Vitamin B12 disorders (Homo sapiens)

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327614166451217777LysosomeIntrinsicFactor DeficiencyDistribution via bloodIleal mucosal cellsepithelial cellsTissueTarget cellCubam receptorAbsorption and transportDietary Cbl:meat, milk, eggs, fish, and shellfishNADPHFMNcbLFMethylmalonic Acid2 * SAMSuccinyl-CoAHcyMTHF2 * SAHFADMUTAdenosylcobalaminNADP+MethioninecbLD-IIMMA111TC receptorTC IIHCCUBNCblCblHCCblHCCblIFIFCblIFAMNCblIFTC IIHCIFCblHCCblHCCblTC II7CblTC IITC receptorCblTC IICbl(cyanocobalamin)Cbl(cob(II)alamin)6cbLJcbLC2 * Cbl(cob(III)alamine)Cbl(cob(III)alamine)5MitochondrionCblcbLBcbLAMethylmalonyl-CoAcbLD-IcbLDMethylcobalamincbLEHomocysteineTHFcbLGcoBM/cbLFCytosolcbLCcbLCcbLCFADFMN466IntracellularMetabolismNADPHCubilinDeficiency1AmnionlessDeficiencyHaptocorrinDeficiencyTranscobalaminDeficiencyTranscobalaminReceptorDefectAdenosylcobalaminSynthesis DefectcblAAdenosylcobalaminSynthesis DefectcblBAdenosylcobalaminSynthesis DefectcblD-MMAAdenosylcobalaminSynthesis DefectcblD-HCMethionineSynthase DeficiencycblGMethionineSynthase DeficiencycblEAdenosylcobalaminand methylcobalaminSynthesis DefectcblCAdenosylcobalaminand methylcobalaminSynthesis DefectcblD-MMA/HCAdenosylcobalaminand methylcobalaminSynthesis DefectcblFAdenosylcobalaminand methylcobalaminSynthesis DefectcblJDiseaseCatalysisPathwayStimulationProteinMetaboliteConversionConnection to diseaseLegendBiomarkerCofactorProtein in Complex


Description

This pathway depicts the metabolism of cobalamin (also known as cbl or Vit. B12) and related diseases (for a full overview of the B12 metabolism, see [1]).

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)).

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Quality Tags

Ontology Terms

 

