Anticholinesterase Inhibition – Published Paper Review

Weinbroum, Avi A. “Pathophysiological and clinical aspects of combat anticholinesterase poisoning.” British Medical Bulletin 72, no. 1 (2004): 119-133. Accessed March 24, 2013.


Anticholinesterase (AChE) is an enzyme and like all enzymes, their function is affected by several factors.

RECALL: Enzymes are affected by pH, temperature, substrate and enzyme concentration and inhibitors. These agents tend to disrupt the area of the enzyme called the active site by changing its conformation and hence hindering enzymatic activity.


Organophosphate – like compounds are inhibitors of the enzyme acetylcholine esterase (AChE) and are referred to as nerve agents (NAs). It is related to those used in pesticides. The extremely lethal irreversibly AChE inhibitors results in an inoperative AChE causing a buildup of acetylcholine (ACh) affecting the entire cholinergic system.


In the 1854, Wurtz synthesized the first organophosphate compound, tetraethyl pyrophosphate.

Sad to say…. organophosphates were used as weapons of mass destruction

1980 Iraq – Iran war

1994-95 – Terrorist attacks in Japan


The extent of absorption and contact with NA are vital issues in verifying biochemical intoxication route for the NA. NA can either be absorbed by the skin and mucous membrane or inhaled. The inhalation of the vapor results in instantaneous absorption due to the alveoli in the lungs causing respiratory ailments ranging from short breath to cardiovascular and respiratory failure and eventually death. Exposure to the skin has a nicotine-like effect causing muscle paralysis and continued developing respiratory indications and ultimately death.


They are chemically obtained from phosphoric acids. They tend to differ slightly by substituting the -OH radical and the acid-base form but are still efficient of being both reversible and irreversible inhibitors to AChE. NAs chemical properties are such that it is both colorless and odorless in its volatile liquid state and denser that air in its gaseous state.

AChE enzyme is categorized as class three, Hydrolase and sub-class as esterase and therefore from the class it is determined that the enzyme hydrolyses esters, especially choline esters, ACh, a neurotransmitter for the cholinergic part of the nervous system.

AChE hydrolyses ACh swiftly and is located in the receptors sites of the nerves by the cholinergic nervous system. Reversible anticholinesterases are not lethal as compared to the irreversible anticholinesterases. Carbamates bind to anionic and the ester of the enzyme resulting in the separation of part of the carbamate and the formation at the location of the ester, an enzyme-cabamylated complex. Hence hydrolysis of ACh is no longer a rapid process. The most attractive binding sites for organophosphate compounds are the ester sites however the stability of the bonds depend on the correct orientation of the enzyme and inhibitor as well as other compounds are prevented from binding with the active site. They interfere with the cleft leaving the enzyme dysfunctional.

With irreversibly inhibition the NAs covalently binds (strongest bond formation) to the active site so therefore it is known as a completive inhibitor. This result in a buildup of the ACh in the neuro-effector junction hindering the synapse process in peripheral and the central cholinergic system causing toxic contamination to the nicotinic (CNS) and muscarinic cleft (muscle system). The covalent bond partakes in an instantaneous chemical reaction which stabilizes the molecule due to the surge in the thermodynamic stabilization resulting in the production of more hydrogen bridges between the phosphate and organic groups.

The skeletel muscles, the pre-ganglionic autonomic nerves and the post-ganglionic parasympathetic nerves are innervated by AChE. The cholinergic systems are bases on the muscarinic and nicotinic systems since they have receptors that display specificity to muscarinic alkaloids and nicotine alkaloids. The post-ganglionic parasympathetic fibers are innervated by the muscarinic sites which regulate the activity of the glands, smooth muscle of the respiratory, cardiovascular and gastrointestinal systems. Autonomic ganglia, part of the nicotinic sites are relied upon for the contractions of the skeletal muscle. When both muscarinic and nicotinic cholinergic neurotransmitter buildup it causes hyper-stimulation of the synaptic process and hence causes paralysis of the skeletal muscles. Comparably the buildup of AChE in the CNS nerve receptors leads to hyper-stimulation and paralysis cardiac brady-asystole, hyper-secretion from secretory glands, respirational collapse, seizures, coma and eventually it is fatal. A small window of opportunity allows antidote drugs, atropine and oximes to work against the inhibitor stimulated nicotinic and muscarinic cholinergic system correspondingly depending on the stage of poisoning.


