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 (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.
Leonardi
Roberta
R
Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Rock
Charles O
CO
Jackowski
Suzanne
S
Zhang
Yong-Mei
YM
D000818:Animals; D002460:Cell Line; D003065:Coenzyme A / Q000737:chemistry; D004789:Enzyme Activation; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D013058:Mass Spectrometry; D008928:Mitochondria / Q000201:enzymology*; D008954:Models, Biological; D019636:Neurodegenerative Diseases / Q000201:enzymology; D010172:Palmitoylcarnitine / Q000378:metabolism*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D020033:Protein Isoforms; D014466:Ultraviolet Rays
D020033:Protein Isoforms; D010172:Palmitoylcarnitine; D017853:Phosphotransferases (Alcohol Group Acceptor); C023088:pantothenate kinase; D003065:Coenzyme A