Bibliography

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  1. Yamada K, Gherasim C, Banerjee R, Koutmos M; ''Structure of Human B12 Trafficking Protein CblD Reveals Molecular Mimicry and Identifies a New Subfamily of Nitro-FMN Reductases.''; J Biol Chem, 2015 PubMed Europe PMC Scholia
  2. Froese DS, Zhang J, Healy S, Gravel RA; ''Mechanism of vitamin B12-responsiveness in cblC methylmalonic aciduria with homocystinuria.''; Mol Genet Metab, 2009 PubMed Europe PMC Scholia
  3. Blau, Nenad, Duran, Marinus, Gibson, K. Michael, Dionisi-Vici, Carlo; '''Physician's Guidee to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases''; , 2014
  4. Watkins D, Rosenblatt DS; ''Inborn errors of cobalamin absorption and metabolism.''; Am J Med Genet C Semin Med Genet, 2011 PubMed Europe PMC Scholia
  5. Froese DS, Gravel RA; ''Genetic disorders of vitamin B12 metabolism: eight complementation groups--eight genes.''; Expert Rev Mol Med, 2010 PubMed Europe PMC Scholia
  6. Wolthers KR, Lou X, Toogood HS, Leys D, Scrutton NS; ''Mechanism of coenzyme binding to human methionine synthase reductase revealed through the crystal structure of the FNR-like module and isothermal titration calorimetry.''; Biochemistry, 2007 PubMed Europe PMC Scholia
  7. Raux E, Schubert HL, Warren MJ; ''Biosynthesis of cobalamin (vitamin B12): a bacterial conundrum.''; Cell Mol Life Sci, 2000 PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
128221view04:13, 29 January 2024EweitzModified description
128220view04:11, 29 January 2024EweitzSoften disease color, standardize case
124608view19:40, 15 November 2022EgonwReplaced an old Wikidata identifier
124266view11:56, 6 October 2022DeSlConverted last interaction from textlabel to graphical line
124265view11:55, 6 October 2022DeSlAdded link to PWM folate metabolism
124264view11:52, 6 October 2022DeSlUpdated IDs for MTHF and THF, based on overlapping PWM
124259view07:53, 6 October 2022DeSlConverted interactions to diseases into graphical lines
120408view09:24, 30 November 2021Fehrhartsmall graphical change in pathway node
119259view19:47, 22 June 2021Finterlyfixed ISBN from ebook to hardcover
119255view19:43, 22 June 2021FinterlyAdded ISBN for book citation
117853view15:20, 22 May 2021EweitzModified title
114414view15:21, 10 January 2021DeSlAdded legend
114413view15:18, 10 January 2021DeSlTypo fix for methionine
104475view17:45, 28 May 2019EgonwConverted a number of Label-Interaction's to graphical lines.
104474view17:37, 28 May 2019EgonwFixed the href URL.
104025view17:39, 25 April 2019IreneHemelModified description
99064view12:23, 29 October 2018DeSlModified description
99063view12:14, 29 October 2018DeSlOntology Term : 'methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency' added !
99062view12:13, 29 October 2018DeSlOntology Term : 'mitochondria dynamics pathway' added !
99061view12:12, 29 October 2018DeSlOntology Term : 'metabolising cell' added !
99060view12:11, 29 October 2018DeSlOntology Term : 'eukaryotic cell' added !
99059view12:11, 29 October 2018DeSlOntology Term : 'methylmalonic acidemia' added !
99058view12:10, 29 October 2018DeSlOntology Term : 'methylmalonic acidemia cb1B type' added !
99057view12:10, 29 October 2018DeSlOntology Term : 'methylmalonic acidemia cb1A type' added !
99056view12:09, 29 October 2018DeSlOntology Term : 'vitamin B12 deficiency' added !
99055view12:09, 29 October 2018DeSlOntology Term : 'methylmalonic aciduria, cobalamin-related pathway' added !
99054view12:09, 29 October 2018DeSlOntology Term : 'methylmalonic aciduria and homocystinuria type cblF' added !
99053view12:09, 29 October 2018DeSlOntology Term : 'methylmalonic aciduria and homocystinuria type cblD' added !
99052view12:09, 29 October 2018DeSlOntology Term : 'methylmalonic aciduria and homocystinuria type cblC' added !
99051view12:09, 29 October 2018DeSlOntology Term : 'cobalamin metabolic pathway' added !
99050view12:07, 29 October 2018DeSlAnnotated last nodes.
99049view12:01, 29 October 2018DeSlRemoved weird signs in lit. ref
99048view11:59, 29 October 2018DeSlAdded other diseases from chapter.
99047view11:01, 29 October 2018DeSlAdded several disease from Blau book.
99021view12:32, 24 October 2018DeSlUpdating last edits.
99003view15:33, 22 October 2018DeSlAdded annotation and complete reaction for cbLE
99002view15:21, 22 October 2018DeSlChanged layout of text boxes for readability.
99000view08:43, 22 October 2018DeSlAdded ID for IF.
98999view08:41, 22 October 2018DeSlChanged font size, added intracellular metabolism textbox.
98998view08:38, 22 October 2018DeSlChanged layout for readability on Website.
98979view05:33, 19 October 2018EgonwRemoved duplicate fields in Biopax publicationXref (causing info to disappear).
98978view05:32, 19 October 2018EgonwFixed weird chars in article title.
98975view19:30, 18 October 2018DeSlAdded more info about MUT and cbLG.
98974view19:23, 18 October 2018DeSlannotated Cbl after cbLD conversion step.
98973view19:15, 18 October 2018DeSlAdded annotation for cbDL-I and II
98972view19:11, 18 October 2018DeSlAdded lit. ref and annotation for cbLD step
98971view19:05, 18 October 2018DeSlAdded more nodes for cbLC conversion step + annotated nodes.
98970view18:15, 18 October 2018DeSlAdded right side (methylcobalamin formation), annotated several metabolites.
98969view18:04, 18 October 2018DeSlAdded conversion to adenosylcobalamin side.
98968view11:12, 18 October 2018DeSlAdded another lit. ref for specific transport info in chapter

