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Activation of Human Mitochondrial Pantothenate Kinase 2 by Palmitoylcarnitine
Roberta Leonardi, Charles O. Rock, Suzanne Jackowski and Yong-Mei Zhang
Proceedings of the National Academy of Sciences of the United States of America
Vol. 104, No. 5 (Jan. 30, 2007), pp. 1494-1499
Published by: National Academy of Sciences
Stable URL: http://www.jstor.org/stable/25426317
Page Count: 6
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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 longchain 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.
Proceedings of the National Academy of Sciences of the United States of America © 2007 National Academy of Sciences