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Succinate Dehydrogenase and Malonate

Succinate dehydrogenase

For medical students2 min readUpdated 2026-10-10

The interaction between the enzyme succinate dehydrogenase and malonic acid (malonate) serves as a classic textbook example of competitive inhibition in biochemistry. As a structural analog of the natural substrate, malonate binds to the active site of the enzyme without allowing the chemical reaction to proceed, resulting in a marked decrease in the rate of the enzymatic process.

SubstrateSuccinate, which donates two hydrogen atoms during the normal reaction

InhibitorMalonate (malonic acid), a structural analog of the substrate

CoenzymeFAD, acting as the prosthetic group of the enzyme

Clinical analogNeostigmine and edrophonium, which block acetylcholinesterase

Mechanism of the Normal Catalytic Reaction

Under physiological conditions, succinate dehydrogenase catalyzes the oxidation of its specific substrate. This process can be divided into several sequential steps:

First, the natural substrate (succinate) specifically binds to the active site of the enzyme.
Exactly two hydrogen atoms are abstracted from the succinate molecule within the active site.
These hydrogen atoms are not released freely; instead, they immediately bind to the enzyme's prosthetic group—the coenzyme FAD (flavin adenine dinucleotide). This transfer forms the reduced form, FADH₂.
The final chemical outcome is the formation of the reaction product—fumarate.
Lastly, fumarate is released and dissociates from the active site, leaving the enzyme ready to accept a new substrate molecule.

Competitive Inhibition by Malonate

Malonic acid (malonate) disrupts the normal reaction course described above. This phenomenon relies on structural analogy: succinate and malonate molecules share a very similar structure, as both substances contain two carboxyl groups.

Due to this similarity, malonate can mimic the substrate and bind to the active site. The inhibitor is anchored in the active site via ionic bonds. However, despite successful binding, the subsequent chemical reaction cannot take place. Two hydrogen atoms cannot be abstracted from the malonate molecule and transferred to the enzyme's prosthetic group (FAD). Consequently, malonate simply occupies the active site, blocking access for succinate. The catalytic process is completely halted, and the overall rate of the enzymatic reaction drops sharply.

Clinical Application: Acetylcholinesterase Inhibitors

The principle of competitive inhibition, vividly illustrated by the succinate dehydrogenase-malonate pair, is widely utilized in modern pharmacology. Many therapeutic drugs are specifically designed as competitive inhibitors of human enzymes.

A prime example includes drugs that target 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 endogenous acetylcholine for binding at the enzyme's active site.
As a result of successful inhibition, overall acetylcholinesterase activity decreases significantly.
Due to the scarcity of active enzyme, the concentration of the substrate (acetylcholine) in the synaptic cleft rises rapidly.
The accumulation of the neurotransmitter leads to a profound amplification of nerve impulse transmission across the synapse.

Indications for AChE Inhibitors

The pharmacological effect achieved through the competitive inhibition of acetylcholinesterase is vital for treating various severe neurological and muscular disorders. Drugs of this class are indicated for conditions directly linked to impaired neuromuscular transmission.

In clinical practice, these competitive inhibitors are used to treat:

Various forms of muscular dystrophies.
Severe motor disorders following physical trauma.
Paralysis of diverse etiologies.
Delayed neurological sequelae of poliomyelitis.

Mnemonic

Malonate "disguises" itself as succinate due to its two carboxyl groups, but cannot pass hydrogen to FAD, acting as a molecular roadblock in the active site.

Frequently asked questions

Which metabolic pathway (cycle) includes the reaction catalyzed by succinate dehydrogenase?

The reaction catalyzed by succinate dehydrogenase is part of the tricarboxylic acid (TCA) cycle, also known as the Krebs cycle. Succinate dehydrogenase participates in the Krebs cycle and resides within the mitochondria.

Where within the cell is succinate dehydrogenase localized?

Succinate dehydrogenase is localized within cellular mitochondria. This enzyme is embedded directly into the inner mitochondrial membrane and serves as 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 soluble 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 velocity ($V_{max}$) remains unchanged, while the Michaelis constant ($K_m$) increases.

$V_{max}$ — remains unchanged, because excess substrate can outcompete the inhibitor from the enzyme's active site.
$K_m$ — increases, reflecting a decrease in the apparent affinity of the enzyme for its 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 transfer to FAD, yielding FADH₂.

Why does malonate bind to succinate dehydrogenase?

Malonate is a structural analog of succinate because it also possesses two carboxyl groups. This allows it to anchor into the enzyme's active site via ionic bonds.

Is a reaction product formed when malonate binds?

No. The transfer of two hydrogen atoms from malonate to the FAD prosthetic group is impossible; thus, the chemical reaction is completely blocked and no product is formed.

What is produced during the normal succinate reaction?

During normal succinate binding, 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 neurotransmitter concentration in the synaptic cleft.

Go deeper

The role of the FAD coenzyme 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.