9 research outputs found
Mechanistic Pathway on Human Ī±āGlucosidase Maltase-Glucoamylase Unveiled by QM/MM Calculations
The
excessive consumption of starch in human diets is associated
with highly prevalent chronic metabolic diseases such as type 2 diabetes
and obesity. Ī±-Glucosidase enzymes contribute to the digestion
of starch into glucose and are thus attractive therapeutic targets
for diabetes. Given that the active sites of the various families
of Ī±-glucosidases have different sizes and structural features,
atomistic descriptions of the catalytic mechanisms of these enzymes
can support the development of potent and selective new inhibitors.
Maltase-glucoamylase (MGAM), in particular, has a N-terminal catalytic
domain (NtMGAM) that has shown high inhibitor selectivity. We provide
here the first theoretical study of the human NtMGAM catalytic domain,
employing a hybrid QM/MM approach with the ONIOM method to disclose
the full atomistic details of the reactions promoted by this domain.
We observed that the catalytic activity follows the classical Koshland
double-displacement mechanistic pathway that uses general acid and
base catalysts. A covalent glycosyl-enzyme intermediate was formed
and hydrolyzed in the first and second mechanistic steps, respectively,
through oxocarbenium ion-like transition state structures. The overall
reaction is of dissociative type. Both transition state geometries
differ from those known to occur in other glycosidases. The activation
free energy for the glycosylation rate-limiting step agrees with the
experimental barrier of 15.8 kcalĀ·mol<sup>ā1</sup>. Both
individual mechanistic steps of the reaction are exoergonic. These
structural results may serve as the basis for the design of transition
state analogue inhibitors that specifically target the intestinal
NtMGAM catalytic domain, thus delaying the production of glucose in
diabetic and obese patients
Mechanistic Pathway on Human Ī±āGlucosidase Maltase-Glucoamylase Unveiled by QM/MM Calculations
The
excessive consumption of starch in human diets is associated
with highly prevalent chronic metabolic diseases such as type 2 diabetes
and obesity. Ī±-Glucosidase enzymes contribute to the digestion
of starch into glucose and are thus attractive therapeutic targets
for diabetes. Given that the active sites of the various families
of Ī±-glucosidases have different sizes and structural features,
atomistic descriptions of the catalytic mechanisms of these enzymes
can support the development of potent and selective new inhibitors.
Maltase-glucoamylase (MGAM), in particular, has a N-terminal catalytic
domain (NtMGAM) that has shown high inhibitor selectivity. We provide
here the first theoretical study of the human NtMGAM catalytic domain,
employing a hybrid QM/MM approach with the ONIOM method to disclose
the full atomistic details of the reactions promoted by this domain.
We observed that the catalytic activity follows the classical Koshland
double-displacement mechanistic pathway that uses general acid and
base catalysts. A covalent glycosyl-enzyme intermediate was formed
and hydrolyzed in the first and second mechanistic steps, respectively,
through oxocarbenium ion-like transition state structures. The overall
reaction is of dissociative type. Both transition state geometries
differ from those known to occur in other glycosidases. The activation
free energy for the glycosylation rate-limiting step agrees with the
experimental barrier of 15.8 kcalĀ·mol<sup>ā1</sup>. Both
individual mechanistic steps of the reaction are exoergonic. These
structural results may serve as the basis for the design of transition
state analogue inhibitors that specifically target the intestinal
NtMGAM catalytic domain, thus delaying the production of glucose in
diabetic and obese patients
Mechanistic Pathway on Human Ī±āGlucosidase Maltase-Glucoamylase Unveiled by QM/MM Calculations
The
excessive consumption of starch in human diets is associated
with highly prevalent chronic metabolic diseases such as type 2 diabetes
and obesity. Ī±-Glucosidase enzymes contribute to the digestion
of starch into glucose and are thus attractive therapeutic targets
for diabetes. Given that the active sites of the various families
of Ī±-glucosidases have different sizes and structural features,
atomistic descriptions of the catalytic mechanisms of these enzymes
can support the development of potent and selective new inhibitors.
Maltase-glucoamylase (MGAM), in particular, has a N-terminal catalytic
domain (NtMGAM) that has shown high inhibitor selectivity. We provide
here the first theoretical study of the human NtMGAM catalytic domain,
employing a hybrid QM/MM approach with the ONIOM method to disclose
the full atomistic details of the reactions promoted by this domain.
