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Abstract

  1. Pyridoxal 5′-phosphate (PLP), the active form of vitamin B6, is the cofactor for over 140 enzyme catalysed reactions. For most of these reactions, an amino acid is the substrate or one of the substrates. Thus PLP-catalysed reactions play a central role in amino acid metabolism, including the synthesis and/or catabolism of neurotransmitter amino acids and amines in the brain. Reduced levels of PLP in the brain can cause epilepsy, probably as a consequence of the neurotransmitter abnormalities.

  2. Vitamin B6 can be present in the diet as pyridoxal, pyridoxamine and pyridoxine, their 5′-phosphate derivatives and, in the case of pyridoxine, as a 5′-glucoside. The phosphate and glucoside derivatives are cleaved by intestinal hydrolases prior to absorption of B6 as pyridoxal, pyridoxamine and pyridoxine.

  3. Conversion of pyridoxal, pyridoxamine and pyridoxine to their 5′-phosphate derivatives in the liver requires pyridoxal kinase. Pyridoxamine 5′-phosphate and pyridoxine 5′-phosphate are then converted to pyridoxal 5′-phosphate by pyridox(am)ine phosphate oxidase (PNPO).

  4. Pyridoxal 5′-phosphate generated in the liver is the principal circulating form of vitamin B6; in plasma much of the vitamer is bound to albumin. Prior to entry into organs such as the brain, pyridoxal 5′-phosphate is cleaved by the ectoenzyme, tissue non-specific alkaline phosphatase. Once in the brain pyridoxal is rephosphorylated by pyridoxal kinase.

  5. Catabolism of pyridoxal 5′phosphate involves the action of a phosphatase producing pyridoxal and then an aldehyde oxidase or aldehyde dehydrogenase producing 4-pyridoxic acid which is excreted in the urine. A number of phosphatases are active on PLP. These include pyridoxal phosphatase, the alkaline phosphatases, acid phosphatases and the PHOSPHO2 gene product. The relative importance of these different phosphatases in PLP homeostasis in different tissues is not known.

  6. The concentrations of pyridoxal 5′-phosphate and pyridoxal in tissues and body fluids are regulated by the activity of the phosphatases and kinases. Some additional regulation may occur through PNPO which regenerates pyridoxal phosphate from pyridoxamine phosphate. Whole body B6 homeostasis involves activation of the catabolic pathway; when ingestion of B6 is in excess of needs, the excess B6 is excreted as 4′-pyridoxic acid.

  7. Reduced expression of tissue non-specific alkaline phosphatase (hypophosphatasia) leads to high levels of PLP in plasma but to low levels in the brain and hence to B6-responsive epilepsy. This highlights the importance of (TNSALP) in mediating transport of PLP from blood to the cells of the brain.

  8. The concentration of pyridoxal 5′-phosphate in the liver shows a marked circadian fluctuation; a lesser degree of circadian variation occurs in the brain. In the daily cycle, increased levels of PLP are achieved by activation of pyridoxal kinase by three PAR bZip transcription factors, DBP (albumin D-site-binding protein), HLF (hepatic leukaemia factor) and TEF (thyrotroph embryonic factor). Knockout of these three transcription factors in the mouse leads to seizures with a low concentration of PLP in the brain.

  9. PNPO deficiency in man causes a severe, potentially fatal, seizure disorder that is resistant to treatment with anticonvulsant drugs and pyridoxine but responds dramatically to treatment with pyridoxal 5′-phosphate. It is caused by recessive mutations in the PNPO gene on chromosome 17q21.32.

  10. Many of the first described cases of PNPO deficiency were premature infants who were in poor condition at birth and whose seizures started within hours of birth. They had changes in their CSF biochemistry that suggested severely deranged metabolism of amino acids and neurotransmitter amines in the brain (e.g. raised threonine and 3-methoxytyrosine). Patients subsequently identified, on the basis of their response to PLP and sequencing of PNPO, have not all shown the characteristic abnormalities of amino acid and amine metabolites. CSF pyridoxal 5′-phosphate levels have been low when measured.

  11. Vitamin B6 can be given therapeutically as pyridoxine (hydrochloride) or as pyridoxal 5′phosphate. There are over 10 inborn errors of metabolism that can be pyridoxine-responsive or pyridoxal 5-phosphate responsive. There are three groups of B6 responsive inborn errors of metabolism (IEM):

    • In the first group, the IEM leads to the accumulation of a small molecule that reacts with PLP and inactivates it. This group includes hyperprolinaemia type II (in which the accumulation of Δ1-pyrroline 5-carboxylate leads to the inactivation of PLP, see Chap. 81) and pyridoxine dependent epilepsy due to mutations in the ALDH7A1 gene encoding antiquitin, an aldehyde dehydrogenase active on alpha-amino-adipic semialdehyde (AASA). In the latter disorder, accumulation of AASA leads to build up of its equilibrium partner Δ1-piperideine 6-carboxylate (P6C) and it is the P6C that inactivates PLP.

    • The second group of B6-responsive IEM’s are those directly affecting synthesis and/or transport of B6 vitamers. This group includes hypophosphatasia and PNPO deficiency (see above).

    • The third group of B6-responsive IEM’s are disorders leading to reduced activity of an enzyme for which pyridoxal 5′-phosphate is the cofactor. These include classical homocystinuria (cystathionine β-synthase deficiency), pyridoxine-responsive anaemia (δ-amino-laevulinate synthase deficiency) and primary hyperoxaluria type I (alanine glyoxylate aminotransferase deficiency) among others. The beneficial effects may occur via the effect of increased co-factor on the catalysed reaction or by a chaperone effect during synthesis of the enzyme.

  12. B6 therapy needs to be used with caution. Doses of pyridoxine above 200 mg per day in an adult have been associated with the development of a peripheral neuropathy. Some children on high doses of pyridoxal 5′-phosphate have shown evidence of significant liver damage.

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