ABSTRACT
Mutations in pyridoxine 5'-phosphate oxidase are known to cause neonatal epileptic encephalopathy. This disorder has no cure or effective treatment and is often fatal. Pyridoxine 5'-phosphate oxidase catalyzes the oxidation of pyridoxine 5'-phosphate to pyridoxal 5'-phosphate, the active cofactor form of vitamin B(6) required by more than 140 different catalytic activities, including enzymes involved in amino acid metabolism and biosynthesis of neurotransmitters. Our aim is to elucidate the mechanism by which a homozygous missense mutation (R229W) in the oxidase, linked to neonatal epileptic encephalopathy, leads to reduced oxidase activity. The R229W variant is approximately 850-fold less efficient than the wild-type enzyme due to an approximately 192-fold decrease in pyridoxine 5'-phosphate affinity and an approximately 4.5-fold decrease in catalytic activity. There is also an approximately 50-fold reduction in the affinity of the R229W variant for the FMN cofactor. A 2.5 A crystal structure of the R229W variant shows that the substitution of Arg-229 at the FMN binding site has led to a loss of hydrogen-bond and/or salt-bridge interactions between FMN and Arg-229 and Ser-175. Additionally, the mutation has led to an alteration of the configuration of a beta-strand-loop-beta-strand structure at the active site, resulting in loss of two critical hydrogen-bond interactions involving residues His-227 and Arg-225, which are important for substrate binding and orientation for catalysis. These results provide a molecular basis for the phenotype associated with the R229W mutation, as well as providing a foundation for understanding the pathophysiological consequences of pyridoxine 5'-phosphate oxidase mutations.
Subject(s)
Epilepsy, Benign Neonatal/enzymology , Pyridoxaminephosphate Oxidase/chemistry , Pyridoxaminephosphate Oxidase/metabolism , Binding Sites , Catalysis , Crystallization , Epilepsy, Benign Neonatal/genetics , Flavin Mononucleotide/chemistry , Humans , Kinetics , Molecular Conformation , Mutation, Missense , Protein Binding , Pyridoxal Phosphate/analogs & derivatives , Pyridoxal Phosphate/chemistry , Pyridoxaminephosphate Oxidase/genetics , Substrate SpecificityABSTRACT
Con la preparación y publicación de este primer compendio de Planta Medicinales, el autor pone al alcance de los distintos sectores de lapoblación todo un conjunto de elementos terapeúticos que vendrán a fortalecer elacervo fármaco vegetal heredado de nuestros antepasados. Se pretende tener una alternativa viable, que contribuya determinantemente en la solución de los más caracterizados problemas de salud que cotidianamente aquejan a los Nicaragüenses, fundamentalmente en lo que a la atención primaria se refiere. Para un adecuado uso, manejo y un acertado entendimiento de las distintas plantas medicinales se pone a disponibilidad 63 plantas medicinales, recursos que la naturaleza ofrece como una alternativa de tratamiento a enfermedades comunes. Se hace una reseña descriptiva de cada planta; su nombre común, nombre científico y familia, hábita de crecimiento, producción y mercado, la descripción popular y botánica, su composición química, los efectos farmacológicos, la toxicidad, así como sus aspectos generales y otros usos., etc
