Nerve function acetylcholinesterase

Some toxic substances, such as cyanide, heavy metals, or herbicides, alter or destroy enzymes so that they function improperly or not at all. Toxicants can affect enzymes in several ways. Heavy metals, for example, tend to bind to sulfur atoms in enzymes, thereby altering the shape and fnnction of the enzyme. On the other hand, insecticide parathion bonds covalently to the nerve enzyme acetylcholinesterase, which can then no longer serve to stop nerve impulses. 

Nerve gas agents that interfere with the action of acetylcholinesterase enzyme essential for nerve function. These are primarily organophosphate compounds, including sarin, VX, and Russian VX. A total of 13 people died and about 6000 sought medical help from a 1995 attack with sarin on the Tokyo subway system. 

The toxicides of organophosphate insecticides vary a great deal. Their major toxic effect is inhibition of acetylcholinesterase, an enzyme essential for nerve function. For example, as little as 120 mg of parathion has been known to kill an adult human and a dose of 2 mg has killed a child. Most accidental poisonings have occurred by absorption through the skin. Since its use began, several hundred people have been killed by parathion. 

While these functions can be a carried out by a single transporter isoform (e.g., the serotonin transporter, SERT) they may be split into separate processes carried out by distinct transporter subtypes, or in the case of acetylcholine, by a degrading enzyme. Termination of cholinergic neurotransmission is due to acetylcholinesterase which hydrolyses the ester bond to release choline and acetic acid. Reuptake of choline into the nerve cell is afforded by a high affinity transporter (CHT of the SLC5 gene family). 

Both the G- and V-agents have the same physiological action on humans. They are potent inhibitors of the enzyme acetylcholinesterase (AChE), which is required for the function of many nerves and muscles in nearly every multicellular animal. Normally, AChE prevents the accumulation of acetylcholine after its release in the nervous system. Acetylcholine plays a vital role in stimulating voluntary muscles and nerve endings of the autonomic nervous system and many structures within the CNS. Thus, nerve agents that are cholinesterase inhibitors permit acetylcholine to accumulate at those sites, mimicking the effects of a massive release of acetylcholine. The major effects will be on skeletal muscles, parasympathetic end organs, and the CNS. 

The primary function of acetylcholinesterase is to terminate the activity of the neurotransmitter, acetylcholine (Fig. 6.4), through hydrolysis at the various cholinergic nerve endings. In this regard, it is probably the most highly efficient enzyme that operates in the human. It is capable of hydrolyzing 300,000 molecules of acetylcholine per molecule of enzyme... 

Many phosphorus derivatives function as irreversible inhibitors of acetylcholinesterase, and are thus potentially toxic. These include a range of organophosphorus insecticides, such as malathion and parathion, and nerve gases such as sarin. 

Acetylcholine is a neurotransmitter that functions in conveying nerve impulses across synaptic clefts within the central and autonomic nervous systems and at junctures of nerves and muscles. Following transmission of an impulse across the synapse by the release of acetylcholine, acetylcholinesterase is released into the synaptic cleft. This enzyme hydrolyzes acetylcholine to choline and acetate and transmission of the nerve impulse is terminated. The inhibition of acetylcholineasterase results in prolonged, uncoordinated nerve or muscle stimulation. Organophosphorus and carbamate pesticides (Chapter 5) along with some nerve gases (i.e., sarin) elicit toxicity via this mechanism. 

Adler, M., Manley, H. A., Purcell, A. L., Deshpande, S. S., Hamilton, T. A., Kan, R. K., et al. (2004) Reduced acetylcholine receptor density, morphological remodeling, and butyrylcholinesterase activity can sustain muscle function in acetylcholinesterase knockout mice. Muscle Nerve 30, 317-327. 

Acetylcholine is a neurotransmitter, a key substance involved with transmission of nerve impulses in the brain, skeletal muscles, and other areas where nerve impulses occur. An essential step in the proper function of any nerve impulse is its cessation (see Figure 6.9), which requires hydrolysis of acetylcholine as shown by Reaction 6.10.1. Some xenobiotics, such as organophosphate compounds (see Chapter 18) and carbamates (see Chapter 15) inhibit acetylcholinesterase, with the result that acetylcholine accumulates and nerves are overstimulated. Adverse effects may occur in the central nervous system, in the autonomic nervous system, and at neuromuscular junctions. Convulsions, paralysis, and finally death may result. 

Cholinesterases, e.g., acetylcholinesterase (AChE, EC 3.1.1.7) and butyrylcholi-nesterase (BChE, EC 3.1.1.8), are serine hydrolases that break down the neurotransmitter acetylcholine and other choline esters [5]. In the neurotransmission processes at the neuromuscular junction, the cationic neurotransmitter acetylcholine (ACh) is released from the presynaptic nerve, diffuses across the synapse and binds to the ACh receptor in the postsynaptic nerve (Fig. 1). Acetylcholinesterase is located between the synaptic nerves and functions as the terminator of impulse transmissions by hydrolysis of acetylcholine to acetic acid and choline as shown in Scheme 4. The process is very efficient, and the hydrolysis rate is close to diffusion controlled [6, 7]. 

Organophosphate pesticides (OPPs) are potent neurotoxins and extremely toxic to animals and humans. They function by inhibiting the action of acetylcholinesterase (AChE) in nerve cells. The OPPs are known as the most common causes of poisoning worldwide. 

By disrupting the biological function of the enzyme acetylcholinesterase, insecticides such as aldicarb, parathion and methamidophos (WHO la) prevent neurotransmitter molecules from being broken down, causing them to accumulate In the spaces between nerve cells. In this way acetyl-cholinesterase inhibitors effectively jam the transmission of nervous signals between nerve cells. 

A few other organophosphates cause this effect, notably tri-orthocresyl phosphate, as described in Chapter 10. It seems to be due to the interaction between the organophosphate and a protein, which may be an enzyme, in the peripheral nerves. The protein seems to have a critical function and the binding to it is irreversible, causing the nerve to degenerate. The result is paralysis in the legs. The cause of this effect does not seem to be related to the interaction with acetylcholinesterase. The effect appears one or two weeks after exposure to the organophosphate. 

---