Pyridoxal 5'-phosphate (PLP), the active form of vitamin B6, functions as a cofactor
in humans for more than 140 enzymes, many of which are involved in neurotransmitter
synthesis and degradation. A deficiency of PLP can present, therefore, as seizures
and other symptoms that are treatable with PLP and/or pyridoxine. Deficiency of PLP
in the brain can be caused by inborn errors affecting B6 vitamer metabolism or by
inactivation of PLP, which can occur when compounds accumulate as a result of inborn
errors of other pathways or when small molecules are ingested. Whole-exome sequencing
of two children from a consanguineous family with pyridoxine-dependent epilepsy revealed
a homozygous nonsense mutation in proline synthetase co-transcribed homolog (bacterial),
PROSC, which encodes a PLP-binding protein of hitherto unknown function. Subsequent
sequencing of 29 unrelated indivduals with pyridoxine-responsive epilepsy identified
four additional children with biallelic PROSC mutations. Pre-treatment cerebrospinal
fluid samples showed low PLP concentrations and evidence of reduced activity of PLP-dependent
enzymes. However, cultured fibroblasts showed excessive PLP accumulation. An E.coli
mutant lacking the PROSC homolog (ΔYggS) is pyridoxine sensitive; complementation
with human PROSC restored growth whereas hPROSC encoding p.Leu175Pro, p.Arg241Gln,
and p.Ser78Ter did not. PLP, a highly reactive aldehyde, poses a problem for cells,
which is how to supply enough PLP for apoenzymes while maintaining free PLP concentrations
low enough to avoid unwanted reactions with other important cellular nucleophiles.
Although the mechanism involved is not fully understood, our studies suggest that
PROSC is involved in intracellular homeostatic regulation of PLP, supplying this cofactor
to apoenzymes while minimizing any toxic side reactions.