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Hepatic cytochromes P450: structural degrons and barcodes, posttranslational modifications and cellular adapters in the ERAD-endgame
- Source :
- Drug metabolism reviews, vol 48, iss 3
- Publication Year :
- 2016
- Publisher :
- Informa UK Limited, 2016.
-
Abstract
- The endoplasmic reticulum (ER)-anchored hepatic cytochromes P450 (P450s) are enzymes that metabolize endo- and xenobiotics i.e. drugs, carcinogens, toxins, natural and chemical products. These agents modulate liver P450 content through increased synthesis or reduction via inactivation and/or proteolytic degradation, resulting in clinically significant drug-drug interactions. P450 proteolytic degradation occurs via ER-associated degradation (ERAD) involving either of two distinct routes: Ubiquitin (Ub)-dependent 26S proteasomal degradation (ERAD/UPD) or autophagic lysosomal degradation (ERAD/ALD). CYP3A4, the major human liver/intestinal P450, and the fast-turnover CYP2E1 species are degraded via ERAD/UPD entailing multisite protein phosphorylation and subsequent ubiquitination by gp78 and CHIP E3 Ub-ligases. We are gaining insight into the nature of the structural determinants involved in CYP3A4 and CYP2E1 molecular recognition in ERAD/UPD [i.e. K48-linked polyUb chains and linear and/or “conformational” phosphodegrons consisting either of consecutive sequences on surface loops and/or disordered regions, or structurally-assembled surface clusters of negatively charged acidic (Asp/Glu) and phosphorylated (Ser/Thr) residues, within or vicinal to which, Lys-residues are targeted for ubiquitination]. Structural inspection of select human liver P450s reveals that such linear or conformational phosphodegrons may indeed be a common P450-ERAD/UPD feature. By contrast, although many P450s such as the slow-turnover CYP2E1 species and rat liver CYP2B1 and CYP2C11 are degraded via ERAD/ALD, little is known about the mechanism of their ALD-targeting. On the basis of our current knowledge of ALD-substrate targeting, we propose a tripartite conjunction of K63-linked Ub-chains, P450 structural “LIR” motifs, and selective cellular “cargo receptors” as plausible P450-ALD determinants.
- Subjects :
- p97
0301 basic medicine
gp78 E3
0302 clinical medicine
Cytochrome P-450 Enzyme System
Ubiquitin
Models
Receptors
Pharmacology (medical)
Protein phosphorylation
Pharmacology & Pharmacy
General Pharmacology, Toxicology and Pharmaceutics
26S proteasome
Autocrine Motility Factor
medicine.diagnostic_test
CHIP
Liver Disease
p62
Endoplasmic Reticulum-Associated Degradation
Pharmacology and Pharmaceutical Sciences
K48 & K63 ubiquitination
Cell biology
Liver
Biochemistry
Generic Health Relevance
030220 oncology & carcinogenesis
Phosphorylation
Cytochromes P450
autophagic lysosomal degradation
phosphodegrons
Ubiquitin-Protein Ligases
Proteolysis
macromolecular substances
Endoplasmic-reticulum-associated protein degradation
Biology
Models, Biological
Article
03 medical and health sciences
E2/E3 ubiquitin ligases
medicine
Animals
Humans
Endoplasmic reticulum
Ubiquitination
ERAD
Biological
Receptors, Autocrine Motility Factor
030104 developmental biology
Proteasome
biology.protein
Lysosomes
Digestive Diseases
Subjects
Details
- ISSN :
- 10979883 and 03602532
- Volume :
- 48
- Database :
- OpenAIRE
- Journal :
- Drug Metabolism Reviews
- Accession number :
- edsair.doi.dedup.....745c8cb07a87e4a681afeb11b5d604a9