PDXK (pyridoxal kinase) is the rate-limiting enzyme for vitamin B6 metabolism, catalyzing the phosphorylation of dietary B6 vitamers (pyridoxal, pyridoxine, and pyridoxamine) to their active forms, primarily pyridoxal 5'-phosphate (PLP) 1. PLP serves as an essential cofactor for over 140 enzymatic reactions across diverse metabolic pathways 2. PDXK expression is regulated through a TATA-box-free promoter containing critical Sp1 binding sites 2. Biallelic PDXK mutations cause autosomal recessive hereditary motor and sensory neuropathy with optic atrophy, characterized by axonal polyneuropathy leading to progressive wheelchair dependence and blindness if untreated 13. Disease pathogenesis involves reduced PDXK enzymatic activity and consequently low circulating PLP levels 1. Notably, this is one of the few inherited neuropathies amenable to targeted treatment: pyridoxal 5'-phosphate supplementation rescues the biochemical profile and produces clinical improvement, including restoration of ambulation 1. Excessive pyridoxine supplementation induces peripheral neuropathy through PDXK inhibition and disrupted GABA neurotransmission in sensory neurons 4. Beyond neurological function, PDXK is selectively required for acute myeloid leukemia cell proliferation, representing a pharmacologically actionable metabolic dependency 5. PDXK also regulates thermoregulation through hypothalamic vitamin B6 metabolism 6.