NAs are highly poisonous complexes that result in fatality within mere seconds. The principal biochemical cause NAs is the capability to irreversible inhibit AChE enzyme resulting in the buildup of ACh in the synaptic cleavage. Antidotes such as atropine and oximes present a crucial windowed-opportunity to act against the inhibitor




Enzyme Browning Reaction





Phenolase exist in common daily activates since they are found on a variety of fruits and vegetables that are consumed. When the fruits and vegetables such as mushrooms, potatoes and bananas are damaged it tends to turn brown over time because the enzyme phenolase present in them are exposed to oxygen and hence oxidizes the substrate found in the cells. 

Enzyme browning reaction can be controlled by several procedures such as the inactivation of the enzyme and the removal of oxygen. A process called blanching is a very effective way in controlling enzyme browning reaction by heating the fruits or vegetable to denature the enzyme before storing. In addition to heating the fruit or vegetable can be stored in ice to prevent oxidation.  Also the addition of citric acid like those found in lime or vinegar decreases the pH at which the enzyme would normally function hence inhibiting enzymatic activity.

Types Reversible Inhibition

Types Reversible Inhibition

Michaelis-Menten Curve:
Effect of a Competitive/Non-Competitive Inhibitor on the Reaction Velocity vs Substrate Concentration Plot


Lineweaver- Burk Plot:
Effect of a Competitive/Non-Competitive Inhibitor on the Reaction Velocity vs Substrate Concentration Plot


Once a Upon an Enzyme (part 2)

Factors Affecting the Rate of Enzyme Reactions


Over the range 0-40 degrees Celsius the rate of reaction doubles for the rise of every 10 degrees Celsius until optimum temperature. Heat supplies activation energy and kinetic energy to the reacting molecules causing them to move more quickly thus increasing the chances of collision. Hence the in a given time the more product will form than at a lower temperature. The temperature at which enzymes catalyzes a reaction at maximum rate is called OPTIMUM TEMPERATURE. Above this temperature heat causes the molecules to vibrate so violently that the hydrophobic and ionic bond that maintain the specific 3D structures break. The enzyme molecules begin to lose its shape and activity and is said to be denatured. At first the substrate molecules loosely fits into the active site until eventually it no longer fits or can no longer be held in the correct position for the reaction to occur.



Every enzyme functions most effectively over a narrow pH range. The optimum pH is that at which the maximum rate is achieved. A pH above or below the specific value will reduce the activity of the enzyme. Changes in pH alter the ionic charge of the acidic and basic R groups thus disrupting ionic bonds that help to maintain the specific shape of an enzyme. The pH change leads to n alteration in enzyme shape particularly at the active site thus the enzyme is unable to function effectively and is said to be denatured.


Enzyme Concentration

If the substrate concentration is at a high level and pH and temperature are constant the rate is proportional to enzyme concentration, the larger the amount of enzyme, the greater the amount of substrate used in the time, provided its excess substrate.

Substrate Concentration

The rate increases with increasing substrate concentration up to a point where any further increases do not produce an increase in rate. As the substrate concentration increases, more and more active sites are filled so more substrate is used and more products are formed in a given time. As the concentration is increased further the active sites become saturated. Thus any extra substrate has to wait until the enzyme-substrate complex has dissociated into products and free enzyme. At high substrate concentration both enzyme concentration and the time for dissociation limit the rate of the reaction.




for further information plz refer to Mr. J.M enzyme youtube video