The effect of
Choline acetyltransferase (ChAT) is a single-strand globular protein and catalyzes biosynthesis reaction of acetylcholine (ACh) neurotransmitter [
Schematic representation of ChAT catalytic role in ACh synthesis: two-enzyme/two-compartment (2E2C) model [
The main goal of this work is to investigate the effect of wide range of concentrations of
The ACh neurocycle is shown in Figure
Schematic representation for two-enzyme/two-compartment model.
All assumptions made for investigating the effect of The presynaptic of cholinergic nerve terminal is described by compartment 1. Inside this compartment ACh is synthesized by the reaction of choline and acetyl-CoA in the presence of catalytic effect of ChAT enzyme. Postsynaptic cleft of neurons together with synaptic cleft are considered as compartment two. Both postsynaptic and synaptic clefts are unified to be in one compartment instead of two or three because both of them are harmonized and are interactive and also to simplify the calculations in solving the model particularly when the dimensionality is too high. Both compartments are assumed to be divided with a permeable membrane. The internal masses transfers in compartment one between synaptic vesicles and cytoplasm and in compartment two between ACh and postsynaptic receptors are neglected because every compartment is assumed to be homogenous. All matters in the presynaptic neuron are transported to the postsynaptic cleft via passive diffusion where all concentrations in compartment 1 should be higher than that in compartment 2; however, choline uptake from the postsynaptic cleft to the presynaptic neurons is performed by facilitated diffusion via high-affinity choline uptake transporters. It is observed that concentrations of all state variables in compartment two are the average of concentrations in postsynaptic and synaptic cleft. Temperature is considered constant where the system is assumed to be isothermal and there is no effect for any temperate changes on the system. Transport of The initial concentration of Feed stream rate to compartment one and outlet flow from compartment two are considered to be constant with a value of
ChAT and AChE are the two cholinergic enzymes considered in the 2E2C model. ChAT is responsible for synthesis of ACh in compartment 1 of the 2E2C model, while AChE catalyzes the degradation of ACh in compartment 2. It is found that incorporation of
The exact mechanisms of ChAT modulation by
To examine the phenomenon of ChAT activity inhibition by
Possible competitive inhibition mechanisms for
The numerical derivation of the ChAT rate equation for the modified pH-dependent ACh synthesis with competitive inhibition of
Dimensionless forms of the ordinary differential equations of ChAT inhibition effects by
Item | Compartment | Differential equation |
---|---|---|
Hydrogen protons | 1 |
|
2 |
|
|
|
||
Acetylcholine (ACh) | 1 |
|
2 |
|
|
|
||
Choline | 1 |
|
2 |
|
|
|
||
Acetate | 1 |
|
2 |
|
|
|
||
|
1 |
|
|
||
Rate of synthesis ( |
1 |
|
|
||
Rate of hydrolysis ( |
2 |
|
The synthesis rate for competitive inhibition of A
By the assumption of rapid equilibrium,
By rapid equilibrium assumption,
From the ionization of
Since
Values of the kinetic parameters.
Parameter | Value | Reference |
---|---|---|
|
5.2 (0.1) | [ |
|
12 | [ |
|
1000 | [ |
|
5 | [ |
|
1 | [ |
|
0.5 | [ |
|
1 | [ |
|
1.066 |
[ |
|
50.33 |
[ |
|
100 |
[ |
|
1 |
[ |
|
|
[ |
|
|
[ |
|
2.25 | [ |
|
0.5 | [ |
|
1.5 | [ |
|
1.5 | [ |
|
1 | [ |
|
1.2 | [ |
|
8.2 |
[ |
|
15 | [ |
|
1.15 | [ |
|
3.9 | [ |
|
0.01 | [ |
|
0.8 | [ |
|
20 nM/h | [ |
|
Assumed | |
|
|
Assumed |
|
|
Assumed |
|
|
Assumed |
|
10.015 | Assumed |
|
0.05 | Assumed |
|
0.1 h | Assumed |
|
20 nM/L | [ |
Figure
Time course of
Figure
Time course according to kinetic mechanism 1 of (a) rate of ACh synthesis (Rate 1) and (b) rate of ACh hydrolysis (Rate 2) at different
These results are compatible with the experimental results obtained by Nunes-Tavares et al. [
One of the main physiological symptoms of AD is a reduction of ACh production in cholinergic neurons [
Time course according to kinetic mechanism 1 of (a) ACh concentration in compartment 1 (ACh1) and (b) ACh concentration in compartment 2 (ACh2) at different
