Vitamin B6-dependent and responsive disorders (WP4228)

Homo sapiens

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Vitamin 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 pathway diagram 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 vitamin B6 dependent epilepsies, particularly occurring in the neonatal life stage, which could lead to irreversible brain damage or death. 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 cerebrospinal fluid (CSF) exist to distinguish the disorders. Oral treatment with PL or PLP is available, as well as intrauterine treatment with vitamin 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 , Finterly Hu , and Eric Weitz

Activity

last edited

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Organisms

Homo sapiens

Communities

Diseases Inherited Metabolic Disorders (IMD) Pathways Rare Diseases

Annotations

Disease Ontology

hypophosphatasia childhood hypophosphatasia pyridoxine-dependent epilepsy infantile hypophosphatasia epilepsy hyperprolinemia type 2 early-onset vitamin B6-dependent epilepsy pyridoxamine 5'-phosphate oxidase deficiency

Pathway Ontology

proline metabolic pathway hypophosphatasia pathway vitamin B6 metabolic pathway hyperprolinemia type II pathway lysine degradation pathway disease pathway

Cell Type Ontology

neural cell

Participants
Query Drugst.One

Label Type Compact URI 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
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
L-proline Metabolite chebi:17203
Pyridoxine-P Metabolite chebi:28803
Pyridoxamine Metabolite chebi:57761
Glutamic acid Metabolite chebi:29985
Alpha aminoadipic semialdehyde Metabolite pubchem.compound:207
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
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
IP Protein ensembl:ENSG00000163295 Intestinal alkaline phosphatases
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, Pyridoxal kinase
PNPO Protein ensembl:ENSG00000108439 pyridoxamine 5'-phosphate oxidase

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. B6-responsive disorders: a model of vitamin dependency. Clayton PT. J Inherit Metab Dis. 2006;29(2–3):317–26. PubMed Europe PMC Scholia
  3. Biochemical and Proteomic Studies of Human Pyridoxal 5’-Phosphate-Binding Protein (PLPBP). Fux A, Sieber SA. ACS Chem Biol. 2020 Jan 17;15(1):254–61. PubMed Europe PMC Scholia