A therapeutic approach to pantothenate kinase associated neurodegeneration

Nat Commun. 2018 Oct 23;9(1):4399. doi: 10.1038/s41467-018-06703-2.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Allosteric Regulation
  • Animals
  • Cells, Cultured
  • Coenzyme A / deficiency
  • Coenzyme A / metabolism
  • Disease Models, Animal
  • Enzyme Stability
  • Female
  • Ligands
  • Magnesium / metabolism
  • Male
  • Mice, Knockout
  • Neurons / metabolism
  • Organ Specificity
  • Pantothenate Kinase-Associated Neurodegeneration / pathology
  • Pantothenate Kinase-Associated Neurodegeneration / therapy*
  • Phosphotransferases (Alcohol Group Acceptor) / genetics*
  • Protein Conformation
  • Protein Multimerization

Substances

  • Ligands
  • Adenosine Triphosphate
  • Phosphotransferases (Alcohol Group Acceptor)
  • pantothenate kinase
  • Magnesium
  • Coenzyme A