scholarly journals Computational Insights into Substrate and Site Specificities, Catalytic Mechanism, and Protonation States of the Catalytic Asp Dyad ofβ-Secretase

Scientifica ◽  
2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Arghya Barman ◽  
Rajeev Prabhakar
Keyword(s):  
Catalytic Mechanism ◽  
Md Simulations ◽  
Peptide Bond ◽  
Docking Studies ◽  
In Silico Screening ◽  
Rate Determining Step ◽  
Rate Limiting Step ◽  
Beta Peptide ◽  
Structural Differences ◽  
Rate Limiting

In this review, information regarding substrate and site specificities, catalytic mechanism, and protonation states of the catalytic Asp dyad ofβ-secretase (BACE1) derived from computational studies has been discussed. BACE1 catalyzes the rate-limiting step in the generation of Alzheimer amyloid beta peptide through the proteolytic cleavage of the amyloid precursor protein. Due to its biological functioning, this enzyme has been considered as one of the most important targets for finding the cure for Alzheimer’s disease. Molecular dynamics (MD) simulations suggested that structural differences in the key regions (inserts A, D, and F and the 10s loop) of the enzyme are responsible for the observed difference in its activities towards the WT- and SW-substrates. The modifications in the flap, third strand, and insert F regions were found to be involved in the alteration in the site specificity of the glycosylphosphatidylinositol bound form of BACE1. Our QM and QM/MM calculations suggested that BACE1 hydrolyzed the SW-substrate more efficiently than the WT-substrate and that cleavage of the peptide bond occurred in the rate-determining step. The results from molecular docking studies showed that the information concerning a single protonation state of the Asp dyad is not enough to run an in silico screening campaign.

scholarly journals The rate-limiting step of protein synthesis in vivo and in vitro and the distribution of growing peptides between the puromycinlabile and puromycin-non-labile sites on polyribosomes

1971 ◽  
Vol 122 (3) ◽  
pp. 267-276 ◽  
Author(s):  
D. C. N. Earl ◽  
Susan T. Hindley
Keyword(s):  
Amino Acids ◽  
Protein Synthesis ◽  
Donor Site ◽  
Peptide Bond ◽  
Rate Limiting Step ◽  
Limiting Step ◽  
Donor And Acceptor ◽  
Rate Limiting

1. At 3 min after an intravenous injection of radioactive amino acids into the rat, the bulk of radioactivity associated with liver polyribosomes can be interpreted as growing peptides. 2. In an attempt to identify the rate-limiting step of protein synthesis in vivo and in vitro, use was made of the action of puromycin at 0°C, in releasing growing peptides only from the donor site, to study the distribution of growing peptides between the donor and acceptor sites. 3. Evidence is presented that all growing peptides in a population of liver polyribosomes labelled in vivo are similarly distributed between the donor and acceptor sites, and that the proportion released by puromycin is not an artifact of methodology. 4. The proportion released by puromycin is about 50% for both liver and muscle polyribosomes labelled in vivo, suggesting that neither the availability nor binding of aminoacyl-tRNA nor peptide bond synthesis nor translocation can limit the rate of protein synthesis in vivo. Attempts to alter this by starvation, hypophysectomy, growth hormone, alloxan, insulin and partial hepatectomy were unsuccessful. 5. Growing peptides on liver polyribosomes labelled in a cell-free system in vitro or by incubating hemidiaphragms in vitro were largely in the donor site, suggesting that either the availability or binding of aminoacyl-tRNA, or peptide bond synthesis, must be rate limiting in vitro and that the rate-limiting step differs from that in vivo. 6. Neither in vivo nor in the hemidiaphragm system in vitro was a correlation found between the proportion of growing peptides in the donor site and changes in the rate of incorporation of radioactivity into protein. This could indicate that the intracellular concentration of amino acids or aminoacyl-tRNA limits the rate of protein synthesis and that the increased incorporation results from a rise to a higher but still suboptimum concentration.

scholarly journals Understanding the reaction mechanism of Kolbe electrolysis on Pt anodes

