release. Sharma GS, Singh LR. Arch Biochem Biophys. 2017 Jan 15;614:23–7. PubMed Europe PMC Scholia