Activation of human mitochondrial pantothenate kinase 2 by palmitoylcarnitine
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 (IC(50) < 1 μM) that it is unclear how the enzyme functions in the presen...
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Main Authors: | , , , |
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Formato: | Artigo |
Idioma: | Inglês |
Publicado em: |
National Academy of Sciences
2007
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Assuntos: | |
Acesso em linha: | https://ncbi.nlm.nih.gov/pmc/articles/PMC1785270/ https://ncbi.nlm.nih.gov/pubmed/17242360 https://ncbi.nlm.nih.govhttp://dx.doi.org/10.1073/pnas.0607621104 |
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Resumo: | 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 (IC(50) < 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. |
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