2021 ◽  
Author(s):  
Sihang Liu ◽  
Nitish Govindarajan ◽  
Hector Prats ◽  
Karen Chan
Keyword(s):  
Reaction Mechanism ◽  
Potential Range ◽  
Microkinetic Model ◽  
Rate Determining Step ◽  
Rate Limiting Step ◽  
Limiting Step ◽  
Tafel Slopes ◽  
Kolbe Electrolysis ◽  
Kolbe Reaction ◽  
Rate Limiting

Kolbe electrolysis has been proposed an efficient electrooxidation process to synthesize (un)symmetrical dimers from biomass-based carboxylic acids. However, the reaction mechanism of Kolbe electrolysis remains controversial. In this work, we develop a DFT- based microkinetic model to study the reaction mechanism of Kolbe electrolysis of acetic acid (CH3COOH) on both pristine and partially oxidized Pt anodes. We show that the shift in the rate-determining step of oxygen evolution reaction (OER) on Pt(111)@α-PtO2 surface from OH* formation to H2O adsorption gives rise to the large Tafel slopes, i.e., the inflection zones, observed at high anodic potentials in experiments on Pt anodes. The activity passivation as a result of the inflection zone is further exacerbated in the presence of Kolbe species (i.e., CH3COO* and CH3*). Our simulations find the CH3COO* decarboxylation and CH3* dimerization steps determine the activity of Kolbe reaction during inflection zone. In contrast to the Pt(111)@α-PtO2 surface, Pt(111) shows no activity towards Kolbe products as the CH3COO* decarboxylation step is limiting throughout the considered potential range. This work resolves major controversies in the mechanistic analyses of Kolbe electrolysis on Pt anodes: the origin of the inflection zone, and the identity of the rate limiting step.

The rate‐limiting step in the folding of the cis‐Pro 167Thr mutant of TEM‐1 β‐lactamase is the trans to cis isomerization of a non‐proline peptide bond

1996 ◽  
Vol 25 (1) ◽  
pp. 104-111 ◽  
Author(s):  
Marc Vanhove ◽  
Xavier Raquet ◽  
Timothy Palzkill ◽  
Roger H. Pain ◽  
Jean‐Marie Frère
Keyword(s):  
Peptide Bond ◽  
Rate Limiting Step ◽  
Limiting Step ◽  
Rate Limiting

Substrate-assisted mechanism of catalytic hydrolysis of misaminoacylated tRNA required for protein synthesis fidelity

2019 ◽  
Vol 476 (4) ◽  
pp. 719-732 ◽  
Author(s):  
Mykola M. Ilchenko ◽  
Mariia Yu. Rybak ◽  
Alex V. Rayevsky ◽  
Oksana P. Kovalenko ◽  
Igor Ya. Dubey ◽  
...  
Keyword(s):  
Amino Acids ◽  
Catalytic Mechanism ◽  
Thermus Thermophilus ◽  
Extensive Study ◽  
Water Molecules ◽  
Amino Acid Residues ◽  
Rate Limiting Step ◽  
Limiting Step ◽  
Mechanism Of Hydrolysis ◽  
Rate Limiting

Abstract d-aminoacyl-tRNA-deacylase (DTD) prevents the incorporation of d-amino acids into proteins during translation by hydrolyzing the ester bond between mistakenly attached amino acids and tRNAs. Despite extensive study of this proofreading enzyme, the precise catalytic mechanism remains unknown. Here, a combination of biochemical and computational investigations has enabled the discovery of a new substrate-assisted mechanism of d-Tyr-tRNATyr hydrolysis by Thermus thermophilus DTD. Several functional elements of the substrate, misacylated tRNA, participate in the catalysis. During the hydrolytic reaction, the 2′-OH group of the А76 residue of d-Tyr-tRNATyr forms a hydrogen bond with a carbonyl group of the tyrosine residue, stabilizing the transition-state intermediate. Two water molecules participate in this reaction, attacking and assisting ones, resulting in a significant decrease in the activation energy of the rate-limiting step. The amino group of the d-Tyr aminoacyl moiety is unprotonated and serves as a general base, abstracting the proton from the assisting water molecule and forming a more nucleophilic ester-attacking species. Quantum chemical methodology was used to investigate the mechanism of hydrolysis. The DFT-calculated deacylation reaction is in full agreement with the experimental data. The Gibbs activation energies for the first and second steps were 10.52 and 1.05 kcal/mol, respectively, highlighting that the first step of the hydrolysis process is the rate-limiting step. Several amino acid residues of the enzyme participate in the coordination of the substrate and water molecules. Thus, the present work provides new insights into the proofreading details of misacylated tRNAs and can be extended to other systems important for translation fidelity.

