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Quantification of Coenzyme A in Cells and Tissues
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Activation of human mitochondrial pantothenate kinase 2 by palmitoylcarnitine

Roberta Leonardi1, Charles O Rock, Suzanne Jackowski

  • 1Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.

Proceedings of the National Academy of Sciences of the United States of America
|January 24, 2007
PubMed

Insights

Pantothenate kinase 2 (PanK2) is activated by palmitoylcarnitine, overcoming acetyl-CoA inhibition. This mitochondrial enzyme regulates Coenzyme A biosynthesis, crucial for energy production and preventing neurodegeneration.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Neuroscience

Background:

  • Pantothenate kinase (PanK2) is a mitochondrial enzyme.
  • Mutations in PanK2 cause progressive neurodegenerative disorders.
  • PanK2 is potently inhibited by acetyl-CoA, raising questions about its in vivo function.

Purpose of the Study:

  • To elucidate the regulatory mechanism of human PanK2.
  • To understand how PanK2 functions despite strong acetyl-CoA inhibition.
  • To investigate the role of PanK2 in mitochondrial Coenzyme A biosynthesis.

Main Methods:

  • Enzyme kinetics studies with purified PanK2.
  • Investigated the effects of acetyl-CoA and palmitoylcarnitine on PanK2 activity.
  • Characterized the interaction between PanK2 and acetyl-CoA.

Main Results:

  • Palmitoylcarnitine is a potent activator of PanK2, competitively antagonizing acetyl-CoA inhibition.
  • Acetyl-CoA competitively inhibits PanK2 with respect to ATP.
  • A stable PanK2.acetyl-CoA complex was isolated, indicating a strong interaction.

Conclusions:

  • Long-chain acylcarnitine activation explains PanK2's in vivo function by counteracting acetyl-CoA inhibition.
  • Mitochondrial localization allows PanK2 to sense palmitoylcarnitine levels.
  • PanK2 up-regulates Coenzyme A biosynthesis in response to mitochondrial demand, supporting beta-oxidation.

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