scholarly journals Molecule dynamics and combined QM/MM study on one-carbon unit transfer reaction catalyzed by GAR transformylase

2005 ◽  
Vol 3 (4) ◽  
pp. 674-682
Author(s):  
Qing-An Qiao ◽  
Yueqing Jin ◽  
Zhengting Cai ◽  
Rongjun Qu ◽  
Chuanlu Yang ◽  
...  
Keyword(s):  
Transfer Reaction ◽  
Energy Surface ◽  
Catalytic Mechanism ◽  
Minimum Energy ◽  
Stepwise Mechanism ◽  
Gar Tfase ◽  
Reactive Center ◽  
Bond Network ◽  
Molecule Dynamics ◽  
Minimum Energy Pathway

AbstractBoth a molecule dynamic study and a combined quantum mechanics and molecule mechanics (QM/MM) study on Glycinamide ribonucleotide transformylase (GAR Tfase) catalytic mechanism are presented. The results indicate a direct one-carbon unit transfer process but not a stepwise mechanism in this reaction. The residues near the active center can fix the cofactor (N10-formyltetrahydrofolate) and GAR in proper relative positions by a H-bond network. The transition state and the minimum energy pathway are located on the potential energy surface. After all the residues (including H2O molecules) are removed from the system the activation energy has increased from 145.1 kJ/mol to 243.3 kJ/mol, and the formly transfer reaction is very hard to achieve. The interactions between coenzyme, GAR and residues near the reactive center are discussed as well.

Rationalizing the pH-Activity Response for Escherichia Coli’s Glycinamide Ribonucleotidetransformylase Through Computational Methods

2019 ◽  
Author(s):  
Adrian Roitberg ◽  
Pancham Lal Gupta
Keyword(s):  
Transfer Reaction ◽  
Catalytic Mechanism ◽  
Ph Dependence ◽  
Ph Effects ◽  
Dependent Manner ◽  
E Coli ◽  
Gar Tfase ◽  
Activity Curve ◽  
Ph Dependent ◽  
Formyl Transfer

<div>Human Glycinamide ribonucleotide transformylase (GAR Tfase), a regulatory enzyme in the de novo purine biosynthesis pathway, has been established as an anti-cancer target. GAR Tfase catalyzes the formyl transfer reaction from the folate cofactor to the GAR ligand. In the present work, we study E. coli GAR Tfase, which has high sequence similarity with the human GAR Tfase with most functional residues conserved. E. coli GAR Tfase exhibits structural changes and the binding of ligands that varies with pH which leads to change the rate of the formyl transfer reaction in a pH-dependent manner. Thus, the inclusion of pH becomes essential for the study of its catalytic mechanism. Experimentally, the pH-dependence of the kinetic parameter kcat is measured to evaluate the pH-range of enzymatic activity. However, insufficient information about residues governing the pH-effects on the catalytic activity leads to ambiguous assignments of the general acid and base catalysts and consequently its catalytic mechanism. In the present work, we use pH-replica exchange molecular dynamics (pH-REMD) simulations to study the effects of pH on E. coli GAR Tfase enzyme. We identify the titratable residues governing the pH-dependent conformational changes in the system. Furthermore, we filter out the protonation states which are essential in maintaining the structural integrity, keeping the ligands bound and assisting the catalysis. We reproduce the experimental pH-activity curve by computing the population of key protonation states. Moreover, we provide a detailed description of residues governing the acidic and basic limbs of the pH-activity curve.</div>

Rationalizing the pH-Activity Response for Escherichia Coli’s Glycinamide Ribonucleotidetransformylase Through Computational Methods

2019 ◽  
Author(s):  
Adrian Roitberg ◽  
Pancham Lal Gupta
Keyword(s):  
Transfer Reaction ◽  
Catalytic Mechanism ◽  
Ph Dependence ◽  
Ph Effects ◽  
Dependent Manner ◽  
E Coli ◽  
Gar Tfase ◽  
Activity Curve ◽  
Ph Dependent ◽  
Formyl Transfer