scholarly journals The influence of active site conformations on the hydride transfer step of the thymidylate synthase reaction mechanism

2015 ◽  
Vol 17 (46) ◽  
pp. 30793-30804 ◽  
Author(s):  
Katarzyna Świderek ◽  
Amnon Kohen ◽  
Vicent Moliner
Keyword(s):  
Reaction Mechanism ◽  
Thymidylate Synthase ◽  
Active Site ◽  
Hydride Transfer ◽  
Md Simulations ◽  
Concerted Mechanism ◽  
X Ray ◽  
Rate Limiting Step ◽  
Limiting Step ◽  
Rate Limiting

QM/MM MD simulations from different X-ray structures support the concerted mechanism character in the rate limiting step of thymidylate synthase catalysis.

scholarly journals Revealing Mechanism and Origin of Reactivity of Au(I)-Catalyzed Functionalized Indenone Formation of Cyclic and Acyclic Acetals of Alkynylaldehydes

2020 ◽  
Author(s):  
Aqeel A. Hussein ◽  
Hafiz S. Ali
Keyword(s):  
Phenyl Ring ◽  
Density Functional ◽  
Reaction Pathway ◽  
Phenyl Group ◽  
Functional Theory ◽  
Rate Determining Step ◽  
Rate Limiting Step ◽  
Electron Withdrawing Group ◽  
Catalytic Cycles ◽  
Rate Limiting

<p><a>Density functional theory exploited with the (SMD)-B3LYP-D3/def2-TZVP//B3LYP/6-31G(d),LANL2DZ level of theory is presented to offer mechanistic insights and explications of experimentally intriguing observations in the Au(I)-catalyzed cyclization of cyclic and acyclic acetals of alkynylaldehydes that lead to indenone formation. The reactivity of catalytic cycles with and without methoxy migration is computationally defined when alkyne terminus is phenylated in addition to the unreactive cycle when alkyne terminus is not phenylated. The reaction mechanism of indenone formation proceeds first with coordination of Au(I) to alkyne to initiate the reaction with 1,5-H shift as a rate-determining step and the fastest 1,5-H shift is achieved when one phenyl ring carries electron-donating group and the other one is substituted with electron-withdrawing group. The absence of tethered acetal unit considerably outpaces any 1,5-H shift and instead activates 1,5-methoxy migration, giving methoxy-migrated indenone, with the step of 1,2-OMe shift is a rate-limiting step during reaction pathway. Following 1,5-H shift the cyclization and 1,2-H shift are kinetically and thermodynamically feasible, which are followed by elimination to persist the iterative cycle, but the reactivity of both steps is highly affected by the existence of phenyl group on alkyne terminus. The unreactivity of alkyne terminus being not beared a phenyl ring is due to that the cyclization is thermodynamically disfavorable, subsequently deactivating the 1,2-H shift kinetically and thermodynamically. </a></p>

The rate-limiting step in the folding of the cis-Pro167Thr mutant of TEM-1 β-lactamase is the trans to cis isomerization of a non-proline peptide bond

1996 ◽  
Vol 25 (1) ◽  
pp. 104-111 ◽  
Author(s):  
Marc Vanhove ◽  
Xavier Raquet ◽  
Timothy Palzkill ◽  
Roger H. Pain ◽  
Jean-Marie Frère
Keyword(s):  
Peptide Bond ◽  
Rate Limiting Step ◽  
Limiting Step ◽  
Rate Limiting

THEORETICAL INVESTIGATION ON THE ACTIVATION OF ETHANE VIA NICKEL ATOM CATALYSIS

2007 ◽  
Vol 06 (02) ◽  
pp. 323-330 ◽  
Author(s):  
LAI-CAI LI ◽  
JUN-LING LIU ◽  
JING SHANG ◽  
XIN WANG ◽  
NING-BEW WONG
Keyword(s):  
Density Functional ◽  
Bond Activation ◽  
Theoretical Work ◽  
Nickel Atom ◽  
Functional Theory ◽  
Activation Pathway ◽  
Rate Determining Step ◽  
Rate Limiting Step ◽  
Limiting Step ◽  
Rate Limiting

