Small-Molecule Diselenides Catalyze Oxidative Protein Folding in Vivo

2010 ◽  
Vol 5 (2) ◽  
pp. 177-182 ◽  
Author(s):  
Joris Beld ◽  
Kenneth J. Woycechowsky ◽  
Donald Hilvert
Keyword(s):  
Protein Folding ◽  
Small Molecule ◽  
Oxidative Protein Folding

Catalysis of Oxidative Protein Folding by Small-Molecule Diselenides†

Biochemistry ◽  
2008 ◽  
Vol 47 (27) ◽  
pp. 6985-6987 ◽  
Author(s):  
Joris Beld ◽  
Kenneth J. Woycechowsky ◽  
Donald Hilvert
Keyword(s):  
Protein Folding ◽  
Small Molecule ◽  
Oxidative Protein Folding

Small molecule diselenide additives for in vitro oxidative protein folding

2016 ◽  
Vol 52 (16) ◽  
pp. 3336-3339 ◽  
Author(s):  
Post Sai Reddy ◽  
Norman Metanis
Keyword(s):  
Protein Folding ◽  
Small Molecule ◽  
Oxidative Folding ◽  
Oxidative Protein Folding

Small molecule diselenides were prepared and found to enhance thein vitrooxidative folding of disulfide-rich protein.

scholarly journals Endoplasmic reticulum oxidoreductin (ERO) provides resilience against reductive stress and hypoxic conditions by mediating luminal redox dynamics

2021 ◽  
Author(s):  
Jose Manuel Ugalde ◽  
Isabel Aller ◽  
Lika Kudrjasova ◽  
Romy Schmidt ◽  
Michelle Schloesser ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Protein Folding ◽  
Redox Homeostasis ◽  
Midpoint Potential ◽  
Oxidative Protein Folding ◽  
Reductive Stress ◽  
Hypoxic Conditions ◽  
Glutathione Redox ◽  
Redox Dynamics

Oxidative protein folding in the endoplasmic reticulum (ER) depends on the coordinated action of protein disulfide isomerases and ER oxidoreductins (EROs). Strict dependence of ERO activity on molecular oxygen as the final electron acceptor implies that oxidative protein folding and other ER processes are severely compromised under hypoxia. While many key players involved in oxidative protein folding are known, our understanding of how redox homeostasis in the ER is maintained and how EROs, the Cys residues of nascent proteins, and the luminal glutathione redox buffer interact is limited. Here, we isolated viable ero1 ero2 double mutants largely deficient in ERO activity, which rendered the mutants highly sensitive to reductive stress and hypoxia. To elucidate the specific redox dynamics in the ER lumen in vivo, we expressed the glutathione redox potential (EGSH) sensor Grx1-roGFP2iL-HDEL with a midpoint potential of -240 mV in the ER of Arabidopsis plants. We found EGSH values of -241 mV in wild-type plants, which is less oxidizing than previously estimated. In the ero1 ero2 mutants, luminal EGSH was reduced further to -253 mV. Recovery to reductive ER stress, as induced by acute exposure to dithiothreitol, was delayed in ero1 ero2 mutants. The characteristic signature of EGSH dynamics in the ER lumen triggered by hypoxia was affected in the ero1 ero2 mutant reflecting a disrupted balance of reductive and oxidizing inputs, including nascent polypeptides and glutathione entry. The ER redox dynamics can now be dissected in vivo, revealing a central role of EROs as major redox integrators to promote luminal redox homeostasis.

scholarly journals Quantitative Analyses of the Yeast Oxidative Protein Folding Pathway In Vitro and In Vivo

2019 ◽  
Vol 31 (4) ◽  
pp. 261-274 ◽  
Author(s):  
Dave M. Beal ◽  
Emma L. Bastow ◽  
Gemma L. Staniforth ◽  
Tobias von der Haar ◽  
Robert B. Freedman ◽  
...  
Keyword(s):  
Protein Folding ◽  
Folding Pathway ◽  
Oxidative Protein Folding ◽  
Quantitative Analyses

scholarly journals A small-molecule catalyst of protein folding in vitro and in vivo

1999 ◽  
Vol 6 (12) ◽  
pp. 871-879 ◽  
Author(s):  
Kenneth J Woycechowsky ◽  
K Dane Wittrup ◽  
Ronald T Raines
Keyword(s):  
Protein Folding ◽  
Small Molecule

120-LB: Small Molecule Activator of Pyruvate Kinase Regulates In Vivo Glucose Homeostasis

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 120-LB
Author(s):  
ABUDUKADIER ABULIZI ◽  
REBECCA L. CARDONE ◽  
STEPHAN SIEBEL ◽  
CHARLES KUNG ◽  
RICHARD KIBBEY
Keyword(s):  
Pyruvate Kinase ◽  
Small Molecule ◽  
Glucose Homeostasis

Quantitative Ranking of Ligand Binding Kinetics with a Multiscale Milestoning Simulation Approach

2018 ◽  
Author(s):  
Benjamin R. Jagger ◽  
Christoper T. Lee ◽  
Rommie Amaro
Keyword(s):  
Molecular Dynamics ◽  
Drug Discovery ◽  
Small Molecule ◽  
Brownian Dynamics ◽  
Model Simulation ◽  
Computational Cost ◽  
Lead Selection ◽  
Delta G ◽  
Dynamics Simulations

<p>The ranking of small molecule binders by their kinetic (kon and koff) and thermodynamic (delta G) properties can be a valuable metric for lead selection and optimization in a drug discovery campaign, as these quantities are often indicators of in vivo efficacy. Efficient and accurate predictions of these quantities can aid the in drug discovery effort, acting as a screening step. We have previously described a hybrid molecular dynamics, Brownian dynamics, and milestoning model, Simulation Enabled Estimation of Kinetic Rates (SEEKR), that can predict kon’s, koff’s, and G’s. Here we demonstrate the effectiveness of this approach for ranking a series of seven small molecule compounds for the model system, -cyclodextrin, based on predicted kon’s and koff’s. We compare our results using SEEKR to experimentally determined rates as well as rates calculated using long-timescale molecular dynamics simulations and show that SEEKR can effectively rank the compounds by koff and G with reduced computational cost. We also provide a discussion of convergence properties and sensitivities of calculations with SEEKR to establish “best practices” for its future use.</p>

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