Vitamin B12 disorders (WP4271)
Homo sapiens
This pathway depicts the metabolism of cobalamin (also known as cbl or vitamin B12) and related diseases (for a full overview of the B12 metabolism, see [https://www.wikipathways.org/index.php/Pathway:WP1533]). Vit. B12 is derived from food sources and thereafter metabolised for 2 reasons; 1. to methylate homocysteine to methionine, and 2. to convert methylmalonyl-CoA to succinyl-CoA. This pathway depicts 15 distinct diseases which are related to a malfunctioning in the absorption and transport section, or the intracellular processing of Cbl. However, the exact function of some proteins which have been linked to these diseases, remains unclear. Substitution of Vit. B12 is a therapeutic option for patients with absorption and transport related diseases, however does not perform so well for patient with intracellular processing defects. This pathway was inspired by Chapter 13 of the book of Blau (ISBN 3642403360 (978-3642403361)).
Authors
Mzolisi Mtshaulana , Kristina Hanspers , Denise Slenter , Egon Willighagen , Irene Hemel , Eric Weitz , Finterly Hu , and Friederike EhrhartActivity
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Organisms
Homo sapiensCommunities
Inherited Metabolic Disorders (IMD) Pathways Rare DiseasesAnnotations
Disease Ontology
vitamin B12 deficiency methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency methylmalonic aciduria and homocystinuria type cblC methylmalonic aciduria and homocystinuria type cblD methylmalonic acidemia methylmalonic acidemia cblA type methylmalonic acidemia cblB type methylmalonic aciduria and homocystinuria type cblFPathway Ontology
methylmalonic aciduria, cobalamin-related pathway cobalamin metabolic pathway mitochondria dynamics pathwayCell Type Ontology
eukaryotic cell obsolete metabolising cell| Label | Type | Compact URI | Comment |
|---|---|---|---|
| Methylmalonic Acid | Metabolite | wikidata:Q239598 | |
| Hcy | Metabolite | wikidata:Q192466 | Hcy = homocysteine |
| NADP+ | Metabolite | chebi:18009 | |
| FAD | Metabolite | chebi:16238 | cofactor |
| Adenosylcobalamin | Metabolite | wikidata:Q47517602 | biologically active form |
| 2 * SAH | Metabolite | chebi:16680 | aka S-adenosyl-L-homocysteine |
| FMN | Metabolite | chebi:17621 | cofactor |
| MMA | Metabolite | wikidata:Q239598 | MMA = methylmalonic acid |
| NADPH | Metabolite | chebi:16474 | |
| 2 * SAM | Metabolite | chebi:15414 | aka S-adenosyl-L-methionine |
| Succinyl-CoA | Metabolite | chebi:15380 | |
| Methionine | Metabolite | chebi:16811 | |
| MTHF | Metabolite | chebi:15641 | Aka methyltetrahydrofolate |
| Cbl | Metabolite | wikidata:Q3329800 | |
| Cbl(cyanocobalamin) | Metabolite | wikidata:Q252251 | Cobalamin has been transformed to cyanocobalamin according to lit., before it can undergo conversion by cbLC. |
| Cbl(cob(II)alamin) | Metabolite | chebi:16304 | Should be cob(II)alamin according to literature |
| 2 * Cbl(cob(III)alamine) | Metabolite | chebi:28911 | Compound is suspected to be cob(III)alamine, since reaction with cbLD should produce oxidised form of cob(II)alamin |
| Cbl(cob(III)alamine) | Metabolite | chebi:28911 | Compound is suspected to be cob(III)alamine, since reaction with cbLD should produce oxidised form of cob(II)alamin |
| Methylmalonyl-CoA | Metabolite | chebi:16625 | |
| Methylcobalamin | Metabolite | chebi:28115 | biologically active formsAccording to enzyme functionallity, becomes [methionine synthase]-cob(II)alamin |
