RESUMEN
The molybdenum cofactor (Moco) is a 520-Da prosthetic group that is synthesized in all domains of life. In animals, four oxidases (among them sulfite oxidase) use Moco as a prosthetic group. Moco is essential in animals; humans with mutations in genes that encode Moco biosynthetic enzymes display lethal neurological and developmental defects. Moco supplementation seems a logical therapy; however, the instability of Moco has precluded biochemical and cell biological studies of Moco transport and bioavailability. The nematode Caenorhabditis elegans can take up Moco from its bacterial diet and transport it to cells and tissues that express Moco-requiring enzymes, suggesting a system for Moco uptake and distribution. Here we show that protein-bound Moco is the stable, bioavailable species of Moco taken up by C. elegans from its diet and is an effective dietary supplement, rescuing a Celegans model of Moco deficiency. We demonstrate that diverse Moco:protein complexes are stable and bioavailable, suggesting a new strategy for the production and delivery of therapeutically active Moco to treat human Moco deficiency.
Asunto(s)
Caenorhabditis elegans/metabolismo , Coenzimas/administración & dosificación , Errores Innatos del Metabolismo de los Metales/terapia , Metaloproteínas/administración & dosificación , Pteridinas/administración & dosificación , Animales , Bacterias/metabolismo , Transporte Biológico , Coenzimas/deficiencia , Coenzimas/farmacocinética , Humanos , Metaloproteínas/deficiencia , Metaloproteínas/farmacocinética , Cofactores de Molibdeno , Unión Proteica , Pteridinas/farmacocinéticaRESUMEN
Copper is an essential trace nutrient metal involved in a multitude of cellular processes. Hereditary defects in copper metabolism result in disorders with a severe clinical course such as Wilson disease and Menkes disease. In Wilson disease, copper accumulation leads to liver cirrhosis and neurological impairments. A lack in genotype-phenotype correlation in Wilson disease points toward the influence of environmental factors or modifying genes. In a number of Non-Wilsonian forms of copper metabolism, the underlying genetic defects remain elusive. Several pure bred dog populations are affected with copper-associated hepatitis showing similarities to human copper metabolism disorders. Gene-mapping studies in these populations offer the opportunity to discover new genes involved in copper metabolism. Furthermore, due to the relatively large body size and long life-span of dogs they are excellent models for development of new treatment strategies. One example is the recent use of canine organoids for disease modeling and gene therapy of copper storage disease. This review addresses the opportunities offered by canine genetics for discovery of genes involved in copper metabolism disorders. Further, possibilities for the use of dogs in development of new treatment modalities for copper storage disorders, including gene repair in patient-derived hepatic organoids, are highlighted.
Asunto(s)
Cobre/metabolismo , Modelos Animales de Enfermedad , Errores Innatos del Metabolismo de los Metales/etiología , Errores Innatos del Metabolismo de los Metales/metabolismo , Animales , Terapia por Quelación , Mapeo Cromosómico , Dietoterapia , Perros , Estudios de Asociación Genética , Degeneración Hepatolenticular/genética , Degeneración Hepatolenticular/metabolismo , Degeneración Hepatolenticular/terapia , Homeostasis , Humanos , Errores Innatos del Metabolismo de los Metales/terapia , Trasplante de ÓrganosAsunto(s)
Cobre/metabolismo , Enfermedades de los Perros/diagnóstico , Síndrome de Fanconi/veterinaria , Hepatopatías/veterinaria , Errores Innatos del Metabolismo de los Metales/veterinaria , Animales , Terapia por Quelación/veterinaria , Enfermedad Hepática Inducida por Sustancias y Drogas , Enfermedades de los Perros/inducido químicamente , Enfermedades de los Perros/terapia , Perros , Síndrome de Fanconi/diagnóstico , Síndrome de Fanconi/terapia , Riñón/patología , Hígado/patología , Hepatopatías/diagnóstico , Masculino , Errores Innatos del Metabolismo de los Metales/diagnóstico , Errores Innatos del Metabolismo de los Metales/terapiaRESUMEN
Acrodermatitis enteropathica results from a defect in zinc metabolism inherited as an autosomal recessive trait. Zinc is chelated in the gastrointestinal tract by an oligopeptide that is normally destroyed in the bowel. Zinc deficiency results in skin and bowel lesions, as well as alterations in mental status. If the disorder is not treated, death occurs from infection and/or marasmus. Blood zinc levels confirm the diagnosis. Dramatic recovery and normal development occur when dietary zinc is supplemented.