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A therapeutic approach to pantothenate kinase associated neurodegeneration

Author

Listed:
  • Lalit Kumar Sharma

    (St. Jude Children’s Research Hospital
    St. Jude Children’s Research Hospital
    Nurix, Inc)

  • Chitra Subramanian

    (St. Jude Children’s Research Hospital)

  • Mi-Kyung Yun

    (St. Jude Children’s Research Hospital)

  • Matthew W. Frank

    (St. Jude Children’s Research Hospital)

  • Stephen W. White

    (St. Jude Children’s Research Hospital)

  • Charles O. Rock

    (St. Jude Children’s Research Hospital)

  • Richard E. Lee

    (St. Jude Children’s Research Hospital)

  • Suzanne Jackowski

    (St. Jude Children’s Research Hospital)

Abstract

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.

Suggested Citation

  • Lalit Kumar Sharma & Chitra Subramanian & Mi-Kyung Yun & Matthew W. Frank & Stephen W. White & Charles O. Rock & Richard E. Lee & Suzanne Jackowski, 2018. "A therapeutic approach to pantothenate kinase associated neurodegeneration," Nature Communications, Nature, vol. 9(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-06703-2
    DOI: 10.1038/s41467-018-06703-2
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