Vitamin B12 disorders (WP4271)

Homo sapiens

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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 Ehrhart

Activity

last edited

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Organisms

Homo sapiens

Communities

Inherited Metabolic Disorders (IMD) Pathways Rare Diseases

Annotations

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 cblF

Pathway Ontology

methylmalonic aciduria, cobalamin-related pathway cobalamin metabolic pathway mitochondria dynamics pathway

Cell Type Ontology

eukaryotic cell obsolete metabolising cell

Participants
Query Drugst.One

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 Metabolite wikidata:Q3329800
Cbl Metabolite wikidata:Q3329800
Cbl Metabolite wikidata:Q3329800
Cbl Metabolite wikidata:Q3329800
Cbl Metabolite wikidata:Q3329800
Cbl Metabolite wikidata:Q3329800
Cbl Metabolite wikidata:Q3329800
Cbl Metabolite wikidata:Q3329800
Cbl Metabolite wikidata:Q3329800
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
Cbl Metabolite wikidata:Q3329800
Methylmalonyl-CoA Metabolite chebi:16625
Methylcobalamin Metabolite chebi:28115 biologically active forms
According to enzyme functionallity, becomes [methionine synthase]-cob(II)alamin
Homocysteine Metabolite wikidata:Q192466
THF Metabolite chebi:20506 Aka tetrahydrofolate
FAD Metabolite chebi:16238 cofactor
FMN Metabolite chebi:17621 cofactor
NADPH Metabolite chebi:16474
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 1
Produced in saliva and stomach
CUBN Protein uniprot:O60494 aka cubilin
HC Protein uniprot:P20061 aka haptocorrin or transcobalamin 1
HC Protein uniprot:P20061 aka haptocorrin or transcobalamin 1
IF Protein uniprot:P27352 aka (gastric) intrinsic factor, transcobalamin III
Located in gastric parietal cells
IF Protein uniprot:P27352 aka intrinsic factor
IF Protein uniprot:P27352 aka intrinsic factor
AMN Protein uniprot:Q9BXJ7 aka amnionless
IF Protein uniprot:P27352 aka intrinsic factor
TC II Protein uniprot:P20062 aka Transcobalamin 2
HC Protein uniprot:P20061 aka haptocorrin or transcobalamin 1
IF Protein uniprot:P27352 aka intrinsic factor
HC Protein uniprot:P20061 aka haptocorrin or transcobalamin 1
HC Protein uniprot:P20061 aka haptocorrin or transcobalamin 1
TC II Protein uniprot:P20062 aka Transcobalamin 2
TC II Protein uniprot:P20062 aka Transcobalamin 2
TC receptor Protein uniprot:Q9NPF0 Aka CD320 receptor
TC II Protein uniprot:P20062 aka Transcobalamin 2
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: 21114891
gene 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 protein
Gene is called MTR, for methyltransferase
coBM/cbLF Protein eccode:2.1.1.133
cbLC Protein uniprot:Q9Y4U1 Gene is called MMAC
cbLC Protein uniprot:Q9Y4U1 Gene is called MMAC
cbLC Protein uniprot:Q9Y4U1 Gene is called MMAC
Protein in complex Protein ensembl:ENSG00000116984 5-methyltetrahydrofolate-homocysteine methyltransferase

References

  1. 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
  2. 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
  3. 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
  4. 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
  5. 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
  6. 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
  7. 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