ArticleJournal of the American Chemical Society2012
Fundamental reaction pathway and free energy profile for inhibition of proteasome by Epoxomicin.
Article in Journal of the American Chemical Society, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 110 citations in OpenAlex.
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- Mechanistic and thermodynamic characterization of oxathiazolones as potent and selective covalent immunoproteasome inhibitors.Computational and structural biotechnology journal · 2021Article
- Exploring the Proteolysis Mechanism of the Proteasomes.The journal of physical chemistry. B · 2020Article
- Insight into Inhibitor Binding in the Eukaryotic Proteasome: Computations of the 20S CP.International journal of molecular sciences · 2018Article
- Insights into Ag(i)-catalyzed addition reactions of amino alcohols to electron-deficient olefins: competing mechanisms, role of catalyst, and origin of chemoselectivity.RSC advances · 2018Article
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- Catalytic Mechanisms for Cofactor-Free Oxidase-Catalyzed Reactions: Reaction Pathways of Uricase-Catalyzed Oxidation and Hydration of Uric Acid.ACS catalysis · 2017Article
- The Architecture of the Anbu Complex Reflects an Evolutionary Intermediate at the Origin of the Proteasome System.Structure (London, England : 1993) · 2017Article
- Schiff base derived from thiosemicarbazone and anthracene showed high potential in overcoming multidrug resistance in vitro with low drug resistance index.Drug design, development and therapy · 2017Article
- Insights into the Competing Mechanisms and Origin of Enantioselectivity for N-Heterocyclic Carbene-Catalyzed Reaction of Aldehyde with Enamide.Scientific reports · 2016Article
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- Computational Approaches for the Discovery of Human Proteasome Inhibitors: An Overview.Molecules (Basel, Switzerland) · 2016Review
- David and Goliath: chemical perturbation of eukaryotes by bacteria.Journal of industrial microbiology & biotechnology · 2016Review
- Reaction Pathway for Cocaine Hydrolase-Catalyzed Hydrolysis of (+)-Cocaine.Theoretical chemistry accounts · 2016Article
- Mechanistic insights into cobalt(ii/iii)-catalyzed C-H oxidation: a combined theoretical and experimental study.Chemical science · 2015Article
- Fundamental reaction pathway and free energy profile of proteasome inhibition by syringolin A (SylA).Organic & biomolecular chemistry · 2015Article
- Selective immunoproteasome inhibitors with non-peptide scaffolds identified from structure-based virtual screening.Bioorganic & medicinal chemistry letters · 2014Article
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Authors and funding
4 authors at 2 institutions in 2 countries.
Funding
Abstract
First-principles quantum mechanical/molecular mechanical free energy calculations have been performed to provide the first detailed computational study on the possible mechanisms for reaction of proteasome with a representative peptide inhibitor, Epoxomicin (EPX). The calculated results reveal that the most favorable reaction pathway consists of five steps. The first is a proton transfer process, activating Thr1-O(γ) directly by Thr1-N(z) to form a zwitterionic intermediate. The next step is nucleophilic attack on the carbonyl carbon of EPX by the negatively charged Thr1-O(γ) atom, followed by a proton transfer from Thr1-N(z) to the carbonyl oxygen of EPX (third step). Then, Thr1-N(z) attacks on the carbon of the epoxide group of EPX, accompanied by the epoxide ring-opening (S(N)2 nucleophilic substitution) such that a zwitterionic morpholino ring is formed between residue Thr1 and EPX. Finally, the product of morpholino ring is generated via another proton transfer. Noteworthy, Thr1-O(γ) can be activated directly by Thr1-N(z) to form the zwitterionic intermediate (with a free energy barrier of only 9.9 kcal/mol), and water cannot assist the rate-determining step, which is remarkably different from the previous perception that a water molecule should mediate the activation process. The fourth reaction step has the highest free energy barrier (23.6 kcal/mol) which is reasonably close to the activation free energy (∼21-22 kcal/mol) derived from experimental kinetic data. The obtained novel mechanistic insights should be valuable for not only future rational design of more efficient proteasome inhibitors but also understanding the general reaction mechanism of proteasome with a peptide or protein.
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