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Correia, Almira
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| Research Statement | | | Our overall research interests continue to center on the structure, function and regulation of two physiologically important classes of hepatic hemoproteins: Cytochromes P450 (P450s, CYPs) and tryptophan 2,3 dioxygenase (TDO). Our specific goals are to: (I) explore and mechanistically characterize the endoplasmic reticulum-associated degradation (ERAD) of proteins by exploiting P450s as cellular models; (II) explore the role of proteasomal processing of P450s in drug-induced immunotoxicity; (III) elucidate the role of heme, if any, on the regulation of P450 synthesis; and (IV) to examine the structure-function relationships and heme-mediated regulation of hepatic hemoprotein tryptophan 2,3 dioxygenase (TDO). A combination of approaches (enzymological, chemical, structural, cell biological, and molecular biological) are being employed in pursuit of these questions. |
Publications | | Wang, X., Medzihradszky, K. F., Maltby, D. and Correia, M. A. Phosphorylation of native and heme-modified CYP3A4 by protein kinase C: A mass spectrometric characterization of the phosphorylated peptides. Biochemistry, 40: 11318-11326, (2001).
Murray, B. P. and Correia, M. A. Ubiquitin-dependent 26 S proteasomal pathway: A role in the degradation of the native human liver CYP3A4 expressed in Saccharomyces cerevisiae? Arch. Biochem. Biophys. 393:106-116 (2001)
Murray, B. P. Zgoda, V. and Correia, M. A. Native CYP2C11: Heterologous expression in Saccharomyces cerevisiae reveals a role for vacuolar proteases rather than the ubiquitin-26 S proteasome system in the degradation of this endoplasmic reticulum enzyme. Mol. Pharmacol. 61:1146-1153 (2002)
Dick, R., Murray, B. P., Reid, M. J. and Correia, M. A. Structure-function relationships of tryptophan 2,3-dioxygenase: Identification of the putative heme-ligating histidine residues. Arch. Biochem. Biophys. 391: 71-78 (2001)
Xue, L., Zgoda, V. G., Arison B. and Correia, M.A. Rat liver CYP3A9: Structure-function relationships to its human liver orthologs:site-directed mutagenesis to an efficient progesterone dihydroxylase. Arch. Biochem. Biophys. 409:113-126 (2003)
Xue, L., Wang, H., Wang, Q., Szklarz, G., Domanski, T. L., Halpert, J. R., and Correia, M. A. The influence of CYP3A4 SRS-2 residues on the cooperativity and/or regioselectivity of aflatoxin B1 oxidation. Chem Res. Tox. 14: 483-491. (2001)
Zgoda, V. G., Arison, B. Mkrtchian, S. Ingelman-Sundberg, M. and Correia, M.A. Hemin-mediated restoration of allylisopropylaceta-mide-inactivated CYP2B1 revisited: The role of GSH and GRP94 in the heme-protein assembly. Arch. Biochem. Biophys. 408:58-68 (2002)
Correia, M.A. Hepatic Cytochrome P450 Degradation: Mechanistic Diversity of the Cellular Sanitation Brigade Drug Metab. Rev., 35:107-143 (2003)
Liao, M., Zgoda, V., Murray, B. P. and Correia, M.A. Vacuolar degradation of rat liver CYP2B1 in Saccharomyces cerevisiae: Validation of the yeast model and structural implications for the degradation of mammalian endoplasmic reticulum P450 proteins Mol. Pharmacol. 67:1460-1469 (2005).
Han, X-M., Lee, G., Heffner, C., Maher, J. and Correia, M.A. Heme-reversible impairment of CYP2B1/2B2 induction in heme depleted rat hepatocytes in primary culture: Translational control by a hepatic eIF2a kinase? J. Pharmacol. Exp. Ther. 314:128-138 (2005).
Correia, M.A., Sadeghi, S. and Mundo-Paredes, E. Cytochrome P450 ubiquitination: Branding for the proteolytic slaughter? Ann. Rev. Pharmacol. Toxicol. 45:439-464 (2005).
Liao, M., Faouzi, S., Karyakin, A. and Correia, M.A. ER-associated degradation (ERAD) of cytochrome P450 3A4 in Saccharomyces cerevisiae: Further characterization of cellular participants and structural determinants. Mol. Pharmacol. 69:1897-1904 (2006)
Correia, M. A. and Liao, M. L. Cellular Proteolytic Systems in P450 Degradation: Evolutionary conservation from Saccharomyces cerevisiae to mammalian liver. Expert Opinion Drug Metab. Toxicol. 3:33-49 (2007).
Faouzi, S., Medzihradszky, K., Heffner, C., Maher, J. and Correia, M. A. Characterization of the physiological turnover of native cytochromes P450 3A in cultured rat hepatocytes: A role for the cytosolic AAA ATPase p97? Biochemistry 46:7793-7803(2007).
Liao, M., Pabarcus, M. K., Wang, Y., Hefner, C., Maltby, D. A., Medzihradszky, K. F., Salas-Castillo, S. P., Yan, J., Maher, J. J., Correia, M. A. 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. 323:979-989 (2007)
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