M. Almira Correia, PhD
Research Interests
My research focuses on two classes of hepatic hemoproteins: the drug-metabolizing enzymes cytochromes P450 and tryptophan 2,3-dioxygenase. My lab has shown that heme regulates these hemoproteins via translational control, exerted through an eIF2α kinase (the so-called heme-regulated inhibitor, HRI) previously believed unique to the erythroid cell and its precursors. We have identified the enzyme in liver as a bona-fide hepatic HRI. Unleashing of this hepatic HRI in acute-heme-deficient states would trigger global suppression of hepatic protein translation, and could contribute to the etiology of acute attacks of hepatic porphyria. A second focus of the Correia lab is to characterize the endoplasmic reticulum-associated degradation (ERAD) of cytochromes P450, specifically the molecular participants as well as the structural determinants or “degrons” that direct certain P450s to autophagic-lysosomal degradation and others to ubiquitin-dependent 26S proteasomal degradation. One such structural CYP3A4 determinant is the Ser478 phosphodegron involved in targeting the enzyme to the Ube2g2/gp78 E2-E3 ubiquitination enzyme complexes.
Selected Publications
- Faouzi S, Medzihradzsky K, Heffner C, Maher J, Correia MA. Characterization of the physiological turnover of native cytochromes P450 3A in cultured rat hepatocytes: A role for the cytosolic AAA ATPase p97? Biochemistry 2007; 46:7793-7803.
- Liao M, Pabarcus MK, Wang Y, Hefner C, Maltby DA, Medzihradszky KF, Salas-Castillo SP, Yan J, Maher J J, Correia MA. Impaired dexamethasone-mediated induction of tryptophan 2,3-dioxygenase in heme-deficient rat hepatocytes: Translational control by a hepatic eIF2{alpha} kinase, the heme-regulated inhibitor (HRI). J Pharmacol Exp Ther 2007;323:979-989.
- Wang, Y-Q., Liao, M., Hoe, N., Acharya, P., Deng, C-H., Krutchinsky, A. and Correia, M. A. A role for protein phosphorylation in CYP3A4 ubiquitin-dependent proteasomal degradation. J. Biol. Chem. 2008; 284:5671-5684, 2009. Epub 2008 Dec18.
- Acharya, P. Engel, E. and Correia, M. A. Hepatic CYP3A protein suppression by high concentrations of proteasomal inhibitors is due to induction of ER-stress, activation of eIF2a kinases PERK and GCN2 and consequent translational shut-off. Mol. Pharmacol. 2009; EPub June 11.
- Professor
- Cellular & Molecular Pharmacology
Research Theme
- Hepatic Physiology and Metabolism
Contact Information
- Almira.correia@
ucsf.edu - Phone: (415) 476-3992
- Fax: (415) 502-2467
-
Mission Bay Campus
- 600 16th Street
- Box 2280, N-576
- San Francisco, CA. 94143 - 2280
Other UCSF Affiliations
- Departments of Pharmaceutical Chemistry and Biopharmaceutical Sciences, SOP
- CCB graduate program
- Div. of Clinical Pharmacology