Vitamin B6 (pyridoxal 5'-phosphate) salvage and homeostasis (PDXK/PNPO/PDXP)

Pyridoxal 5'-phosphate (PLP) is the active form of vitamin B6 and the obligatory cofactor of ~140 human enzymes — transaminases, decarboxylases, racemases and others across amino-acid, one-carbon, heme and neurotransmitter metabolism. Because humans cannot synthesise the vitamin de novo, PLP is produced and homeostatically balanced by a small salvage pathway that interconverts the dietary B6 vitamers and their phosphorylated forms. Pyridoxal kinase (PDXK) phosphorylates the three unphosphorylated vitamers — pyridoxal, pyridoxine and pyridoxamine — with ATP (and a divalent metal) to pyridoxal 5'-phosphate (PLP), pyridoxine 5'-phosphate (PNP) and pyridoxamine 5'-phosphate (PMP). The FMN-dependent pyridoxine 5'-phosphate oxidase (PNPO) then carries out the terminal, rate-limiting step, oxidising PNP and PMP to the active PLP cofactor. Balancing this, the magnesium-dependent pyridoxal phosphatase PDXP (chronophin) dephosphorylates PLP back to pyridoxal, tuning intracellular PLP levels; PDXP also has a well-documented moonlighting role dephosphorylating the actin-regulatory protein cofilin (phospho-Ser3) to promote actin depolymerisation. Inherited PNPO deficiency causes a severe pyridoxal-5'-phosphate-responsive neonatal epileptic encephalopathy, underscoring how tightly neuronal PLP supply depends on this pathway.