Cellular proteolytic systems in P450 degradation: evolutionary conservation from Saccharomyces cerevisiae to mammalian liver.
Mammalian hepatic cytochromes P450 (P450s) are endoplasmic reticulum (ER)-anchored haemoproteins with the bulk of their catalytic domains exposed to the cytosol and engaged in the metabolism of numerous xeno- and endobiotics. The native P450s exhibit widely ranging half-lifes and predominantly turn over via either autophagic-lysosomal degradation (ALD) or ubiquitin-dependent 26S proteasomal degradation (UPD). The basis for this heterogeneity and differential proteolytic targeting is unknown. On the other hand, structurally/functionally inactivated P450s are predominantly degraded via UPD in a process known as ER-associated degradation (ERAD). ALD/UPD/ERAD pathways are evolutionarily highly conserved. The availability of Saccharomyces cerevisiae mutants with specific genetic defects/deletions in various ALD/UPD/ERAD-associated proteins and corresponding isogenic wild-type strains has enabled the molecular dissection of the degradation pathways for heterologously expressed mammalian P450s, leading to the identification of specific protein participants. These findings collectively attest to a highly versatile cellular system for the physiological disposal of native, senescent and/or inactivated, structurally damaged mammalian liver P450s.
Correia
Maria Almira
MA
University of California, Department of Cellular and Molecular Pharmacology, Mission Bay Campus, San Francisco, CA 94158-2517, USA. almira.correia@ucsf.edu
Liao
Mingxiang
M
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D019143:Evolution, Molecular; D006801:Humans; D008099:Liver / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism*; D008954:Models, Biological; D010447:Peptide Hydrolases / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000201:enzymology / Q000235:genetics
D003577:Cytochrome P-450 Enzyme System; D010447:Peptide Hydrolases