Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.25.1 (proteasome)
 28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Proteins comprising the first nucleotide-binding- and R-domains of wild-type and Delta F508 cystic fibrosis transmembrane conductance regulator (CFTR) have been synthesised by in vitro transcription/translation. The kinetics and extent of degradation of wild-type and Delta F508 cytoplasmic domain proteins in rabbit reticulocyte lysates, in which proteasome activity was inhibited, were similar, with a half-life of approximately 4h. The results show for the first time, that the benzo(c)quinolizinium compounds, MPB-07 and MPB-91, selectively inhibit degradation of the Delta F508 cytoplasmic domain protein. Studies using protease inhibitors demonstrated that both Delta F508 and wild-type proteins are substrates for cysteine proteases. The studies provide evidence that benzo(c)quinolizinium compounds protect a proteolytic cleavage site by direct binding to the first cytoplasmic domain of Delta F508-CFTR and this is a likely mechanism for increasing Delta F508-CFTR trafficking in intact cells.
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PMID:Benzo(c)quinolizinium drugs inhibit degradation of Delta F508-CFTR cytoplasmic domain. 1250 15

The most common mutation (F508del) causing cystic fibrosis (CF) results in misfolding of the CF transmembrane conductance regulator (CFTR), leading to its degradation via the proteasome pathway. To study the mechanism of action of several pharmacological chaperones benzo[c]quinolizinium (MPB), we analyzed their effects on two CF mutations; F508del-CFTR and G622D-CFTR. The replacement of Gly622 by an aspartic acid (G622D) alters the trafficking and activity of the protein. G622D, similar to F508del, was functionally rescued by the glucosidase inhibitor miglustat but, unlike F508del, could not be rescued by MPB. A structure-activity relationship for F508del functional correction revealed the following profile: MPB-104-91-07-80 > 05 > 89 >> 9-hydroxyphenanthrene = phenanthrene. Coimmunoprecipitation experiments on human airway epithelial F508del/F508del CF15 cells showed that MPB did not prevent the interaction of F508del-CFTR with heat shock protein (HSP)70, HSP90, or calnexin. Functional rescue of F508del-CFTR by MPB and miglustat was abolished by brefeldin A (BFA) but potentiated by thapsigargin (TG) and geldanamycin. The proteasome inhibitor MG132 potentiated the effect of miglustat but only modestly affected that of MPB. It is noteworthy that MPB inhibited proteasome activity in F508del-CFTR-expressing cells but did not directly affect the activity of purified 20S proteasome. With the mutant G622D-CFTR, MPB did not inhibit proteasome activity, as in mock-transfected cells. Inhibition of cellular degradation machinery by MPB is not only CFTR-dependent, but it also follows similar structure-activity relationship as demonstrated by functional correction. We conclude that G622D is a partial trafficking-deficient mutant with dysfunctional chloride channel activity, and that Gly622 is part of the putative site for interaction of MPB with CFTR, protecting the channel from proteasome-mediated degradation.
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PMID:Proteasome-dependent pharmacological rescue of cystic fibrosis transmembrane conductance regulator revealed by mutation of glycine 622. 1823 Jun 92

Skeletal muscles exhibit radical changes in physiology and metabolism in response to exercise. While exercise induces highly specific physiological changes, e.g., hypertrophy, associated with weightlifting or oxygen utilization associated with aerobic-type exercises, the foundation of these changes is driven by the summation of exercise-induced alterations in muscle protein metabolism. Practically, any type of exercise stimulates muscle protein turnover, the purpose being both to renew, and also modify, the myocellular composition of proteins in line with adaptations according to the mechanical and metabolic demands imposed. The mechanism(s) by which exercise stimulates protein turnover has been the subset of intense study. These studies have been led by the use of stable isotopically labeled amino acids. Essentially, use of these heavier variants (e.g., (13)C AA vs. (12)C) coupled to mass spectrometry has enabled study of the dynamic responses of muscle protein turnover to exercise. Using these techniques, it has become patently clear that exercise stimulates muscle protein turnover, i.e., muscle protein synthesis (MPS) and breakdown (MPB). Moreover, intake of specific nutrients (i.e., dietary proteins) potentiates MPS while attenuating MPB, facilitating maintenance of proteostasis and exercise adaptation. The mechanisms driving these protein metabolic responses to exercise include the coordinated activation of mRNA translation pathways (e.g., mechanistic target of rapamycin) and multiple MPB pathways (e.g., autophagy and ubiquitin-proteasome). These processes are triggered by exercise-induced hormone, auto/paracrine-acting growth factors, mechanical transduction, and intramyocellular second messenger pathways. Finally, there remains poor understanding of how distinct exercise modes (e.g., resistance vs. endurance) lead to such distinct adaptations from a protein metabolic and molecular standpoint.
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PMID:Exercise and Regulation of Protein Metabolism. 2647 11