Protein degradation: the role of mixed-function oxidases

The mechanisms by which protein oxidation is mediated in the cell are of both biological and pharmacological importance. Oxidases responsible for the metabolism of xenobiotics catalyze the oxidative inactivation of select enzymes. Oxidation mediated by mixed-function oxidase (MFO) systems renders proteins more susceptible to proteolysis and, consequently, appears to be a signal for protein degradation. The mode of action of MFO systems is discussed in detail for a specific, well-characterized system--the MFO-catalyzed oxidation of glutamine synthetase (GS). Findings for this system are then generalized to help explain how other metabolic enzymes are oxidized by MFO systems. The broader consequences of oxidative mechanisms are discussed. For example, the accumulation of modified proteins during aging and in some premature aging diseases may be due in part to shifts in the relative rates of oxidation and degradation for these proteins. Further, the oxidation of key metabolic enzymes appears to be responsible for the bacteriocidal action of neutrophils. There is also some evidence that the degradation of endogenous proteins increases following ingestion of, or exposure to, agents that induce MFO activity.