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Alternative exon usage in the single CPT1 gene of Drosophila generates functional diversity in the kinetic properties of the enzyme. Differential expression of alternatively spliced variants in Drosophila tissues

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Price, Nigel T., Jackson, Vicky N., Müller, Jürgen, Moffat, Kevin G., Matthews, Karen L., Orton, Tim and Zammit, Victor A. (2010) Alternative exon usage in the single CPT1 gene of Drosophila generates functional diversity in the kinetic properties of the enzyme. Differential expression of alternatively spliced variants in Drosophila tissues. Journal of Biological Chemistry, Vol.285 (No.11). pp. 7857-7865. doi:10.1074/jbc.M109.072892

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Official URL: http://dx.doi.org/10.1074/jbc.M109.072892

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Abstract

The Drosophila melanogaster genome contains only one CPT1 gene (Jackson, V. N., Cameron, J. M., Zammit, V. A., and Price, N. T. (1999) Biochem. J. 341, 483-489). We have now extended our original observation to all insect genomes that have been sequenced, suggesting that a single CPT1 gene is a universal feature of insect genomes. We hypothesized that insects may be able to generate kinetically distinct variants by alternative splicing of their single CPT1 gene. Analysis of the insect genomes revealed that (a) the single CPT1 gene in each and every insect genome contains two alternative exons and (ii) in all cases, the putative alternative splicing site occurs within a small region corresponding to 21 amino acid residues that are known to be essential for the binding of substrates and of malonyl-CoA in mammalian CPT1A. We performed PCR analyses of mRNA from different Drosophila tissues; both of the anticipated splice variants of CPT1 mRNA were found to be expressed in all of the tissues tested (both in larvae and adults), with the expression level for one of the splice variants being significantly different between flight muscle and the fat body of adult Drosophila. Heterologous expression of the full-length cDNAs corresponding to the two putative variants of Drosophila CPT1 in the yeast Pichia pastoris revealed two important differences between the properties of the two variants: (i) their affinity (K-0.5) for one of the substrates, palmitoyl-CoA, differed by 5-fold, and (ii) the sensitivity to inhibition by malonyl-CoA at fixed, higher palmitoyl-CoA concentrations was 2-fold different and associated with different kinetics of inhibition. These data indicate that alternative splicing that specifically affects a structurally crucial region of the protein is an important mechanism through which functional diversity of CPT1 kinetics is generated from the single gene that occurs in insects.

Item Type: Journal Article
Subjects: Q Science > QD Chemistry
Divisions: Faculty of Science > Life Sciences (2010- ) > Biological Sciences ( -2010)
Faculty of Medicine > Warwick Medical School > Biomedical Sciences > Translational & Experimental Medicine > Metabolic and Vascular Health (- until July 2016)
Faculty of Medicine > Warwick Medical School
Journal or Publication Title: Journal of Biological Chemistry
Publisher: American Society for Biochemistry and Molecular Biology
ISSN: 0021-9258
Official Date: 12 March 2010
Dates:
DateEvent
12 March 2010Published
Volume: Vol.285
Number: No.11
Number of Pages: 9
Page Range: pp. 7857-7865
DOI: 10.1074/jbc.M109.072892
Status: Peer Reviewed
Publication Status: Published
Access rights to Published version: Restricted or Subscription Access
Funder: British Heart Foundation

Data sourced from Thomson Reuters' Web of Knowledge

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