We observed that the catalytic activity follows the classical Koshland
double-displacement mechanistic pathway that uses general acid and
base catalysts. A covalent glycosyl-enzyme intermediate was formed
and hydrolyzed in the first and second mechanistic steps, respectively,
through oxocarbenium ion-like transition state structures. The overall
reaction is of dissociative type. Both transition state geometries
differ from those known to occur in other glycosidases. The activation
free energy for the glycosylation rate-limiting step agrees with the
experimental barrier of 15.8 kcalĀ·mol<sup>ā1</sup>. Both
individual mechanistic steps of the reaction are exoergonic. These
structural results may serve as the basis for the design of transition
state analogue inhibitors that specifically target the intestinal
NtMGAM catalytic domain, thus delaying the production of glucose in
diabetic and obese patients
Mechanistic Pathway on Human Ī±āGlucosidase Maltase-Glucoamylase Unveiled by QM/MM Calculations
The
excessive consumption of starch in human diets is associated
with highly prevalent chronic metabolic diseases such as type 2 diabetes
and obesity. Ī±-Glucosidase enzymes contribute to the digestion
of starch into glucose and are thus attractive therapeutic targets
for diabetes. Given that the active sites of the various families
of Ī±-glucosidases have different sizes and structural features,
atomistic descriptions of the catalytic mechanisms of these enzymes
can support the development of potent and selective new inhibitors.
Maltase-glucoamylase (MGAM), in particular, has a N-terminal catalytic
domain (NtMGAM) that has shown high inhibitor selectivity. We provide
here the first theoretical study of the human NtMGAM catalytic domain,
employing a hybrid QM/MM approach with the ONIOM method to disclose
the full atomistic details of the reactions promoted by this domain.
We observed that the catalytic activity follows the classical Koshland
double-displacement mechanistic pathway that uses general acid and
base catalysts. A covalent glycosyl-enzyme intermediate was formed
and hydrolyzed in the first and second mechanistic steps, respectively,
through oxocarbenium ion-like transition state structures. The overall
reaction is of dissociative type. Both transition state geometries
differ from those known to occur in other glycosidases. The activation
free energy for the glycosylation rate-limiting step agrees with the
experimental barrier of 15.8 kcalĀ·mol<sup>ā1</sup>. Both
individual mechanistic steps of the reaction are exoergonic. These
structural results may serve as the basis for the design of transition
state analogue inhibitors that specifically target the intestinal
NtMGAM catalytic domain, thus delaying the production of glucose in
diabetic and obese patients
Mechanistic Pathway on Human Ī±āGlucosidase Maltase-Glucoamylase Unveiled by QM/MM Calculations
The
excessive consumption of starch in human diets is associated
with highly prevalent chronic metabolic diseases such as type 2 diabetes
and obesity. Ī±-Glucosidase enzymes contribute to the digestion
of starch into glucose and are thus attractive therapeutic targets
for diabetes. Given that the active sites of the various families
of Ī±-glucosidases have different sizes and structural features,
atomistic descriptions of the catalytic mechanisms of these enzymes
can support the development of potent and selective new inhibitors.
Maltase-glucoamylase (MGAM), in particular, has a N-terminal catalytic
domain (NtMGAM) that has shown high inhibitor selectivity. We provide
here the first theoretical study of the human NtMGAM catalytic domain,
employing a hybrid QM/MM approach with the ONIOM method to disclose
the full atomistic details of the reactions promoted by this domain.
We observed that the catalytic activity follows the classical Koshland
double-displacement mechanistic pathway that uses general acid and
base catalysts. A covalent glycosyl-enzyme intermediate was formed
and hydrolyzed in the first and second mechanistic steps, respectively,
through oxocarbenium ion-like transition state structures. The overall
reaction is of dissociative type. Both transition state geometries
differ from those known to occur in other glycosidases. The activation
free energy for the glycosylation rate-limiting step agrees with the
experimental barrier of 15.8 kcalĀ·mol<sup>ā1</sup>. Both
individual mechanistic steps of the reaction are exoergonic. These
structural results may serve as the basis for the design of transition
state analogue inhibitors that specifically target the intestinal
NtMGAM catalytic domain, thus delaying the production of glucose in
diabetic and obese patients
Mechanistic Pathway on Human Ī±āGlucosidase Maltase-Glucoamylase Unveiled by QM/MM Calculations
The
excessive consumption of starch in human diets is associated
with highly prevalent chronic metabolic diseases such as type 2 diabetes
and obesity. Ī±-Glucosidase enzymes contribute to the digestion
of starch into glucose and are thus attractive therapeutic targets
for diabetes. Given that the active sites of the various families
of Ī±-glucosidases have different sizes and structural features,
atomistic descriptions of the catalytic mechanisms of these enzymes
can support the development of potent and selective new inhibitors.
