Regulation of Cytochrome P450 by Posttranslational Modification

Abstract

Cytochrome P450s are a family of enzymes represented in all kingdoms with expression in many species. Over 3,000 enzymes have been identified in nature. Humans express 57 putatively functional enzymes with a variety of critical physiological roles. They are involved in the metabolic oxidation, peroxidation, and reduction of many endogenous and exogenous compounds including xenobiotics, steroids, bile acids, fatty acids, eicosanoids, environmental pollutants, and carcinogens [Nelson, D. R., Kamataki, T., Waxman, D. J.,17 Guengerich, F. P., Estabrook, R. W., Feyereisen, R., Gonzalez, F. J., Coon, M. J.,18 Gunsalus, I. C., Gotoh, O. (1993) The P450 superfamily: update on new sequences, gene 19 mapping, accession numbers, early trivial names of enzymes, and nomenclature. DNA Cell 20 Biol. 12(1):1- 51.]. The development of numerous diseases and disorders including cancer and cardiovascular and endocrine dysfunction has been linked to P450s.

Several levels of regulation, including transcription, translation, and posttranslational modification, participate in maintaining the proper function of P450s. Modifications including phosphorylation, glycosylation, nitration, and ubiquitination have been described for P450s. Their physiological significance includes modulation of enzyme activity, targeting to specific cellular compartments, and tagging for proteasomal degradation. Knowledge of P450 posttranslational regulation is derived from studies with relatively few enzymes. In many cases, there is only enough evidence to suggest the occurrence and a possible role for the modification. Thus, many P450 enzymes have not been fully characterized. With the introduction of current proteomics tools, we are primed to answer many important questions regarding regulation of P450 in response to a posttranslational modification. This review considers regulation of P450 in a context that describes the potential role and physiological significance of each modification.

Key Words :

• Cytochrome P450
• Posttranlational modification
• Phosphorylation
• Ubiquitination
• Nitration
• Glycosylation