Pyridoxal 5′-phosphate deficiency causes a loss of aromatic l-amino acid decarboxylase in patients and human neuroblastoma cells, implications for aromatic l-amino acid decarboxylase and vitamin B6 deficiency states
Pyridoxal 5′-phosphate, the active form of vitamin B6, is an essential cofactor for multiple enzymes, including aromaticl-amino acid decarboxylase that catalyses the final stage in the production of the neurotransmitters dopamine and serotonin. In two patients with inherited disorders of vitamin B6 metabolism, we observed reductions in plasma aromaticl-amino acid decarboxylase activity. In one patient, this change was related to an increase in Km for pyridoxal 5′-phosphate. Furthermore, pyridoxal 5′-phosphate-deficient human SH-SY5Y neuroblastoma cells were found to exhibit reduced levels of aromaticl-amino acid decarboxylase activity and protein but with no alteration in expression. Further reductions in activity and protein were observed with the addition of the vitamin B6 antagonist 4-deoxypyridoxine, which also reduced aromaticl-amino acid decarboxylase mRNA levels. Neither pyridoxal 5′-phosphate deficiency nor the addition of 4-deoxypyridoxine affected aromaticl-amino acid decarboxylase stability over 8 h with protein synthesis inhibited. Increasing extracellular availability of pyridoxal 5′-phosphate was not found to have any significant effect on intracellular pyridoxal 5′-phosphate concentrations or on aromaticl-amino acid decarboxylase. These findings suggest that maintaining adequate pyridoxal 5′-phosphate availability may be important for optimal treatment of aromaticl-amino acid decarboxylase deficiency andl-dopa-responsive conditions.
Document Type: Research Article
Affiliations: 1: Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK 2: Neurometabolic Unit, National Hospital for Neurology and Neurosurgery, London, UK 3: Clinical and Molecular Genetics Unit, UCL Institute of Child Health, London, UK 4: Medical Neurogenetics, Atlanta, Georgia, USA
Publication date: 01 July 2010