External references

DataNodes

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NameTypeDatabase referenceComment
2 * Cbl (cob(III)alamine)MetaboliteCHEBI:28911 (ChEBI) Compound is suspected to be cob(III)alamine, since reaction with cbLD should produce oxidised form of cob(II)alamin
2 * SAHMetaboliteCHEBI:16680 (ChEBI) aka S-adenosyl-L-homocysteine
2 * SAMMetaboliteCHEBI:15414 (ChEBI) aka S-adenosyl-L-methionine
AMNProteinQ9BXJ7 (Uniprot-TrEMBL) aka amnionless
AdenosylcobalaminMetaboliteQ47517602 (Wikidata) biologically active form
CUBNProteinO60494 (Uniprot-TrEMBL) aka cubilin
Cbl (cob(II)alamin)MetaboliteCHEBI:16304 (ChEBI) Should be cob(II)alamin according to literature
Cbl (cob(III)alamine)MetaboliteCHEBI:28911 (ChEBI) Compound is suspected to be cob(III)alamine, since reaction with cbLD should produce oxidised form of cob(II)alamin
Cbl (cyanocobalamin)MetaboliteQ27286306 (Wikidata) Cobalamin has been transformed to cyanocobalamin according to lit., before it can undergo conversion by cbLC.
CblMetaboliteQ3329800 (Wikidata)
CofactorMetaboliteCHEBI:28115 (ChEBI)
FADMetaboliteCHEBI:16238 (ChEBI) cofactor
FMNMetaboliteCHEBI:17621 (ChEBI) cofactor
HCProteinP20061 (Uniprot-TrEMBL) aka haptocorrin or transcobalamin 1
HcyMetaboliteQ192466 (Wikidata) Hcy = homocysteine
HomocysteineMetaboliteQ192466 (Wikidata)
IFProteinP27352 (Uniprot-TrEMBL) aka intrinsic factor
MMAMetaboliteQ239598 (Wikidata) MMA = methylmalonic acid
MTHFMetaboliteCHEBI:25345 (ChEBI) Aka methyltetrahydrofolate
MUTProteinP22033 (Uniprot-TrEMBL) aka methylmalonyl-CoA mutase or MCM
MethionineMetaboliteCHEBI:16811 (ChEBI)
MethylcobalaminMetaboliteCHEBI:28115 (ChEBI)
  • biologically active forms
  • According to enzyme functionallity, becomes [methionine synthase]-cob(II)alamin
Methylmalonic AcidMetaboliteQ239598 (Wikidata)
Methylmalonyl-CoAMetaboliteCHEBI:16625 (ChEBI)
NADP+MetaboliteCHEBI:18009 (ChEBI)
NADPHMetaboliteCHEBI:16474 (ChEBI)
Protein in ComplexProteinENSG00000116984 (Ensembl) 5-methyltetrahydrofolate-homocysteine methyltransferase
Succinyl-CoAMetaboliteCHEBI:15380 (ChEBI)
TC IIProteinP20062 (Uniprot-TrEMBL) aka Transcobalamin 2
TC receptorProteinQ9NPF0 (Uniprot-TrEMBL) Aka CD320 receptor
THFMetaboliteCHEBI:67016 (ChEBI) Aka tetrahydrofolate
cbLAProteinQ8IVH4 (Uniprot-TrEMBL) Gene: MMAA
cbLBProteinQ96EY8 (Uniprot-TrEMBL) gene: MMAB
cbLCProteinQ9Y4U1 (Uniprot-TrEMBL) Gene is called MMAC
cbLD-IIProteinQ9H3L0 (Uniprot-TrEMBL) aka cbLD-MMA
cbLD-IProteinQ9H3L0 (Uniprot-TrEMBL) aka cbLD-Hcy
cbLDProteinQ9H3L0 (Uniprot-TrEMBL)
  • "cblD protein might be responsible for branching of the cobalamin metabolism pathways to the cytosolic or mitochondrial compartments" Pubmed: 21114891
  • gene is called MMADHC
cbLEProteinQ9UBK8 (Uniprot-TrEMBL)
  • Gene is MTRR, protein aka methionine synthase reductase (MSR)
  • reductive regeneration of cob(I)alamin (vitamin B12) cofactor
cbLFProtein2.1.1.133 (Enzyme Nomenclature)
cbLGProteinQ99707 (Uniprot-TrEMBL)
  • aka MS or methionine synthase for protein
  • Gene is called MTR, for methyltransferase
cbLJProtein2.1.1.131 (Enzyme Nomenclature)
coBM/cbLFProtein2.1.1.133 (Enzyme Nomenclature)

Annotated Interactions

No annotated interactions

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