Decarboxylation: Function, Role & Diseases

Decarboxylation generally represents a cleavage of carbon dioxide from an organic acid. In the case of carboxylic acids, decarboxylation proceeds very well by heating and enzymatic reactions. Oxidative decarboxylation plays a particularly important role, leading in the organism to acetyl-CoA in the degradation of pyruvate and to succinyl-CoA in the degradation of α-ketoglutarate.

What is decarboxylation?

Decarboxylation generally represents a cleavage of carbon dioxide from an organic acid. Decarboxylation plays an important role in metabolism. The term decarboxylation describes the splitting off of carbon dioxide from organic molecules. In this process, a so-called carboxyl group already exists within the molecule, which can be split off by the action of heat or enzymatic reactions. The carboxyl group contains a carbon atom, which is connected to an oxygen atom by a double bond and to a hydroxyl group by a single bond. The hydrogen atom of the hydroxyl group takes the place of the carboxyl group after carbon dioxide cleavage. For example, carboxylic acids are converted into hydrocarbons. When carbohydrates, fats and proteins are broken down, carbon dioxide, water and energy are produced in the overall balance of catabolic metabolism. The energy released is temporarily stored in the form of ATP and reused for biological work, heat generation or for building up the body’s own substances. In the context of metabolism, the decarboxylations of pyruvate and α-ketoglutarate are of enormous importance.

Function and role

Decarboxylations occur constantly in the human organism. One important substrate is pyruvate, which is decarboxylated with the help of thiamine pyrophosphate (TPP). Hydroxyethyl TPP (hydroxyethyl thiamine pyrophosphate) and carbon dioxide are formed. The enzyme responsible for this reaction is pyruvate dehydrogenase component (E1). Thiamine pyrophosphate is a derivative of vitamin B1. The resulting hydroxyethyl-TPP complex reacts with lipoic acid amide to form acetyl-dihydroliponamide. Thiamine pyrophosphate (TPP) is formed back again in the process. The pyruvate dehydrogenase component is also responsible for this reaction. In a further step, acetyl-dihydroliponamide reacts with coenzyme A to form acetyl-CoA. The enzyme dihydrolipoyl transacetylase (E2) is responsible for this reaction. Acetyl-CoA represents the so-called activated acetic acid. This compound enters the citrate cycle as a substrate and represents an important metabolite for both anabolic and catabolic metabolism. The activated acetic acid can thus be further degraded to carbon dioxide and water or converted to important biological substrates. One metabolite, which is already derived from the citrate cycle, is α-ketoglutarate. α-Ketoglutarate is also converted by similar conversions with elimination of carbon dioxide. This produces the end product succinyl-CoA. Succinyl-CoA is an intermediate product of many metabolic processes. It is further converted as part of the citrate cycle. Many amino acids only enter the citrate cycle via the intermediate stage succinyl-CoA. In this way, the amino acids valine, methionine, threonine or isoleucine are integrated into the general metabolic processes. Overall, the decarboxylation reactions of pyruvate and α-ketoglutarate are located at the interface of anabolic to catabolic metabolic processes. They possess central importance for metabolism. At the same time, carbon dioxide formation by decarboxylation enters into the general carbon dioxide balance. The importance of oxidative decarboxylation lies in the fact that metabolites of metabolism are formed as a result of it, which can serve both for energy production for the organism and for the build-up of endogenous substances. Decarboxylation also plays an important role in the conversion of glutamate to γ-aminobutyric acid (GABA). This reaction, catalyzed with the help of glutamate decarboxylase, is the only pathway for the biosynthesis of GABA. GABA is the most important inhibitory neurotransmitter in the central nervous system. Furthermore, it also plays a crucial role in the inhibition of the pancreatic hormone glucagon.

Diseases and disorders

Disorders of oxidative decarboxylation can be triggered by a deficiency of vitamin B1. As mentioned above, vitamin B1 or its derivative thiamine pyrophosphate (TPP) plays the crucial role in oxidative decarboxylation.Therefore, a deficiency of vitamin B1 leads to disturbances of the energy and building metabolism. Impairments of the carbohydrate metabolism and the nervous system result. Polyneuropathy may develop. In addition, symptoms of fatigue, irritability, depression, visual disturbances, poor concentration, loss of appetite and even muscle atrophy occur. Furthermore, memory disorders, frequent headaches and anemia are observed. Due to the impaired energy production, the immune system is also weakened. Muscle weakness mainly affects the calf muscles. Heart weakness, shortness of breath or edema also occur. In its extreme form, vitamin B1 deficiency is known as beriberi. Beriberi occurs particularly in regions where the diet is very poor in vitamin B1. This mainly affects populations with a diet based on soy products and hulled rice. Another disease, which is due to a disorder of decarboxylation, is the so-called spastic tetraplegic cerebral palsy type 1. For this disease, in which infantile cerebral palsy is present, the trigger is a genetic defect. Thus, a mutation in the GAD1 gene leads to a deficiency of the enzyme glutamate decarboxylase. Glutamate decarboxylase is responsible for the conversion of glutamate to γ-aminobutyric acid (GABA) with carbon dioxide cleavage. As mentioned above, GABA is the main inhibitory neurotransmitter of the central nervous system. If too little GABA is produced, brain damage occurs at an early stage. In the case of infantile cerebral palsy, this leads to spastic paralysis, ataxia and athetosis. The spastic paralyses are caused by the permanently increased muscle tone, which results in a rigid posture. At the same time, the coordination of movements is disturbed in many affected persons, which is also referred to as ataxia. In addition, involuntary extending and bizarre movements may occur in the context of athetosis because of a constant alternation between hypo- and hypertonus of the muscles.