Vitamin B6-dependent and responsive disorders (WP4228)
Homo sapiens
Vitamine B6 is absorbed in different vitamers, which undergo several (de)phosphorylation steps, to be able to pas the blood-brain barrier. Within the brain, PLP (Pyridoxal-P) is the only active cofactor for intracellular enzyme reactions. PLP catalyses over 100 reactions, mainly related to amino acids and neurotransmitter metabolism. Bold lines in the Figure show how the major source of PLP is divided in the body. A number of genetic defects have been identified as the underlying cause of vitamine B6 dependent epilepsies, particularly occurring in the neonatal life stage, which could lead to irreversible brain damage or could be fatal. The disorders related to this pathway can be divided in two categories: reduced production/availability of PLP or inactivation of PLP by formation of Knoevenagel products. Specific biomarkers from urine, plasma or Cerebral Spinal Fluid (CSF) exist to distinguish the disorders. Oral treatment with PL or PLP is available, as well as intrauterine treatment with vitamine B6 for mothers in the early stages of pregnancy. This pathway was inspired by Ed. 5 Chapter 34 of the book of Blau (ISBN 9783030677268) (ed.4 Chapter 11).
Authors
Lisa Martina Held , Denise Slenter , Egon Willighagen , Kristina Hanspers , Irene Hemel , Martina Summer-Kutmon , Friederike Ehrhart , Susan Coort , Marvin Martens , and Finterly HuCited In
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Organism
Homo sapiensCommunities
Diseases Inborn Errors of Metabolism (IEM) Pathways Rare DiseasesAnnotations
Pathway Ontology: disease pathway hypophosphatasia pathway lysine degradation pathway vitamin B6 metabolic pathway hyperprolinemia type II pathway proline metabolic pathway
Disease Ontology: infantile hypophosphatasia childhood hypophosphatasia hyperprolinemia type 2 pyridoxine-dependent epilepsy pyridoxamine 5'-phosphate oxidase deficiency early-onset vitamin B6-dependent epilepsy epilepsy hypophosphatasia
Cell Type Ontology: neural cell
Participants
| Label | Type | Compact Identifier | Comment |
|---|---|---|---|
| 2-keto 6-aminocaproic acid | Metabolite | chebi:17534 | |
| L-lysine | Metabolite | chebi:18019 | |
| pyridoxal | Metabolite | chebi:17310 | |
| Pipecolic acid | Metabolite | chebi:30913 | |
| P5C | Metabolite | chebi:17388 | delta1-pyrroline-5-carboxylate (P5C) |
| PLP | Metabolite | chebi:18405 | Pyridoxal-5-Phosphate (=PLP) |
| pyridoxamine-p | Metabolite | chebi:18335 | |
| Pyridoxal-P | Metabolite | chebi:18405 | |
| PLP | Metabolite | chebi:18405 | Pyridoxal-5-Phosphate (=PLP) |
| piperideine-2-carboxylate | Metabolite | chebi:16187 | |
| Vitamin B6 | Metabolite | chebi:27306 | |
| pyridoxal | Metabolite | chebi:17310 | AKA PL |
| glutamic semialdehyde | Metabolite | chebi:58066 | Drawing in Chapter 11 Blau contains an error for this metabolite, one carbon is missing from the structure! |
| Saccharopine | Metabolite | chebi:16927 | |
| pyridoxamine-p | Metabolite | chebi:18335 | |
| L-proline | Metabolite | chebi:17203 | |
| Pyridoxine-P | Metabolite | chebi:28803 | |
| pyridoxamine | Metabolite | chebi:57761 | |
| Pyridoxal-P | Metabolite | chebi:18405 | |
| glutamic acid | Metabolite | chebi:29985 | |
| alpha aminoadipic semialdehyde | Metabolite | pubchem.compound:207 | |
| pyridoxamine | Metabolite | chebi:57761 | |
| pyridoxamine-p | Metabolite | chebi:18335 | |
| alpha aminoadipic acid | Metabolite | chebi:37024 | |
| Pyridoxine | Metabolite | chebi:16709 | |
| pyridoxine-glucoside | Metabolite | chebi:17382 | pyridoxine-5'-beta-D-glucoside aka PNG aka pyridoxine-glucoside |
| Pyridoxine-P | Metabolite | chebi:28803 | |
| Pyridoxine | Metabolite | chebi:16709 | |
| P6C | Metabolite | chebi:16987 | piperideine-6-carboxylate |
| PNPO | GeneProduct | ensembl:ENSG00000108439 | pyridoxamine 5'-phosphate oxidase |
| PLPBP | Protein | uniprot:O94903 | AKA PROSC'The pyridoxal 5'-phosphate-binding protein (PLPBP) is an evolutionarily conserved protein linked to pyridoxal 5'-phosphate-binding. Although mutations in PLPBP were shown to cause vitamin B6-dependent epilepsy, its cellular role and function remain elusive. ' [PMID:31825581]Dimer [PMID:31825581] |
| ALPL | Protein | ensembl:ENSG00000162551 | Alkaline phosphatase |
| P5C dehydrogenase | Protein | interpro:IPR005931 | |
| Antiquitin | Protein | ensembl:ENSG00000164904 | Aldehyde dehydrogenase 7 family, member A1, also known as ALDH7A1 or antiquitin |
| PIGV anchor | Protein | ensembl:ENSG00000060642 | |
| PK | Protein | uniprot:O00764 | Phosphate kinase |
| PK | Protein | uniprot:O00764 | Phosphate kinase |
| PK | Protein | uniprot:O00764 | Phosphate kinase |
| PK | Protein | uniprot:O00764 | Phosphate kinase, Pyridoxal kinase |
| PK | Protein | uniprot:O00764 | Phosphate kinase |
| PK | Protein | uniprot:O00764 | Phosphate kinase |
| PNPO | Protein | ensembl:ENSG00000108439 | pyridoxamine 5'-phosphate oxidase |
| PLPBP | Protein | uniprot:O94903 | AKA PROSC'The pyridoxal 5'-phosphate-binding protein (PLPBP) is an evolutionarily conserved protein linked to pyridoxal 5'-phosphate-binding. Although mutations in PLPBP were shown to cause vitamin B6-dependent epilepsy, its cellular role and function remain elusive. ' [PMID:31825581]Dimer [PMID:31825581] |
References
- Blau N, Duran M, Gibson KM, Dionisi-Vici C. Physician’s Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases [Internet]. Springer; 2014. 867 p. Available from: https://books.google.com/books/about/Physician_s_Guide_to_the_Diagnosis_Treat.html?hl=&id=wJRBnwEACAAJ OpenLibrary Worldcat
- Clayton PT. B6-responsive disorders: a model of vitamin dependency. J Inherit Metab Dis. 2006;29(2–3):317–26. PubMed Europe PMC Scholia
- Fux A, Sieber SA. Biochemical and Proteomic Studies of Human Pyridoxal 5’-Phosphate-Binding Protein (PLPBP). ACS Chem Biol. 2020 Jan 17;15(1):254–61. PubMed Europe PMC Scholia