Degradation of rat hepatic cytochrome P-450 heme by 3,5-dicarbethoxy-2, 6-dimethyl-4-ethyl-1,4-dihydropyridine to irreversibly bound protein adducts
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Cited by (79)
Ubiquitin-dependent proteasomal degradation of human liver cytochrome P450 2E1: Identification of sites targeted for phosphorylation and ubiquitination
2011, Journal of Biological ChemistryCitation Excerpt :However, it is now increasingly evident that in common with other type I monotopic ER proteins, P450s such as CYPs 3A (both native and structurally inactivated) undergo ER-associated degradation (ERAD) involving the ubiquitin (Ub)-dependent 26 S proteasomal system (UPS) (6–9, 12–16). This process entails the ubiquitination of the predominantly cytosol (C)-localized monotopic ER proteins by an E2 Ub-conjugating enzyme (Ubc)-E3 Ub ligase complex, its concurrent extraction from the ER membrane by the p97-AAA ATPase, and its delivery to the 26 S proteasome (12–17, 39, 40). CYPs 3A thus may qualify as typical ERAD-C substrates.
Liver Cytochrome P450 3A endoplasmic reticulum-associated degradation: A major role for the P97 AAA ATPase in cytochrome P450 3A extraction into the cytosol
2011, Journal of Biological ChemistryCitation Excerpt :We therefore infer by analogy to yeast that in rat hepatocytes, an intact functional p97-Npl4-Ufd1 complex is similarly involved in the delivery of ER-anchored CYP3A to the cytosolic 26 S proteasome for its subsequent degradation and that this process too is also critically dependent on ATP-derived energy. Taken together with our previously published findings (11–17), the present findings underscore that both the native and DDEP-inactivated CYP3A species are genuine ERAD-C substrates, subscribing to all of the requisite criteria of an ERAD-C process (29–31). The findings above also reveal that CYP3A ubiquitination occurs to a substantial degree in the ER while the P450 protein is still tethered to the ER membrane.
Liver cytochrome P450 3A ubiquitination in vivo by gp78/autocrine motility factor receptor and C terminus of Hsp70-interacting protein (CHIP) E3 ubiquitin ligases: Physiological and pharmacological relevance
2010, Journal of Biological ChemistryCitation Excerpt :Using various in vivo and in vitro reconstituted eukaryotic systems, we have shown that both native3 and structurally inactivated CYPs 3A incur ubiquitin (Ub)-dependent proteasomal degradation (UPD), in a typical ER-associated degradation (ERAD) process involving phosphorylation, ubiquitination, ER membrane extraction into the cytosol, and subsequent degradation by the 26S proteasome (2–13). Indeed mechanism-based CYP3A inactivation often results in active site structural lesions within their cytosolic domain (2, 6, 7), thereby qualifying these proteins as bona fide ERAD-C substrates. The pathways of P450 degradation appear to be highly conserved in all eukaryotes from yeast to man (11–22).
A role for protein phosphorylation in cytochrome P450 3A4 ubiquitin-dependent proteasomal degradation
2009, Journal of Biological ChemistryCitation Excerpt :However, the relative rate of this degradation is considerably increased after CYP3A inactivation (2, 3, 6). Indeed, CYP3A suicide inactivation by 3,5-dicarbethoxy-2,6-dimethyl-4-ethyl-1,4-dihydropyridine, the agent employed in our previous studies (2, 3, 6, 68), and that by CuOOH or H2O2 is mechanistically very similar, involving oxidative fragmentation of the heme to reactive products that irreversibly bind to the P450 active site (49, 69, 70). This structural insult damages the P450 protein, marking it for ubiquitination and thus rapid clearance via UPD (2, 3, 6, 7, 68).
Ubiquitin-dependent 26S proteasomal pathway: A role in the degradation of native human liver CYP3A4 expressed in Saccharomyces cerevisiae?
2001, Archives of Biochemistry and BiophysicsUbiquitination of neuronal nitric-oxide synthase in vitro and in vivo
2000, Journal of Biological ChemistryCitation Excerpt :These observations are consistent with the finding that liver microsomal P450 cytochromes, which are heme-thiolate enzymes similar to NOS, are ubiquitinated and proteasomally degraded after suicide inactivation (23, 24). In the case of suicide inactivation of liver P450 cytochromes, structural changes and not the functional inactivation per se appears to be the “trigger” for proteolysis (25, 26). In particular, the cross-linking of heme to the protein, which occurs during suicide inactivation of cytochrome P450, plays a prominent role in the enhanced turnover of cytochrome P450 (23-25, 27).