TAILIEUCHUNG - Báo cáo khoa học: Mitochondrial targeting of intact CYP2B1 and CYP2E1 and N-terminal truncated CYP1A1 proteins in Saccharomyces cerevisiae ) role of protein kinase A in the mitochondrial targeting of CYP2E1

Previously we showed that intact rat cytochrome P450 2E1, cytochrome P450 2B1 and truncated cytochrome P450 1A1 are targeted to mito-chondria in rat tissues and COS cells. However, some reports suggest that truncated cytochrome P450 2E1 is targeted to mitochondria. | ỊFEBS Journal Mitochondrial targeting of intact CYP2B1 and CYP2E1 and N-terminal truncated CYP1A1 proteins in Saccharomyces cerevisiae - role of protein kinase A in the mitochondrial targeting of CYP2E1 Naresh B. V. Sepuri Sanjay Yadav Hindupur K. Anandatheerthavarada and Narayan G. Avadhani Department of AnimalBiology Schoolof Veterinary Medicine University of Pennsylvania Philadelphia PA USA Keywords chimeric targeting signals CYP2E1 evolutionary conservations mitochondrial protein targeting xenobiotic metabolism Correspondence N. G. Avadhani Department of Animal Biology Schoolof Veterinary Medicine University of Pennsylvania 3800 Spruce Street Philadelphia PA 19104 USA Fax 1 215 573 6651 Tel 1 215 898 8819 E-mail narayan@ Received 30 April 2007 revised 6 July 2007 accepted 13 July 2007 doi Previously we showed that intact rat cytochrome P450 2E1 cytochrome P450 2B1 and truncated cytochrome P450 1A1 are targeted to mitochondria in rat tissues and COS cells. However some reports suggest that truncated cytochrome P450 2E1 is targeted to mitochondria. In this study we used a heterologous yeast system to ascertain the conservation of targeting mechanisms and the nature of mitochondria-targeted proteins. Mitochondrial integrity and purity were established using electron microscopy and treatment with digitonin and protease. Full-length cytochrome P450 2E1 and cytochrome P450 2B1 were targeted both to microsomes and mitochondria whereas truncated cytochrome P450 1A1 5 and 33 cytochrome P450 1A1 were targeted to mitochondria. Inability to target intact cytochrome P450 1A1 was probably due to lack of cytosolic endoprotease activity in yeast cells. Mitochondrial targeting of cytochrome P450 2E1 was severely impaired in protein kinase A-deficient cells. Similarly a phosphorylation site mutant cytochrome P450 2E1 Ser129A was poorly targeted to the mitochondria thus confirming the importance of protein kinase A-mediated protein .

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