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Diseases of the Nervous System
Published in George Feuer, Felix A. de la Iglesia, Molecular Biochemistry of Human Disease, 2020
George Feuer, Felix A. de la Iglesia
A number of enzymes also altered in the nerve during Wallerian degeneration. In the degenerating nerve the levels of acetylcholinesterase falls following lesions, butyrylcholinesterase is increased or unaltered at the beginning, and it slowly returns to the normal level. These differences are related to their cellular distribution; acetylcholinesterase is found in the neurons, whereas butyrylcholinesterase is associated with the myelin sheath. Choline acetylase is greatly reduced in association with a decrease of acetylcholine content (Figure 13). These changes may be linked with observed alterations of protein and lipid synthesis, and these cellular components are intrinsic parts of enzyme activity.
Enzymes
Published in S.J. Mulé, Henry Brill, Chemical and Biological Aspects of Drug Dependence, 2019
In a recent study in our own laboratory, a series of methyl through dodecyl JV-Alkyl substituted normeperidine congeners were studied as inhibitors of both acetyl and butyrylcholinesterase.12 In this study attempts were also made to correlate the physical-chemical parameters of these compounds such as molecular parachors, hemolytic activity, alkyl chain length, and Rm values with both enzyme inhibition and analgesic potency. Like the benzomorphans, the normeperidine congeners were also found to be mixed inhibitors of acetylcholinesterase. In addition, they produced the same type of inhibition with butyrylcholinesterase when acetylcholine was used as substrate. Simple linear relationships were observed with butyrylcholinesterase when alkyl chain length, Rm values, and molecular parachors were plotted as a function of the logarithm of the enzyme inhibitor dissociation constants. More complex relationships were noted with acetylcholinesterase and these parameters. When analgesia was determined as a function of the alkyl chain substituent on the normeperidine molecule, a biphasic correlation was observed between chain length and ED50. Analgesia increased until a chain length of about six carbons was reached and then decreased. These results suggest that the analgesic receptor possesses a definitive nonpolar geometric area that contributes to the binding of the analgesiophore through Van der Waal’s interactions. Small changes in binding energies were reflected as significant increases in analgesic potency.
The Effects of Synthetic Phosphonates on Living Systems
Published in Richard L. Hilderbrand, The Role of Phosphonates in Living Systems, 2018
The cholinesterases are subdivided functionally into two types, acetylcholinesterase and butyrylcholinesterase. Acetylcholinesterase (EC 3.1.1.7, AChE or true cholinesterase) is found in the central nervous system, ganglia, motor end-plates, and erythrocytes. AChE preferentially hydrolyzes the neurotransmitter acetylcholine, which is produced at cholinergic synapses by the activity of choline acetylase with choline and acetyl coenzyme A. Following release acetylcholine migrates to a receptor in the postsynaptic membrane of another neuron and produces a change in cation conductance, which is followed by depolarization of the membrane. Following this synaptic transmission, the acetylcholine is released from the neuroeffector site and is available for hydrolysis by AChE while the neuronal membrane returns to a resting potential. Inhibited AChE is unable to hydrolyze acetylcholine and allows accumulation of acetylcholine at the synapse. Some organophosphates will interfere with binding of acetylcholine to the receptor; however, under normal conditions this is not a significant effect since the concentration required to produce this effect is 100 to 1000 times the concentration required to inhibit cholinesterase.36
Solanaceae glycoalkaloids: α-solanine and α-chaconine modify the cardioinhibitory activity of verapamil
Published in Pharmaceutical Biology, 2022
Szymon Chowański, Magdalena Winkiel, Monika Szymczak-Cendlak, Paweł Marciniak, Dominika Mańczak, Karolina Walkowiak-Nowicka, Marta Spochacz, Sabino A. Bufo, Laura Scrano, Zbigniew Adamski
In addition, SGAs are potent inhibitors of enzymes involved in the breakdown of the neurotransmitter acetylcholine. Blocking acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) causes the accumulation of acetylcholine in the central nervous system. This could result, e.g., in impaired balance and motor coordination, shortness of breath and increased heart rate (Friedman 2006). SGAs also show high activity in insects. For example, they have substantial effects on the activity of the insect myocardium, affecting not only the frequency and force of insect heart contraction but also the duration of circadian phases of heart activity (Ventrella et al. 2015; Marciniak et al. 2019). Furthermore, SGAs affect the structure of fat body cells and the midgut and change the carbohydrate profile of insect haemolymph (Spochacz et al. 2018, 2020, 2021). Therefore, due to similar effects observed in insects and mammals, insects can serve as good models for testing the effects of these substances on mammals, including humans.
