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)).ad1Hcy = homocysteineb2fcofactorbiologically active formaka S-adenosyl-L-homocysteineb2fcofactorMMA = methylmalonic acidaka S-adenosyl-L-methionineb2faka methylmalonyl-CoA mutase or MCMaka cbLD-MMAAka methyltetrahydrofolateaka Transcobalamin 2aka haptocorrin or transcobalamin 1Produced in saliva and stomachaka cubilinaka haptocorrin or transcobalamin 1aka haptocorrin or transcobalamin 1aka (gastric) intrinsic factor, transcobalamin IIILocated in gastric parietal cellsaka intrinsic factoraka intrinsic factoraka amnionlessaka intrinsic factoraka Transcobalamin 2aka haptocorrin or transcobalamin 1aka intrinsic factoraka haptocorrin or transcobalamin 1aka haptocorrin or transcobalamin 1aka Transcobalamin 2aka Transcobalamin 2Aka CD320 receptoraka Transcobalamin 2Cobalamin has been transformed to cyanocobalamin according to lit., before it can undergo conversion by cbLC.Should be cob(II)alamin according to literatureGene is called MMACCompound is suspected to be cob(III)alamine, since reaction with cbLD should produce oxidised form of cob(II)alaminCompound is suspected to be cob(III)alamine, since reaction with cbLD should produce oxidised form of cob(II)alamingene: MMABGene: MMAAaka cbLD-Hcy"cblD protein might be responsible for branching of the cobalamin metabolism pathways to the cytosolic or mitochondrial compartments" Pubmed: 21114891gene is called MMADHCbiologically active formsAccording to enzyme functionallity, becomes [methionine synthase]-cob(II)alaminGene is MTRR, protein aka methionine synthase reductase (MSR)reductive regeneration of cob(I)alamin (vitamin B12) cofactorAka tetrahydrofolateaka MS or methionine synthase for proteinGene is called MTR, for methyltransferaseGene is called MMACGene is called MMACGene is called MMACcofactorcofactorb2f5-methyltetrahydrofolate-homocysteine methyltransferasecbLD promotes oxidation of cob(II)alamina5fce7Translocation outside the mitochondrionReaction possibly contains multiple steps (not clear from original drawing).dbace7cbLF is related to transport out of lysosome.a77"Catalyzes the transfer of a methyl group from methyl-cobalamin to homocysteine, yielding enzyme-bound cob(I)alamin and methionine. Subsequently, remethylates the cofactor using methyltetrahydrofolate" [https://www.uniprot.org/uniprot/Q99707]ce7transport outside of lysosomea77b2freductive regeneration of cob(I)alamin (vitamin B12) cofactorb2fb2fe76Translocation into Mitochondrionb2fCbl binds to HCCbl-TC II complex binds to TC receptorInternalisation of Cbl-TC II complex, creates free Cble76Transport of Cbl-TC II complex to tissuese76e76In the duodenum, pancreatic enzymes degrade the Cbl-HC complex, releasing free CblUptake by epithelial cells in terminal ileum via receptor mediated endocytosise76Receptor mediated endocytosisFree Cbl enters the portal circulation, bound to transcobalamine76reductive dealkylationce7cbLD promotes oxidation of cob(II)alamina5fa77ce7ce7Release from food proteinsBifunctional enzyme, information comes from pubmed:11215515dba11215515PubMedBiosynthesis of cobalamin (vitamin B12): a bacterial conundrum.Cell Mol Life Sci2000Raux ESchubert HLWarren MJ26364851PubMedStructure of Human B12 Trafficking Protein CblD Reveals Molecular Mimicry and Identifies a New Subfamily of Nitro-FMN Reductases.J Biol Chem2015Yamada KGherasim CBanerjee RKoutmos Mvitamin B12 deficiencyDOID:0050731Disease19700356PubMedMechanism of vitamin B12-responsiveness in cblC methylmalonic aciduria with homocystinuria.Mol Genet Metab2009Froese DSZhang JHealy SGravel RAmethylmalonic aciduria, cobalamin-related pathwayPW:0001811Pathway Ontology9783642403361ISBN'Physician's Guidee to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases2014Blau, NenadDuran, MarinusGibson, K. MichaelDionisi-Vici, Carlocobalamin metabolic pathwayPW:0000397Pathway Ontologymethylmalonic aciduria due to methylmalonyl-CoA mutase deficiencyDOID:0060740Diseasemethylmalonic aciduria and homocystinuria type cblCDOID:0050715Diseasemethylmalonic aciduria and homocystinuria type cblDDOID:0050716Diseasemethylmalonic acidemiaDOID:14749Diseaseeukaryotic cellCL:0000255Cell Type17892308PubMedMechanism of coenzyme binding to human methionine synthase reductase revealed through the crystal structure of the FNR-like module and isothermal titration calorimetry.Biochemistry2007Wolthers KRLou XToogood HSLeys DScrutton NS21114891PubMedGenetic disorders of vitamin B12 metabolism: eight complementation groups--eight genes.Expert Rev Mol Med2010Froese DSGravel RAmetabolising cellCL:0000181Cell Typemitochondria dynamics pathwayPW:0001961Pathway Ontologymethylmalonic acidemia cb1A typeDOID:0060742Diseasemethylmalonic acidemia cb1B typeDOID:0060743Diseasemethylmalonic aciduria and homocystinuria type cblFDOID:0050717Disease21312325PubMedInborn errors of cobalamin absorption and metabolism.Am J Med Genet C Semin Med Genet2011Watkins DRosenblatt DS