scholarly journals TASEP modelling provides a parsimonious explanation for the ability of a single uORF to upregulate downstream ORF translation during the Integrated Stress Response

2017 ◽  
Author(s):  
Dmitry E Andreev ◽  
Maxim Arnold ◽  
Gary Loughran ◽  
Dmitrii Rachinskii ◽  
Pavel V Baranov
Keyword(s):  
Stress Response ◽  
Stress Resistance ◽  
General Mechanism ◽  
Integrated Stress Response ◽  
Rate Limiting Step ◽  
Parsimonious Explanation ◽  
Limiting Step ◽  
The Relationship ◽  
Rate Limiting ◽  
Insight Into

ABSTRACTTranslation initiation is the rate limiting step of protein synthesis that is downregulated during Integrated Stress Response (ISR). In our previous work (Andreev, O’Connor et al 2015), we demonstrated that most human mRNAs resistant to this inhibition possess translated uORFs and in some cases a single uORF is sufficient for the resistance. Here we developed a computational model of Initiation Complexes Interference with Elongating Ribosomes (ICIER) to gain insight into the mechanism. We explored the relationship between the flux of scanning ribosomes upstream and downstream of a single uORF depending on uORF features. Paradoxically our analysis predicts that reducing ribosome flux upstream of certain uORFs increases initiation downstream. The model reveals derepression of downstream translation as general mechanism of uORF-mediated stress resistance. It predicts that stress resistance can be achieved with long or slowly translated uORFs that do not favor high levels of translation re-initiation and start with non-leaky initiators.

scholarly journals TASEP modelling provides a parsimonious explanation for the ability of a single uORF to derepress translation during the integrated stress response

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Dmitry E Andreev ◽  
Maxim Arnold ◽  
Stephen J Kiniry ◽  
Gary Loughran ◽  
Audrey M Michel ◽  
...  
Keyword(s):  
Stress Response ◽  
Stress Resistance ◽  
Open Reading Frames ◽  
General Mechanism ◽  
Integrated Stress Response ◽  
Rate Limiting Step ◽  
Upstream Open Reading Frames ◽  
The Relationship ◽  
Rate Limiting ◽  
Insight Into

Translation initiation is the rate-limiting step of protein synthesis that is downregulated during the Integrated Stress Response (ISR). Previously, we demonstrated that most human mRNAs that are resistant to this inhibition possess translated upstream open reading frames (uORFs), and that in some cases a single uORF is sufficient for the resistance. Here we developed a computational model of Initiation Complexes Interference with Elongating Ribosomes (ICIER) to gain insight into the mechanism. We explored the relationship between the flux of scanning ribosomes upstream and downstream of a single uORF depending on uORF features. Paradoxically, our analysis predicts that reducing ribosome flux upstream of certain uORFs increases initiation downstream. The model supports the derepression of downstream translation as a general mechanism of uORF-mediated stress resistance. It predicts that stress resistance can be achieved with long slowly decoded uORFs that do not favor translation reinitiation and that start with initiators of low leakiness.

scholarly journals Mechanism of the Iridium-Catalyzed Silylation of Aromatic C–H Bonds

2020 ◽  
Author(s):  
Caleb Karmel ◽  
John Hartwig
Keyword(s):  
Computational Studies ◽  
Iridium Complexes ◽  
Phen Ligand ◽  
Rate Limiting Step ◽  
Limiting Step ◽  
The Difference ◽  
Silyl Complex ◽  
Rate Limiting ◽  
Insight Into ◽  
Hydride Ligands

<p>The iridium-catalyzed silylation of aromatic C–H bonds has become a synthetically valuable reaction because it forms aryl silanes with high sterically derived regioselectivity with silane reagents that are produced and consumed on large scales. Many groups, including our own, have reported iridium complexes of phenanthroline or bipyridine ligands as catalysts for this reaction. Yet, little is known about the mechanism by which the iridium-catalyzed silylation of arenes occurs. Indeed, no iridium-silyl complexes have been prepared that react with C-H bonds to form C-Si bonds in a fashion that is chemically and kinetically competent to be part of the catalytic cycle. </p><p><br></p> <p>In this manuscript, we report the synthesis and reactivity of iridium-silyl compelexes of the 2,9-Me<sub>2</sub>Phen ligand that generates the most active known catalyst for the silylation of aromatic C-H bonds. We show by experiment and computation that the most stable and most reactive silyl complex of this ligand contains two silyl and one hydride ligands and by kinetic analysis of the catalytic reaction determine the rate-limiting step for arenes with varying electronic properties. Computational studies indicate that the steric encumberance of the phenanthroline ligand controls the number of silyl ligands bound to iridium and that the difference in the number of silyl ligands leads to large differences to the rates of the reaction. These studies provide insight into the origins of the high activity of the catalyst containing the 2,9-Me<sub>2</sub>Phen ligand.</p>

