Activation of human mitochondrial pantothenate kinase 2 by palmitoylcarnitine.

نویسندگان

  • Roberta Leonardi
  • Charles O Rock
  • Suzanne Jackowski
  • Yong-Mei Zhang
چکیده

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 microM) 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 beta-oxidation.

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عنوان ژورنال:
  • Proceedings of the National Academy of Sciences of the United States of America

دوره 104 5  شماره 

صفحات  -

تاریخ انتشار 2007