Vitamin B6 (pyridoxal 5'-phosphate) supply by PdxS/PdxT synthesis or vitamer salvage, and PLP homeostasis

Pyridoxal 5'-phosphate (PLP) is the active form of vitamin B6 and the cofactor of a large set of enzymes, including transaminases, decarboxylases and racemases of amino-acid, one-carbon, heme and neurotransmitter metabolism. Cells obtain PLP in two ways. Fungi, plants, archaea and many bacteria can make PLP de novo with the two-subunit PLP synthase: the PdxT (SNO) subunit hydrolyses glutamine and passes the ammonia to the PdxS (SNZ/PDX1) subunit, which builds PLP directly from ribose 5-phosphate and glyceraldehyde 3-phosphate. This route does not use deoxyxylulose 5-phosphate; the separate DXP-dependent route of some bacteria is described in modules/pyridoxal_5_phosphate_biosynthesis.yaml. All cells can also salvage the B6 vitamers. Pyridoxal kinase (PDXK; BUD16 in budding yeast) phosphorylates pyridoxal, pyridoxine and pyridoxamine with ATP to PLP, pyridoxine 5'-phosphate (PNP) and pyridoxamine 5'-phosphate (PMP), and the FMN-dependent PNP/PMP oxidase (PNPO; PDX3 in yeast) oxidises PNP and PMP to PLP. Animals cannot make PLP de novo and depend on salvage of dietary vitamers. In mammals, PLP levels are also tuned by the magnesium-dependent pyridoxal phosphatase PDXP (chronophin), which dephosphorylates PLP back to pyridoxal and also dephosphorylates the actin regulator cofilin. Inherited PNPO deficiency causes a PLP-responsive neonatal epileptic encephalopathy.

Generalised from a human salvage/homeostasis module. The human content (PDXK, PNPO, PDXP and their gene reviews) is kept; fungal exemplars and a de novo entry are added. The PLP supply part is a ONE_OR_MORE variant set because fungi, plants and many bacteria have both the PdxS/PdxT synthase and salvage, whereas animals have only salvage. The PdxS/PdxT synthase is modelled with a separate annoton per subunit: the PdxS (SNZ) annoton carries the overall PLP synthase activity (GO:0036381) and the PdxT (SNO) annoton carries glutaminase activity (GO:0004359), as in the SNO2 gene review. Only SNZ1/SNO1 are used as S. cerevisiae exemplars; the SNZ2/SNZ3/SNO2/SNO3 copies are induced by thiamine limitation and appear to supply PLP for thiamine pyrimidine synthesis (modules/eukaryotic_thiamine_biosynthesis.yaml). S. cerevisiae BUD17, a pyridoxal kinase paralogue of BUD16, is not used because its activity has not been established. The PDXP homeostasis part is optional and characterised in mammals; no fungal PLP phosphatase is assigned. Vitamer uptake (S. cerevisiae TPN1) is outside the module. GO-CAM notes: the SGD model (PLPSAL-PWY) has only BUD16 and PDX3 and no causal edges. The PomBase model adds snz1/sno1 (with sno1 glutaminase directly positively regulating snz1 synthase), two pyridoxal kinases (SPCC18.10 and SPAC6F6.11c), pdx3, and two pyridoxal reductases (plr1, akr7; pyridoxine 4-dehydrogenase, GO:0050236) that interconvert pyridoxal and pyridoxine; the reductases are vitamer interconversion rather than PLP formation and are outside this module. PomBase gives pdx3 no location and places it in pyridoxine biosynthesis and pyridoxamine metabolism rather than PLP salvage.