Activation of human mitochondrial pantothenate kinase 2 by palmitoylcarnitine
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Edited by Gottfried Schatz, University of Basel, Reinach, Switzerland, and approved December 3, 2006 (received for review August 31, 2006)
Abstract
The human isoform 2 of pantothenate kinase (PanK2) is localized to the mitochondria, and mutations in this protein are associated with a progressive neurodegenerative disorder. PanK2 inhibition by acetyl-CoA is so stringent (IC50 < 1 μM) that it is unclear how the enzyme functions in the presence of intracellular CoA concentrations. Palmitoylcarnitine was discovered to be a potent activator of PanK2 that functions to competitively antagonize acetyl-CoA inhibition. Acetyl-CoA was a competitive inhibitor of purified PanK2 with respect to ATP. The interaction between PanK2 and acetyl-CoA was stable enough that a significant proportion of the purified protein was isolated as the PanK2·acetyl-CoA complex. The long-chain acylcarnitine activation of PanK2 explains how PanK2 functions in vivo, by providing a positive regulatory mechanism to counteract the negative regulation of PanK2 activity by acetyl-CoA. Our results suggest that PanK2 is located in the mitochondria to sense the levels of palmitoylcarnitine and up-regulate CoA biosynthesis in response to an increased mitochondrial demand for the cofactor to support β-oxidation.
Footnotes
- *To whom correspondence should be addressed. E-mail: yongmei.zhang{at}stjude.org
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Author contributions: R.L., C.O.R., S.J., and Y.-M.Z. designed research; R.L. and Y.-M.Z. performed research; R.L., C.O.R., S.J., and Y.-M.Z. analyzed data; and R.L., C.O.R., S.J., and Y.-M.Z. wrote the paper.
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The authors declare no conflict of interest.
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This article is a PNAS direct submission.
- Abbreviations:
- IMS,
- intermembrane space;
- OMM,
- outer mitochondrial membrane;
- PanK,
- pantothenate kinase;
- PKAN,
- pantothenate kinase-associated neurodegeneration.
- © 2007 by The National Academy of Sciences of the USA