Maltase-glucoamylase (MGAM), in particular, has a N-terminal catalytic
domain (NtMGAM) that has shown high inhibitor selectivity. We provide
here the first theoretical study of the human NtMGAM catalytic domain,
employing a hybrid QM/MM approach with the ONIOM method to disclose
the full atomistic details of the reactions promoted by this domain.
We observed that the catalytic activity follows the classical Koshland
double-displacement mechanistic pathway that uses general acid and
base catalysts. A covalent glycosyl-enzyme intermediate was formed
and hydrolyzed in the first and second mechanistic steps, respectively,
through oxocarbenium ion-like transition state structures. The overall
reaction is of dissociative type. Both transition state geometries
differ from those known to occur in other glycosidases. The activation
free energy for the glycosylation rate-limiting step agrees with the
experimental barrier of 15.8 kcalĀ·mol<sup>ā1</sup>. Both
individual mechanistic steps of the reaction are exoergonic. These
structural results may serve as the basis for the design of transition
state analogue inhibitors that specifically target the intestinal
NtMGAM catalytic domain, thus delaying the production of glucose in
diabetic and obese patients
Mechanistic Pathway on Human Ī±āGlucosidase Maltase-Glucoamylase Unveiled by QM/MM Calculations
The
excessive consumption of starch in human diets is associated
with highly prevalent chronic metabolic diseases such as type 2 diabetes
and obesity. Ī±-Glucosidase enzymes contribute to the digestion
of starch into glucose and are thus attractive therapeutic targets
for diabetes. Given that the active sites of the various families
of Ī±-glucosidases have different sizes and structural features,
atomistic descriptions of the catalytic mechanisms of these enzymes
can support the development of potent and selective new inhibitors.
Maltase-glucoamylase (MGAM), in particular, has a N-terminal catalytic
domain (NtMGAM) that has shown high inhibitor selectivity. We provide
here the first theoretical study of the human NtMGAM catalytic domain,
employing a hybrid QM/MM approach with the ONIOM method to disclose
the full atomistic details of the reactions promoted by this domain.
We observed that the catalytic activity follows the classical Koshland
double-displacement mechanistic pathway that uses general acid and
base catalysts. A covalent glycosyl-enzyme intermediate was formed
and hydrolyzed in the first and second mechanistic steps, respectively,
through oxocarbenium ion-like transition state structures. The overall
reaction is of dissociative type. Both transition state geometries
differ from those known to occur in other glycosidases. The activation
free energy for the glycosylation rate-limiting step agrees with the
experimental barrier of 15.8 kcalĀ·mol<sup>ā1</sup>. Both
individual mechanistic steps of the reaction are exoergonic. These
structural results may serve as the basis for the design of transition
state analogue inhibitors that specifically target the intestinal
NtMGAM catalytic domain, thus delaying the production of glucose in
diabetic and obese patients
Relevant Interactions of Antimicrobial Iron Chelators and Membrane Models Revealed by Nuclear Magnetic Resonance and Molecular Dynamics Simulations
The
dynamics and interaction of 3-hydroxy-4-pyridinone fluorescent
iron chelators, exhibiting antimicrobial properties, with biological
membranes were evaluated through NMR and molecular dynamics simulations.
Both NMR and MD simulation results support a strong interaction of
the chelators with the lipid bilayers that seems to be strengthened
for the rhodamine containing compounds, in particular for compounds
that include ethyl groups and a thiourea link. For the latter type
of compounds the interaction reaches the hydrophobic core of the lipid
bilayer. The molecular docking and MD simulations performed for the
potential interaction of the chelators with DC-SIGN receptors provide
valuable information regarding the cellular uptake of these compounds
since the results show that the fluorophore fragment of the molecular
framework is essential for an efficient binding. Putting together
our previous and present results, we put forward the hypothesis that
all the studied fluorescent chelators have access to the cell, their
uptake occurs through different pathways and their permeation properties
correlate with a better access to the cell and its compartments and,
consequently, with the chelators antimicrobial properties
Reactivity of Cork Extracts with (+)-Catechin and Malvidin-3ā<i>O</i>āglucoside in Wine Model Solutions: Identification of a New Family of Ellagitannin-Derived Compounds (Corklins)
The aim of this study was to evaluate
the reactivity of phenolic compounds extracted from cork stoppers
to wine model solutions with two major wine components, namely, (+)-catechin
and malvidin-3-<i>O</i>-glucoside. Besides the formation
of some compounds already described in the literature, these reactions
also yielded a new family of ellagitannin-derived compounds, named
herein as corklins. This new family of compounds that were found to
result from the interaction between ellagitannins in alcoholic solutions
and (+)-catechin were structurally characterized by mass spectroscopy,
nuclear magnetic resonance, and computational methods