Search results for "Enzyme catalysis"

Origin of Enzymatic Kinetic Isotope Effects in Human Purine Nucleoside Phosphorylase

2017

Here we report a study of the effect of heavy isotope labeling on the reaction catalyzed by human purine nucleoside phosphorylase (hPNP) to elucidate the origin of its catalytic effect and of the enzymatic kinetic isotope effect (EKIE). Using quantum mechanical and molecular mechanical (QM/MM) molecular dynamics (MD) simulations, we study the mechanism of the hPNP enzyme and the dynamic effects by means of the calculation of the recrossing transmission coefficient. A free energy surface (FES), as a function of both a chemical and an environmental coordinate, is obtained to show the role of the environment on the chemical reaction. Analysis of reactive and nonreactive trajectories allows us …

Heavy enzymes and the rational redesign of protein catalysts

2019

Abstract An unsolved mystery in biology concerns the link between enzyme catalysis and protein motions. Comparison between isotopically labelled “heavy” dihydrofolate reductases and their natural‐abundance counterparts has suggested that the coupling of protein motions to the chemistry of the catalysed reaction is minimised in the case of hydride transfer. In alcohol dehydrogenases, unnatural, bulky substrates that induce additional electrostatic rearrangements of the active site enhance coupled motions. This finding could provide a new route to engineering enzymes with altered substrate specificity, because amino acid residues responsible for dynamic coupling with a given substrate present…

A Dehydrogenase Dual Hydrogen Abstraction Mechanism Promotes Estrogen Biosynthesis: Can We Expand the Functional Annotation of the Aromatase Enzyme?

2018

Cytochrome P450 (CYP450) enzymes are involved in the metabolism of exogenous compounds and in the synthesis of signaling molecules. Among the latter, human aromatase (HA) promotes estrogen biosynthesis, which is a key pharmacological target against breast cancers. After decades of debate, interest in gaining a comprehensive picture of HA catalysis has been renewed by the recent discovery that compound I (Cpd I) is the reactive species of the peculiar aromatization step. Herein, for the first time, a complete atomic-level picture of all controversial steps of estrogen biosynthesis is presented. By performing cumulative quantum-classical molecular dynamics and metadynamics simulations of abou…

Revisiting the pH-gated conformational switch on the activities of HisKA-family histidine kinases

2020

13 páginas, 6 figuras, 3 tablas

Minimization of dynamic effects in the evolution of dihydrofolate reductase

2015

Protein isotope labeling is a powerful technique to probe functionally important motions in enzyme catalysis and can be applied to investigate the conformational dynamics of proteins.

2018

The origin of substrate preference in promiscuous enzymes was investigated by enzyme isotope labelling of the alcohol dehydrogenase from Geobacillus stearothermophilus (BsADH). At physiological temperature, protein dynamic coupling to the reaction coordinate was insignificant. However, the extent of dynamic coupling was highly substrate-dependent at lower temperatures. For benzyl alcohol, an enzyme isotope effect larger than unity was observed, whereas the enzyme isotope effect was close to unity for isopropanol. Frequency motion analysis on the transition states revealed that residues surrounding the active site undergo substantial displacement during catalysis for sterically bulky alcohol…

1,2,3-Triazole in Heterocyclic Compounds, Endowed with Biological Activity, through 1,3-Dipolar Cycloadditions

2014

1,3-Dipolar cycloaddition reactions can be considered a powerful synthetic tool in the building of heterocyclic rings, with applications in different fields. In this review we focus on the synthesis of biologically active compounds possessing the 1,2,3-triazole core through 1,3-dipolar cycloaddition reactions. The 1,2,3-triazole skeleton can be present as a single disubstituted ring, as a linker between two molecules, or embedded in a polyheterocycle. The cycloaddition reactions are usually catalysed by copper or ruthenium. Domino reactions can be achieved through dipolarophile anion formation, generally followed by cyclisation. The variety of attainable heterocyclic structures gives an ill…

Exploration of the Activation Mechanism of the Epigenetic Regulator MLL3: A QM/MM Study

2021

The mixed lineage leukemia 3 or MLL3 is the enzyme in charge of the writing of an epigenetic mark through the methylation of lysine 4 from the N-terminal domain of histone 3 and its deregulation has been related to several cancer lines. An interesting feature of this enzyme comes from its regulation mechanism, which involves its binding to an activating dimer before it can be catalytically functional. Once the trimer is formed, the reaction mechanism proceeds through the deprotonation of the lysine followed by the methyl-transfer reaction. Here we present a detailed exploration of the activation mechanism through a QM/MM approach focusing on both steps of the reaction, aiming to provide new…

Adaptive Processes Concerned with Absorption and Metabolism of Xylitol

1969

The turnover rate of a monosaccharide or poly alcohol in most cases depends on the mode of application. With the exception of glucose or galactose carbohydrates are metabolized faster after intravenous application than after oral application. This shows, that absorption from the gastro-intestinal tract is a rate limiting factor. Dealing with adaptive processes we therefore have to be concerned with absorptive mechanisms on one hand and enzymatic reactions in the cellular metabolism on the other hand.

A simple model for barrier frequencies for enzymatic reactions.

2010

We present a simple model to rationalize the effects of environment on the reaction barrier frequencies derived from free energy profiles. These frequencies are relevant in deviations of a rate constant from its transition state theory value and in determining which environmental dynamics participate in the reaction. In particular, this simple model can be used to understand the changes in the reaction barrier frequencies of an enzymatic catalyzed reaction and the corresponding uncatalyzed process in aqueous solution, a change which has implications for dynamical environmental effects on the enzymatic reaction. Two possible cases are analyzed, in which the polarity (charge separation/locali…