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A therapeutic approach to pantothenate kinase associated neurodegeneration.
Sharma, Lalit Kumar; Subramanian, Chitra; Yun, Mi-Kyung; Frank, Matthew W; White, Stephen W; Rock, Charles O; Lee, Richard E; Jackowski, Suzanne.
Afiliación
  • Sharma LK; Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
  • Subramanian C; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
  • Yun MK; Nurix, Inc, 1700 Owens Street, Suite 205, San Francisco, CA, 94158, USA.
  • Frank MW; Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
  • White SW; Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
  • Rock CO; Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
  • Lee RE; Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
  • Jackowski S; Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
Nat Commun ; 9(1): 4399, 2018 10 23.
Article en En | MEDLINE | ID: mdl-30352999
Pantothenate kinase (PANK) is a metabolic enzyme that regulates cellular coenzyme A (CoA) levels. There are three human PANK genes, and inactivating mutations in PANK2 lead to pantothenate kinase associated neurodegeneration (PKAN). Here we performed a library screen followed by chemical optimization to produce PZ-2891, an allosteric PANK activator that crosses the blood brain barrier. PZ-2891 occupies the pantothenate pocket and engages the dimer interface to form a PANK•ATP•Mg2+•PZ-2891 complex. The binding of PZ-2891 to one protomer locks the opposite protomer in a catalytically active conformation that is refractory to acetyl-CoA inhibition. Oral administration of PZ-2891 increases CoA levels in mouse liver and brain. A knockout mouse model of brain CoA deficiency exhibited weight loss, severe locomotor impairment and early death. Knockout mice on PZ-2891 therapy gain weight, and have improved locomotor activity and life span establishing pantazines as novel therapeutics for the treatment of PKAN.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fosfotransferasas (Aceptor de Grupo Alcohol) / Neurodegeneración Asociada a Pantotenato Quinasa Tipo de estudio: Risk_factors_studies Límite: Animals Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2018 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
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XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fosfotransferasas (Aceptor de Grupo Alcohol) / Neurodegeneración Asociada a Pantotenato Quinasa Tipo de estudio: Risk_factors_studies Límite: Animals Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2018 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido