4-aminobutyrate transaminase

4-Aminobutyrate transaminase (also known as GABA transaminase or GABA-T) is an enzyme that catalyzes the conversion of gamma-aminobutyric acid (GABA) and alpha-ketoglutarate to succinic semialdehyde and glutamate. This reaction is a key step in the GABA shunt, a critical pathway that contributes to the metabolism of the inhibitory neurotransmitter GABA in the central nervous system and in various tissues. The enzyme is encoded by the ABAT gene in humans.

Function

4-Aminobutyrate transaminase plays a pivotal role in the GABAergic system by regulating the levels of GABA, an essential neurotransmitter in the brain that inhibits excitatory signals and helps maintain neuronal balance. By converting GABA into succinic semialdehyde, GABA-T limits the availability of GABA, thus influencing neural excitability and neurotransmission. This enzymatic activity is crucial for the proper functioning of the nervous system, affecting processes such as anxiety, sleep, and muscle tone.

Structure

The enzyme is a pyridoxal phosphate (PLP)-dependent enzyme, meaning it requires the cofactor PLP, a derivative of vitamin B6, to function. The structure of 4-aminobutyrate transaminase includes two main domains: the PLP-binding domain and the substrate-binding domain, which together facilitate the enzymatic reaction.

Clinical Significance

Alterations in GABA-T activity have been implicated in various neurological and psychiatric disorders, including epilepsy, anxiety disorders, and schizophrenia. Inhibitors of GABA transaminase, such as vigabatrin, are used clinically to increase GABA levels in the brain and are effective in the treatment of certain types of epilepsy and other neurological conditions.

Inhibitors

Several compounds can inhibit the activity of 4-aminobutyrate transaminase, leading to increased levels of GABA in the brain. These inhibitors include both pharmaceuticals and natural substances, with vigabatrin being the most notable example. Vigabatrin's mechanism of action involves irreversible inhibition of GABA-T, which is beneficial in conditions where an increase in GABAergic activity is desired.

Genetic Aspects

Mutations in the ABAT gene, which encodes the 4-aminobutyrate transaminase enzyme, can lead to deficiencies in the enzyme's activity. Such deficiencies are associated with a spectrum of neurological disorders, highlighting the enzyme's importance in neural function and development.

See Also

• Gamma-aminobutyric acid
• Neurotransmitter
• Epilepsy
• Vigabatrin