A Kinetic Study on the Methanogenesis Process in Anaerobic Digestion

1989 ◽  
Vol 21 (4-5) ◽  
pp. 175-186 ◽  
Author(s):  
C. Y. Lin ◽  
T. Noike ◽  
H. Furumai ◽  
J. Matsumoto
Keyword(s):  
Anaerobic Digestion ◽  
Substrate Concentration ◽  
Volatile Fatty Acid ◽  
Kinetic Mechanism ◽  
High Concentration ◽  
Two Phase ◽  
Rate Limiting Step ◽  
Limiting Step ◽  
The Relationship ◽  
Rate Limiting

Results obtained from experiments on two-phase anaerobic digestion using a high concentration of a volatile fatty acid (VFA) mixture were used to elucidate the kinetic mechanism of the methanogenesis process. The mixture consisted of the major intermediate products of anaerobic digestion, i.e., acetic acid (HAc), propionic acid (HPr) and butyric acid (HBu). The relationship between the rate of substrate utilization and substrate concentration in the digesters was in the form of a Michaelis-Menten equation. The rate-limiting step of the methanogenesis process, i.e., the conversion of HAc to methane, was speeded up in the digesters and this was proved kinetically. A method for determining kinetic constants for substrate-specific microorganisms was suggested. A simulation model for predicting the effluent substrate concentration was demonstrated. The effluent substrate concentration of an anaerobic digester fed by a multisubstrate was found to be simulatively predictable from its influent component substrates.

scholarly journals Kinetic and structure–activity studies of the triazolium ion-catalysed benzoin condensation

2021 ◽  
Author(s):  
Richard S. Massey ◽  
Jacob Murray ◽  
Christopher J. Collett ◽  
Jiayun Zhu ◽  
Andrew D. Smith ◽  
...  
Keyword(s):  
Initial Rate ◽  
Activity Analysis ◽  
Rate Limiting Step ◽  
Structure Activity ◽  
Limiting Step ◽  
Benzoin Condensation ◽  
Rate Evaluation ◽  
Rate Limiting ◽  
Insight Into

An initial rate evaluation of the triazolium-catalysed benzoin condensation permitted a Hammett structure–activity analysis providing insight into the rate-limiting step.

scholarly journals Analysis of P-Body Assembly in Saccharomyces cerevisiae

2007 ◽  
Vol 18 (6) ◽  
pp. 2274-2287 ◽  
Author(s):  
Daniela Teixeira ◽  
Roy Parker
Keyword(s):  
Deletion Mutants ◽  
Processing Bodies ◽  
Mrna Decapping ◽  
P Bodies ◽  
Translation Repression ◽  
Rate Limiting Step ◽  
Limiting Step ◽  
Body Component ◽  
Rate Limiting ◽  
Insight Into

Recent experiments have defined cytoplasmic foci, referred to as processing bodies (P-bodies), that contain untranslating mRNAs in conjunction with proteins involved in translation repression and mRNA decapping and degradation. However, the order of protein assembly into P-bodies and the interactions that promote P-body assembly are unknown. To gain insight into how yeast P-bodies assemble, we examined the P-body accumulation of Dcp1p, Dcp2p, Edc3p, Dhh1p, Pat1p, Lsm1p, Xrn1p, Ccr4p, and Pop2p in deletion mutants lacking one or more P-body component. These experiments revealed that Dcp2p and Pat1p are required for recruitment of Dcp1p and of the Lsm1-7p complex to P-bodies, respectively. We also demonstrate that P-body assembly is redundant and no single known component of P-bodies is required for P-body assembly, although both Dcp2p and Pat1p contribute to P-body assembly. In addition, our results indicate that Pat1p can be a nuclear-cytoplasmic shuttling protein and acts early in P-body assembly. In contrast, the Lsm1-7p complex appears to primarily function in a rate limiting step after P-body assembly in triggering decapping. Taken together, these results provide insight both into the function of individual proteins involved in mRNA degradation and the mechanisms by which yeast P-bodies assemble.

