Mechanism of normal catalytic reaction
Under physiological conditions, succinate dehydrogenase catalyzes the oxidation of its specific substrate. This process can be divided into several sequential stages:
- First, the natural substrate (succinate) specifically binds to the active site of the enzyme.
- In the active site, exactly two hydrogen atoms are cleaved from the succinate molecule.
- These hydrogen atoms do not remain free, but immediately attach to the prosthetic group of the enzyme — the coenzyme FAD (flavin adenine dinucleotide). As a result of this transfer, the reduced form FADH₂ is formed.
- The final result of the chemical transformation is the formation of the reaction product — fumarate.
- At the final stage, fumarate is released and removed from the active site, after which the enzyme is ready to accept a new substrate molecule.
Competitive inhibition by malonate
Malonic acid (malonate) is able to disrupt the normal course of the reaction described above. This phenomenon is based on structural analogy: the molecules of succinate and malonate are very similar in structure, as both substances contain two carboxyl groups in their structure.
Due to this similarity, malonate is able to trick the enzyme and bind to its active site. The binding of the inhibitor in the active site is accomplished through the formation of ionic bonds. However, despite successful binding, further chemical reaction becomes impossible. It is impossible to cleave two hydrogen atoms from the malonate molecule and transfer them to the prosthetic group of the enzyme (FAD). As a result, malonate simply occupies the active site, blocking access to it for succinate. The catalytic process completely stops, and the overall rate of the enzymatic reaction in the system drops sharply.
Clinical application of the mechanism: acetylcholinesterase inhibitors
The principle of competitive inhibition, vividly illustrated by the "succinate dehydrogenase – malonate" pair, is actively used in modern pharmacology. Many drugs are developed precisely as competitive inhibitors of specific enzymes in the human body.
A telling example is drugs that affect the enzyme acetylcholinesterase (AChE). Normally, AChE catalyzes the hydrolysis of the essential neurotransmitter acetylcholine, breaking it down into choline and acetic acid.
Medications such as neostigmine and edrophonium act as competitive inhibitors of this enzyme. Their mechanism of action is as follows:
- The drugs compete with natural acetylcholine for binding at the active site of the enzyme.
- As a result of successful inhibition, the overall activity of acetylcholinesterase significantly decreases.
- Due to a shortage of active enzyme, the concentration of the substrate (acetylcholine) in the synaptic cleft begins to increase rapidly.
- The accumulation of the neurotransmitter leads to a powerful enhancement of nerve impulse conduction across the synapse.
Indications for AChE inhibitors
The pharmacological effect achieved through competitive inhibition of acetylcholinesterase is vital for treating a range of severe neurological and muscular pathologies. Drugs of this group are indicated for conditions directly related to impaired normal neuromuscular transmission.
In clinical practice, such competitive inhibitors are used to treat:
- Various forms of muscular dystrophies.
- Severe motor disorders resulting from previous injuries.
- Paralyses of various origins.
- Long-term neurological sequelae of poliomyelitis.
Briefly: answers to topical questions
Which metabolic pathway (cycle) includes the reaction catalyzed by succinate dehydrogenase?
The reaction catalyzed by succinate dehydrogenase is part of the tricarboxylic acid cycle (TCA cycle, Krebs cycle). Succinate dehydrogenase participates in the Krebs cycle and is located in the mitochondria.
Where exactly in the cell is the enzyme succinate dehydrogenase localized?
Succinate dehydrogenase is localized in the mitochondria of cells. This enzyme is embedded directly into the inner mitochondrial membrane and is an essential structural component of the electron transport chain (Complex II). Unlike most other Krebs cycle enzymes and flavin-dependent dehydrogenases, succinate dehydrogenase is not freely located in the mitochondrial matrix.
How do the kinetic parameters Vmax and Km change during competitive inhibition by malonate?
During competitive inhibition of succinate dehydrogenase by malonate, the maximum reaction rate ($V_{max}$) remains unchanged, while the Michaelis constant ($K_m$) increases.
- $V_{max}$ — does not change, as the inhibitor is displaced from the active site of the enzyme in the presence of excess substrate.
- $K_m$ — increases, reflecting a decrease in the apparent affinity of the enzyme for the substrate.
The interaction between the enzyme and malonic acid is a classic model of competitive inhibition.
To which class in the international enzyme classification does succinate dehydrogenase belong?
Succinate dehydrogenase belongs to the class of oxidoreductases. It is an FAD-dependent dehydrogenase: the reaction involves the removal of 2 hydrogen atoms from succinate and their attachment to FAD to form FADH₂.
Malonate "mimics" succinate due to its two carboxyl groups, but cannot donate hydrogen to FAD, acting as a plug in the active site.
Class and exam questions
Why does malonate bind to succinate dehydrogenase?
Malonate is a structural analogue of succinate because it also has two carboxyl groups. This allows it to bind in the active site of the enzyme using ionic bonds.
Is the reaction product formed when malonate binds?
No. The transfer of two hydrogen atoms from malonate to the FAD prosthetic group is impossible, so the chemical reaction is completely blocked and no product is formed.
What is formed as a result of the normal reaction of succinate?
During normal binding of succinate to the active site, hydrogen atoms are transferred to FAD to form FADH₂, and succinate is converted into the reaction product — fumarate.
What is the mechanism of action of neostigmine?
Neostigmine is a competitive inhibitor of acetylcholinesterase. It competes with acetylcholine for the active site of the enzyme, reducing its activity and increasing the concentration of the neurotransmitter in the synaptic cleft.
What else to study on this topic
- The role of the coenzyme FAD in redox reactions.
- Biochemical properties and functions of fumarate.
- The mechanism of acetylcholine hydrolysis into choline and acetic acid.
- Pathophysiology of muscular dystrophies and neuromuscular transmission disorders.
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