| Homocysteine | Metabolite | wikidata:Q192466 | |
| THF | Metabolite | chebi:20506 | Aka tetrahydrofolate |
| Cofactor | Metabolite | chebi:28115 | |
| cbLF | Protein | eccode:2.1.1.133 | |
| MUT | Protein | uniprot:P22033 | aka methylmalonyl-CoA mutase or MCM |
| cbLD-II | Protein | uniprot:Q9H3L0 | aka cbLD-MMA |
| TC receptor | Protein | uniprot:Q9NPF0 | |
| TC II | Protein | uniprot:P20062 | aka Transcobalamin 2 |
| HC | Protein | uniprot:P20061 | aka haptocorrin or transcobalamin 1Produced in saliva and stomach |
| CUBN | Protein | uniprot:O60494 | aka cubilin |
| HC | Protein | uniprot:P20061 | aka haptocorrin or transcobalamin 1 |
| IF | Protein | uniprot:P27352 | aka (gastric) intrinsic factor, transcobalamin IIILocated in gastric parietal cells |
| IF | Protein | uniprot:P27352 | aka intrinsic factor |
| AMN | Protein | uniprot:Q9BXJ7 | aka amnionless |
| TC receptor | Protein | uniprot:Q9NPF0 | Aka CD320 receptor |
| cbLJ | Protein | eccode:2.1.1.131 | |
| cbLC | Protein | uniprot:Q9Y4U1 | Gene is called MMAC |
| cbLB | Protein | uniprot:Q96EY8 | gene: MMAB |
| cbLA | Protein | uniprot:Q8IVH4 | Gene: MMAA |
| cbLD-I | Protein | uniprot:Q9H3L0 | aka cbLD-Hcy |
| cbLD | Protein | uniprot:Q9H3L0 | 'cblD protein might be responsible for branching of the cobalamin metabolism pathways to the cytosolic or mitochondrial compartments' Pubmed: 21114891gene is called MMADHC |
| cbLE | Protein | uniprot:Q9UBK8 | Gene is MTRR, protein aka methionine synthase reductase (MSR)reductive regeneration of cob(I)alamin (vitamin B12) cofactor |
| cbLG | Protein | uniprot:Q99707 | aka MS or methionine synthase for proteinGene is called MTR, for methyltransferase |
| coBM/cbLF | Protein | eccode:2.1.1.133 | |
| Protein in complex | Protein | ensembl:ENSG00000116984 | 5-methyltetrahydrofolate-homocysteine methyltransferase |
References
- Physician’s Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases [Internet]. Blau N, Duran M, Gibson KM, Dionisi-Vici C. Springer; 2014. 0 p. Available from: https://books.google.com/books/about/Physician_s_Guide_to_the_Diagnosis_Treat.html?hl=&id=wJRBnwEACAAJ OpenLibrary Worldcat
- Biosynthesis of cobalamin (vitamin B12): a bacterial conundrum. Raux E, Schubert HL, Warren MJ. Cell Mol Life Sci. 2000 Dec;57(13–14):1880–93. PubMed Europe PMC Scholia
- Mechanism of coenzyme binding to human methionine synthase reductase revealed through the crystal structure of the FNR-like module and isothermal titration calorimetry. Wolthers KR, Lou X, Toogood HS, Leys D, Scrutton NS. Biochemistry. 2007 Oct 23;46(42):11833–44. PubMed Europe PMC Scholia
- Mechanism of vitamin B12-responsiveness in cblC methylmalonic aciduria with homocystinuria. Froese DS, Zhang J, Healy S, Gravel RA. Mol Genet Metab. 2009 Dec;98(4):338–43. PubMed Europe PMC Scholia
- Genetic disorders of vitamin B₁₂ metabolism: eight complementation groups--eight genes. Froese DS, Gravel RA. Expert Rev Mol Med. 2010 Nov 29;12:e37. PubMed Europe PMC Scholia
- Inborn errors of cobalamin absorption and metabolism. Watkins D, Rosenblatt DS. Am J Med Genet C Semin Med Genet. 2011 Feb 15;157C(1):33–44. PubMed Europe PMC Scholia
- Structure of Human B12 Trafficking Protein CblD Reveals Molecular Mimicry and Identifies a New Subfamily of Nitro-FMN Reductases. Yamada K, Gherasim C, Banerjee R, Koutmos M. J Biol Chem. 2015 Dec 4;290(49):29155–66. PubMed Europe PMC Scholia