scholarly journals Mechanism of the Iridium-Catalyzed Silylation of Aromatic C–H Bonds

2020 ◽  
Author(s):  
Caleb Karmel ◽  
John Hartwig
Keyword(s):  
Computational Studies ◽  
Iridium Complexes ◽  
Phen Ligand ◽  
Rate Limiting Step ◽  
Limiting Step ◽  
The Difference ◽  
Silyl Complex ◽  
Rate Limiting ◽  
Insight Into ◽  
Hydride Ligands

<p>The iridium-catalyzed silylation of aromatic C–H bonds has become a synthetically valuable reaction because it forms aryl silanes with high sterically derived regioselectivity with silane reagents that are produced and consumed on large scales. Many groups, including our own, have reported iridium complexes of phenanthroline or bipyridine ligands as catalysts for this reaction. Yet, little is known about the mechanism by which the iridium-catalyzed silylation of arenes occurs. Indeed, no iridium-silyl complexes have been prepared that react with C-H bonds to form C-Si bonds in a fashion that is chemically and kinetically competent to be part of the catalytic cycle. </p><p><br></p> <p>In this manuscript, we report the synthesis and reactivity of iridium-silyl compelexes of the 2,9-Me<sub>2</sub>Phen ligand that generates the most active known catalyst for the silylation of aromatic C-H bonds. We show by experiment and computation that the most stable and most reactive silyl complex of this ligand contains two silyl and one hydride ligands and by kinetic analysis of the catalytic reaction determine the rate-limiting step for arenes with varying electronic properties. Computational studies indicate that the steric encumberance of the phenanthroline ligand controls the number of silyl ligands bound to iridium and that the difference in the number of silyl ligands leads to large differences to the rates of the reaction. These studies provide insight into the origins of the high activity of the catalyst containing the 2,9-Me<sub>2</sub>Phen ligand.</p>

scholarly journals Insight into wild-type and T1372E TET2-mediated 5hmC oxidation using ab initio QM/MM calculations

2018 ◽  
Vol 9 (44) ◽  
pp. 8433-8445 ◽  
Author(s):  
Hedieh Torabifard ◽  
G. Andrés Cisneros
Keyword(s):  
Ab Initio ◽  
Wild Type ◽  
Rate Limiting Step ◽  
Limiting Step ◽  
Rate Limiting ◽  
Insight Into

T1372E TET2 stalls at 5hmC due to unfavorable orientation of substrate, which increases barrier of the rate limiting step.

Ornithine Decarboxylase Activity in Cultured Endothelial Cells Stimulated by Serum, Thrombin and Serotonin

1978 ◽  
Vol 39 (02) ◽  
pp. 496-503 ◽  
Author(s):  
P A D’Amore ◽  
H B Hechtman ◽  
D Shepro
Keyword(s):  
Endothelial Cells ◽  
Ornithine Decarboxylase ◽  
Decarboxylase Activity ◽  
Aortic Endothelial Cells ◽  
Ornithine Decarboxylase Activity ◽  
Rate Limiting Step ◽  
Bovine Aortic Endothelial Cells ◽  
Limiting Step ◽  
Rate Limiting ◽  
Serum Serotonin

SummaryOrnithine decarboxylase (ODC) activity, the rate-limiting step in the synthesis of polyamines, can be demonstrated in cultured, bovine, aortic endothelial cells (EC). Serum, serotonin and thrombin produce a rise in ODC activity. The serotonin-induced ODC activity is significantly blocked by imipramine (10-5 M) or Lilly 11 0140 (10-6M). Preincubation of EC with these blockers together almost completely depresses the 5-HT-stimulated ODC activity. These observations suggest a manner by which platelets may maintain EC structural and metabolic soundness.

Dynamics of hepatic and peripheral insulin effects suggest common rate-limiting step in vivo

Diabetes ◽  
1993 ◽  
Vol 42 (2) ◽  
pp. 296-306 ◽  
Author(s):  
D. C. Bradley ◽  
R. A. Poulin ◽  
R. N. Bergman
Keyword(s):  
Rate Limiting Step ◽  
Limiting Step ◽  
Rate Limiting
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