1,2,4-Triazole-based anticonvulsant agents with additional ROS scavenging activity are effective in a model of pharmacoresistant epilepsy
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Barbara Kaproń, Robert Czarnomysy, Mariusz Wysokiński, Rudolf Andrys, Kamil Musilek, Andrea Angeli, Claudiu T. Supuran, Tomasz Plech
Human recombinant acetylcholinesterase (hrAChE) and butyrylcholinesterase (hrBChE) were preincubated with various concentrations (i.e. 1, 10, 100, 500 µM) of compounds TP-10, TP-315, TP-427 (Figure 5). Reference drug (tacrine) was used in concentrations of 1 and 10 µM. Only the highest concentration used in the experiments (500 µM) decreased the activity of hrAChE by ∼54% (TP-10), ∼66% (TP-315), ∼61% (TP-427). Following the exposure to lower concentrations of the tested compounds (1–100 µM), the enzyme activity remained at ∼79–85% (TP-10), ∼80–86% (TP-315), and ∼84–87% (TP-427) of the control. Butyrylcholinesterase was even less sensitive to inhibition by the investigated compounds than hrAChE. At lower concentrations (1–100 µM), hrBChE activity was still close to or higher than 90% (Figure 5, lower graph). When the hrBChE was preincubated with 500 µM of TP-10, TP-315, and TP-427, its activity decreased to 84, 59, and 78%, respectively. In summary, the investigated 1,2,4-triazole-3-thione derivatives are very poor inhibitors of hrAChE and hrBChE, suggesting minimal off-target cholinergic effects.
The insight of in vitro and in silico studies on cholinesterase inhibitors from the roots of Cimicifuga dahurica (Turcz.) Maxim.
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2018
Jang Hoon Kim, Nguyen Phuong Thao, Yoo Kyong Han, Young Suk Lee, Bui Thi Thuy Luyen, Ha Van Oanh, Young Ho Kim, Seo Young Yang
Cholinesterases (ChEs), which are enzymes that hydrolyse choline esters, are classified as acetylcholinesterase (EC 3.1.1.7, AChE) and butyrylcholinesterase (EC 3.1.1.8, BuChE)1. AChE is responsible for the conversion of acetylcholine (ACh) into choline and acetic acid in cholinergic synapses. AChE is formed as a tetramer of ∼70-kDa monomeric subunits1,2. Its 3D structure was revealed by examining the enzyme of electric eels3. AChE has an active site with α-helix and β-sheet structures and a catalytic triad of serine, histidine, and glutamic acid1,3. BuChE, an enzyme that breaks down artificial butyrylcholine, is known to hydrolyse ACh and other ester derivatives in the body4,5. BuChE, which is a tetrameric serine esterase consisting of monomers of ∼90-kDa molecular mass, showed over 65% structural similarity to AChE4,6. ACh is a neurotransmitter that is produced from the acetylation reaction of choline and acetyl-CoA by choline acetyltransferase, and is distributed in the central and peripheral nervous systems7. ACh plays a key role in nerve-nerve communication by binding to ACh receptors8. This molecule is associated with maintenance of cognitive function and memory5,8. In particular, Alzheimer’s disease (AD) patients are characterised by a decline in ACh levels8. Two ChEs have been regarded as target enzymes for treatment of AD1,5,8.