<div>Human Glycinamide ribonucleotide transformylase (GAR Tfase), a regulatory enzyme in the de novo purine biosynthesis pathway, has been established as an anti-cancer target. GAR Tfase catalyzes the formyl transfer reaction from the folate cofactor to the GAR ligand. In the present work, we study E. coli GAR Tfase, which has high sequence similarity with the human GAR Tfase with most functional residues conserved. E. coli GAR Tfase exhibits structural changes and the binding of ligands that varies with pH which leads to change the rate of the formyl transfer reaction in a pH-dependent manner. Thus, the inclusion of pH becomes essential for the study of its catalytic mechanism. Experimentally, the pH-dependence of the kinetic parameter kcat is measured to evaluate the pH-range of enzymatic activity. However, insufficient information about residues governing the pH-effects on the catalytic activity leads to ambiguous assignments of the general acid and base catalysts and consequently its catalytic mechanism. In the present work, we use pH-replica exchange molecular dynamics (pH-REMD) simulations to study the effects of pH on E. coli GAR Tfase enzyme. We identify the titratable residues governing the pH-dependent conformational changes in the system. Furthermore, we filter out the protonation states which are essential in maintaining the structural integrity, keeping the ligands bound and assisting the catalysis. We reproduce the experimental pH-activity curve by computing the population of key protonation states. Moreover, we provide a detailed description of residues governing the acidic and basic limbs of the pH-activity curve.</div>

scholarly journals MEPSA: minimum energy pathway analysis for energy landscapes: Fig. 1.

2015 ◽  
pp. btv453 ◽  
Author(s):  
Iñigo Marcos-Alcalde ◽  
Javier Setoain ◽  
Jesús I. Mendieta-Moreno ◽  
Jesús Mendieta ◽  
Paulino Gómez-Puertas
Keyword(s):  
Pathway Analysis ◽  
Minimum Energy ◽  
Energy Landscapes ◽  
Minimum Energy Pathway

Structural Basis of Hydrogenotrophic Methanogenesis

2020 ◽  
Vol 74 (1) ◽  
pp. 713-733
Author(s):  
Seigo Shima ◽  
Gangfeng Huang ◽  
Tristan Wagner ◽  
Ulrich Ermler
Keyword(s):  
Transfer Reaction ◽  
Catalytic Mechanism ◽  
Methanogenic Archaea ◽  
Energy Coupling ◽  
Structural Basis ◽  
Biomass Degradation ◽  
Hydrogenotrophic Methanogenesis ◽  
Sufficient Energy ◽  
Ion Gradient ◽  
Electron Reduction

Most methanogenic archaea use the rudimentary hydrogenotrophic pathway—from CO2 and H2 to methane—as the terminal step of microbial biomass degradation in anoxic habitats. The barely exergonic process that just conserves sufficient energy for a modest lifestyle involves chemically challenging reactions catalyzed by complex enzyme machineries with unique metal-containing cofactors. The basic strategy of the methanogenic energy metabolism is to covalently bind C1 species to the C1 carriers methanofuran, tetrahydromethanopterin, and coenzyme M at different oxidation states. The four reduction reactions from CO2 to methane involve one molybdopterin-based two-electron reduction, two coenzyme F420–based hydride transfers, and one coenzyme F430–based radical process. For energy conservation, one ion-gradient-forming methyl transfer reaction is sufficient, albeit supported by a sophisticated energy-coupling process termed flavin-based electron bifurcation for driving the endergonic CO2 reduction and fixation. Here, we review the knowledge about the structure-based catalytic mechanism of each enzyme of hydrogenotrophic methanogenesis.

Exploration of hydrogen bond networks and potential energy surfaces of methanol clusters using a two-stage clustering algorithm

2017 ◽  
Vol 19 (1) ◽  
pp. 544-556 ◽  
Author(s):  
Po-Jen Hsu ◽  
Kun-Lin Ho ◽  
Sheng-Hsien Lin ◽  
Jer-Lai Kuo
Keyword(s):  
Hydrogen Bond ◽  
Potential Energy ◽  
Potential Energy Surfaces ◽  
Clustering Algorithm ◽  
Energy Surface ◽  
Hydrogen Bond Network ◽  
Two Stage ◽  
Hydrogen Bond Networks ◽  
Bond Network ◽  
Energy Surfaces

A two-stage algorithm based both on the similarity in shape and hydrogen bond network is developed to explore the potential energy surface of methanol clusters.

scholarly journals Preferred WMSA catalytic mechanism of the nucleotidyl transfer reaction in human DNA polymerase κ elucidates error-free bypass of a bulky DNA lesion

2012 ◽  
Vol 40 (18) ◽  
pp. 9193-9205 ◽  
Author(s):  
Lee Lior-Hoffmann ◽  
Lihua Wang ◽  
Shenglong Wang ◽  
Nicholas E. Geacintov ◽  
Suse Broyde ◽  
...  
Keyword(s):  
Dna Polymerase ◽  
Transfer Reaction ◽  
Catalytic Mechanism ◽  
Dna Lesion ◽  
Human Dna
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