These results are compatible with experimental results obtained by Kar et al. [
Figures
Time course according to kinetic mechanism 1 of (a) choline concentration in compartment 1 (Ch1) and (b) choline concentration in compartment 2 (Ch2) at different
Figure
Time course according to kinetic mechanism 1 of (a) acetate concentration in compartment 1 (Ac1) and (b) acetate concentration in compartment 2 (Ac2) at different
Figure
Time course according to kinetic mechanism 1 of (a) pH in compartment 1 (pH1) and (b) pH in compartment 2 (pH2) at different
The effect of
In this kinetic mechanism, there is a competitive inhibition of
By the assumption of rapid equilibrium,
From the ionization of
Also,
Since
Incorporating the rate of ChAT synthesis
Figure
Time course of generated
Figure
Time course of (a) rate of ACh synthesis (Rate 1) and (b) rate of ACh hydrolysis (Rate 2) at different
Figure
Time course of (a) ACh concentration in compartment 1 (ACh1) and (b) ACh concentration in compartment 2 (ACh2) at different
Figures
Time course of (a) choline concentration in compartment 1 (Ch1) and (b) choline concentration in compartment 2 (Ch2) at different
Figure
Time course according to kinetic mechanism 2 of (a) acetate concentration in compartment 1 (Ac1) and (b) acetate concentration in compartment 2 (Ac2) at different
Figure
Time course according to kinetic mechanism 2 of (a) pH in compartment 1 (pH1) and (b) pH in compartment 2 (pH2) at different
It is clear that kinetic mechanism 2 in terms of competitive inhibition of
Possible noncompetitive inhibition mechanisms for
Figure
Time course of
Figure
Time course of (a) rate of ACh synthesis (Rate 1) and (b) rate of ACh hydrolysis (Rate 2) at different
Figure
Figure
Time course of (a) ACh concentration in compartment 1 (ACh1) and (b) ACh concentration in compartment 2 (ACh2) at different
Figure
Time course of (a) choline concentration in compartment 1 (Ch1) and (b) choline concentration in compartment 2 (Ch2) at different
Magnification of Figure
Magnification of Figure
The limited effect of A
Figure
Time course of (a) acetate concentration in compartment 1 (Ac1) and (b) acetate concentration in compartment 2 (Ac2) at different
Figure
Figure
Time course of (a) pH in compartment 1 (pH1) and (b) pH in compartment 2 (pH2) at different
Figure
The effect of
It is found that for all kinetic mechanisms the concentration of generated
The results of the second kinetic mechanism where
In the third kinetic mechanism, where
The results of kinetic mechanism 3 are compatible with the experimental results obtained by Nunes-Tavares et al. [
It is observed that, after time of 100 (corresponding to 10 hr), there is no effect for any further change of
In this work, the effect of
Enzyme
Substrate
Reaction product
Hydrogen ions concentration (kmol/m3)
Hydroxyl ions concentration (kmol/m3)
Acetylcholine concentration (kmol/m3)
Choline concentration (kmol/m3)
Acetyl-CoA concentration (kmol/m3)
Acetate concentration (kmol/m3)
Concentration of acetylcholinesterase enzyme in compartment 2 (kg enzyme/m3)
Concentration of choline acetyltransferase in compartment 1 (kg enzyme/m3)
Kinetic constants for the choline acetyltransferase catalyzed reaction (kmol/m3)
Kinetic constants for the coenzyme A catalyzed reaction (kmol/m3)
Kinetic constants for the acetylcholinesterase catalyzed reaction (kmol/m3)
Area of membrane separating compartments 1 and 2 (m2)
Volumetric flow rate into compartment 1 (m3/s)
Rate of water formation in compartment
Rate of reaction in compartment
Recycle flow rate ratio
Volume of compartment
Time (s)
Membrane permeability for hydrogen ions (m/s)
Membrane permeability for hydroxyl ions (m/s)
Membrane permeability for acetylcholine (m/s)
Membrane permeability for choline (m/s)
Membrane permeability for acetyl-CoA (m/s)
Membrane permeability for acetate (m/s)
Membrane permeability for acetic acid (m/s)
Equilibrium constant for water (kmol2/m6).
Acetylcholinesterase
Choline acetyltransferase
Coenzyme A
Acetylcholine
Acetate
Continuous stirred tank reactor.
Compartment 1
Compartment 2
Feed condition.
The authors declare that there is no conflict of interests regarding the publication of this paper.