Abstract
Caffeine is an alkaloid with a stimulant effect in the body. It can interfere in transmissions based on acetylcholine, epinephrine, norepinephrine, serotonin, dopamine and glutamate. Clinical studies indicate that it can be involved in the slowing of Alzheimer disease pathology and some other effects. The effects are not well understood. In the present work, we focused on the question whether caffeine can inhibit acetylcholinesterase (AChE) and/or, butyrylcholinesterase (BChE), the two enzymes participating in cholinergic neurotransmission. A standard Ellman test with human AChE and BChE was done for altering concentrations of caffeine. The test was supported by an in silico examination as well. Donepezil and tacrine were used as standards. In compliance with Dixon’s plot, caffeine was proved to be a non-competitive inhibitor of AChE and BChE. However, inhibition of BChE was quite weak, as the inhibition constant, Ki, was 13.9 ± 7.4 mol/L. Inhibition of AChE was more relevant, as Ki was found to be 175 ± 9 μmol/L. The predicted free energy of binding was −6.7 kcal/mol. The proposed binding orientation of caffeine can interact with Trp86, and it can be stabilize by Tyr337 in comparison to the smaller Ala328 in the case of human BChE; thus, it can explain the lower binding affinity of caffeine for BChE with reference to AChE. The biological relevance of the findings is discussed.
Highlights
IntroductionTwo structurally close esterases with different functions can be found. While acetylcholinesterase (AChE) (EC 3.1.1.7.) is involved in the termination of neurotransmission, the role of butyrylcholinesterase (BChE) (EC 3.1.1.8.) is not understood
In the body, two structurally close esterases with different functions can be found
The proposed binding orientation of caffeine can interact with Trp86, and it can be stabilize by Tyr337 in comparison to the smaller Ala328 in the case of human BChE; it can explain the lower binding affinity of caffeine for BChE with reference to AChE
Summary
Two structurally close esterases with different functions can be found. While acetylcholinesterase (AChE) (EC 3.1.1.7.) is involved in the termination of neurotransmission, the role of butyrylcholinesterase (BChE) (EC 3.1.1.8.) is not understood. Acetylcholine is a low molecular weight neurotransmitter presented in both the central and peripheral nervous system. It is responsible for signal transmission from nerves to terminal glands and muscles. Irreversible and pseudo-irreversible inhibitors represented by the aforementioned pesticides, nerve agents, rivastigmine, pyridostigmine and neostigmine have nearly equal affinity to AChE and BChE [4]. The adenosine receptors are not the only targets of caffeine. It can meet acetylcholine-, epinephrine-, norepinephrine-, serotonin-, dopamine- and glutamate-mediated neurotransmission [18,19,20,21,22]. Caffeine can act via acetylcholine receptors only or whether it can be involved in the regulation of the neurotransmitter, acetylcholine, via cholinesterases
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