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). d7f f03 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] fc7 pyridoxamine 5'-phosphate oxidase Alkaline phosphatase Intestinal alkaline phosphatases delta1-pyrroline-5-carboxylate (P5C) Pyridoxal-5-Phosphate (=PLP) Aldehyde dehydrogenase 7 family, member A1, also known as ALDH7A1 or antiquitin Pyridoxal-5-Phosphate (=PLP) AKA PL Drawing in Chapter 11 Blau contains an error for this metabolite, one carbon is missing from the structure! pyridoxine-5'-beta-D-glucoside aka PNG aka pyridoxine-glucoside piperideine-6-carboxylate Phosphate kinase Phosphate kinase Intestinal alkaline phosphatases Phosphate kinase Phosphate kinase, Pyridoxal kinase Phosphate kinase Phosphate kinase pyridoxamine 5'-phosphate oxidase 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] fc7 P P P P P P P P P dephosphorylation Knoevenagel condensation Leads to cerebral PLP deficiency Sponteneous reaction Feedback inhibitions rephoshorylation Feedback inhibition TNSAP P5C dehydrogenase attachment to cellular membrane by anchor system Sponteneous reaction Knoevenagel condensation dephosphorylation Rephosphorylation rephosphorylation Phosphate kinase Phosphate kinase Oxidation Oxidation Rephosphorylation attachment to cellular membrane by anchor system Transport possible due to hydrolysis hydrolysis Transport possible due to hydrolysis hydrolysis tissue non-specific alkaline phosphatase aka TNSALP DISEASE aka Alpha-amino adipic semialdehyde (AASA) dehydrogenase deficiency DISEASE DISEASE Pyridox(am)ine 5'-phosphate oxidase deficiency DISEASE Pyridox(am)ine 5'-phosphate oxidase deficiency DISEASE aka Alpha-amino adipic semialdehyde (AASA) dehydrogenase deficiency aka PROSC deficiency, vitamin B6-dependent early-onset Epilepsy. hypophosphatasia DOID:14213 Disease proline metabolic pathway PW:0001079 Pathway Ontology 9783642403361 ISBN Physician's Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases, Chapter 11 SBN 978-3-642-40337-8 2014 Blau, N. Duran, M. Gibson, K.M. Dionisi-Vici, C. childhood hypophosphatasia DOID:0110915 Disease hypophosphatasia disease pathway PW:0001881 Pathway Ontology vitamin B6 metabolic pathway PW:0000138 Pathway Ontology pyridoxine-dependent epilepsy DOID:0080768 Disease infantile hypophosphatasia DOID:0110914 Disease epilepsy DOID:1826 Disease hyperprolinemia type II disease pathway PW:0001932 Pathway Ontology lysine degradation pathway PW:0000073 Pathway Ontology hyperprolinemia type 2 DOID:0080543 Disease 31825581 PubMed Biochemical and Proteomic Studies of Human Pyridoxal 5′-Phosphate-Binding Protein (PLPBP) ACS Chem Biol . 2020 Anja Fux Stephan A Sieber early-onset vitamin B6-dependent epilepsy DOID:0080769 Disease 16763894 PubMed B6-responsive disorders: a model of vitamin dependency J Inherit Metab Dis . 2006 Peter T Clayton disease pathway PW:0000013 Pathway Ontology pyridoxamine 5'-phosphate oxidase deficiency DOID:0111329 Disease neural cell CL:0002319 Cell Type