Biochemical properties of human pantothenate kinase 2 isoforms and mutations linked to pantothenate kinase-associated neurodegeneration

doi:10.1074/jbc.M508825200

HOME

QUICK SEARCH:

	Author:		Keyword(s):
Year:		Vol:		Page:

A more recent version of this article appeared on January 6, 2006

This Article

	Full Text (Accepted Manuscript)
	All Versions of this Article: 281/1/107 most recent M508825200v1
	Alert me when this article is cited
	Alert me if a correction is posted

Services

	Email this article to a friend
	Similar articles in this journal
	Similar articles in PubMed
	Alert me to new issues of the journal
	Download to citation manager
	Request Permissions

Citing Articles

	Citing Articles via HighWire
	Citing Articles via Google Scholar

Google Scholar

	Articles by Zhang, Y.-M.
	Articles by Jackowski, S.
	Search for Related Content

PubMed

	PubMed Citation
	Articles by Zhang, Y.-M.
	Articles by Jackowski, S.

Social Bookmarking

	What's this?

Papers In Press, published online ahead of print November 3, 2005
J. Biol. Chem, 10.1074/jbc.M508825200
Submitted on August 10, 2005
Accepted on November 3, 2005

Biochemical properties of human pantothenate kinase 2 isoforms and mutations linked to pantothenate kinase-associated neurodegeneration

Yong-Mei Zhang, Charles O. Rock, and Suzanne Jackowski

Department of Infectious Disease, St. Jude Children's Research Hospital, Memphis, TN 38105-2794

Corresponding Author: suzanne.jackowski{at}stjude.org

The PANK2 gene encodes the human pantothenate kinase 2 protein isoforms, and PANK2 mutations are linked to pantothenate kinase-associated neurodegeneration (PKAN). Two PanK2 protein forms are proteolytically processed to form a mitochondrial-localized, mature PanK2. Another isoform arises from a proposed initiation at a leucine codon and is not processed further. The fifth isoform is postulated to arise from an alternative splicing event and was found to encode an inactive protein. Fourteen mutant PanK2 proteins with single amino acid substitutions, associated with either early or late onset disease, were evaluated for activity. The PanK2[G521R], the most frequent mutation in PKAN, was devoid of activity and did not fold properly. However, 9 of the mutant proteins associated with disease possessed catalytic activities that were indistinguishable from wild-type, including the frequently encountered PanK2[T528M] missense mutation. PanK2 was extremely sensitive to feedback inhibition by CoA thioesters (IC50s between 250-500 nM), and the regulation of the active PanK2 mutants was comparable to that of the wild-type protein. Co-expression of the PanK2[G521R] and wild-type PanK2 did not interfere with wild-type enzyme activity arguing against a dominant negative effect of the PanK2[G521R] mutation in heterozygous patients. These data describe the unique biochemical features of the PanK2 isoforms and suggest that catalytic defects may not be the sole cause for the neurodegenerative phenotype.

Add to CiteULike CiteULike Add to Complore Complore Add to Connotea Connotea Add to Del.icio.us Del.icio.us Add to Digg Digg Add to Reddit Reddit Add to Technorati Technorati What's this?

This article has been cited by other articles:

B. S. Hong, G. Senisterra, W. M. Rabeh, M. Vedadi, R. Leonardi, Y.-M. Zhang, C. O. Rock, S. Jackowski, and H.-W. Park
Crystal Structures of Human Pantothenate Kinases: INSIGHTS INTO ALLOSTERIC REGULATION AND MUTATIONS LINKED TO A NEURODEGENERATION DISORDER
J. Biol. Chem., September 21, 2007; 282(38): 27984 - 27993.
[Abstract] [Full Text] [PDF]

Y.-J. Lu, F. Zhang, K. D. Grimes, R. E. Lee, and C. O. Rock
Topology and Active Site of PlsY: THE BACTERIAL ACYLPHOSPHATE:GLYCEROL-3-PHOSPHATE ACYLTRANSFERASE
J. Biol. Chem., April 13, 2007; 282(15): 11339 - 11346.
[Abstract] [Full Text] [PDF]

R. Leonardi, C. O. Rock, S. Jackowski, and Y.-M. Zhang
Activation of human mitochondrial pantothenate kinase 2 by palmitoylcarnitine
PNAS, January 30, 2007; 104(5): 1494 - 1499.
[Abstract] [Full Text] [PDF]