The reaction mechanism of the activation of ethane by nickel atom has been investigated by density functional theory (DFT). The geometries and vibration frequencies of reactants, intermediates, transition states and products have been calculated at the B3LYP/6-311 + +G(d, p) level. Two main pathways, C – C bond activation and C – H bond activation, are identified. In former channel, the rate-limiting step is found to be hydrogen-transferring step with a high barrier of 227 kJ · mol-1. In the C – H bond activation pathway, the second hydrogen-transferring step is the rate-determining step of the whole reaction. The barrier of the step is 71 kJ · mol-1. Our results show that the studied reaction would undergo along C – H bond activation pathway to form the products H 2 molecule and Ni ⋯ethene complex. The present theoretical work indicates that Ni atom is more active than Ni + cation in activating ethane.

scholarly journals Exploring the mechanism of tryptophan 2,3-dioxygenase

2008 ◽  
Vol 36 (6) ◽  
pp. 1120-1123 ◽  
Author(s):  
Sarah J. Thackray ◽  
Christopher G. Mowat ◽  
Stephen K. Chapman
Keyword(s):  
Catalytic Mechanism ◽  
Kynurenine Pathway ◽  
Oxidation Catalysts ◽  
Function Structure ◽  
Indoleamine 2,3 Dioxygenase ◽  
Rate Limiting Step ◽  
Limiting Step ◽  
Biochemical Analyses ◽  
Rate Limiting ◽  
Haem Proteins

The haem proteins TDO (tryptophan 2,3-dioxygenase) and IDO (indoleamine 2,3-dioxygenase) are specific and powerful oxidation catalysts that insert one molecule of dioxygen into L-tryptophan in the first and rate-limiting step in the kynurenine pathway. Recent crystallographic and biochemical analyses of TDO and IDO have greatly aided our understanding of the mechanisms employed by these enzymes in the binding and activation of dioxygen and tryptophan. In the present paper, we briefly discuss the function, structure and possible catalytic mechanism of these enzymes.

scholarly journals Revealing Mechanism and Origin of Reactivity of Au(I)-Catalyzed Functionalized Indenone Formation of Cyclic and Acyclic Acetals of Alkynylaldehydes

2020 ◽  
Author(s):  
Aqeel A. Hussein ◽  
Hafiz S. Ali
Keyword(s):  
Phenyl Ring ◽  
Density Functional ◽  
Reaction Pathway ◽  
Phenyl Group ◽  
Functional Theory ◽  
Rate Determining Step ◽  
Rate Limiting Step ◽  
Electron Withdrawing Group ◽  
Catalytic Cycles ◽  
Rate Limiting

<p><a>Density functional theory exploited with the (SMD)-B3LYP-D3/def2-TZVP//B3LYP/6-31G(d),LANL2DZ level of theory is presented to offer mechanistic insights and explications of experimentally intriguing observations in the Au(I)-catalyzed cyclization of cyclic and acyclic acetals of alkynylaldehydes that lead to indenone formation. The reactivity of catalytic cycles with and without methoxy migration is computationally defined when alkyne terminus is phenylated in addition to the unreactive cycle when alkyne terminus is not phenylated. The reaction mechanism of indenone formation proceeds first with coordination of Au(I) to alkyne to initiate the reaction with 1,5-H shift as a rate-determining step and the fastest 1,5-H shift is achieved when one phenyl ring carries electron-donating group and the other one is substituted with electron-withdrawing group. The absence of tethered acetal unit considerably outpaces any 1,5-H shift and instead activates 1,5-methoxy migration, giving methoxy-migrated indenone, with the step of 1,2-OMe shift is a rate-limiting step during reaction pathway. Following 1,5-H shift the cyclization and 1,2-H shift are kinetically and thermodynamically feasible, which are followed by elimination to persist the iterative cycle, but the reactivity of both steps is highly affected by the existence of phenyl group on alkyne terminus. The unreactivity of alkyne terminus being not beared a phenyl ring is due to that the cyclization is thermodynamically disfavorable, subsequently deactivating the 1,2-H shift kinetically and thermodynamically. </a></p>

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