GABA-T
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In
enzymology Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
, 4-aminobutyrate transaminase (), also called GABA transaminase or 4-aminobutyrate aminotransferase, or GABA-T, is an enzyme that
catalyzes Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...
the chemical reaction: :4-aminobutanoate + 2-oxoglutarate \rightleftharpoons succinate semialdehyde + L-glutamate Thus, the two substrates of this enzyme are 4-aminobutanoate ( GABA) and 2-oxoglutarate. The two products are
succinate semialdehyde Succinic semialdehyde (SSA) is a GABA metabolite. It is formed from GABA by the action of GABA transaminase and further oxidised to become succinic acid, which enters TCA cycle. See also * Succinic semialdehyde dehydrogenase deficiency Succin ...
and
L-glutamate Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can synt ...
. This enzyme belongs to the family of transferases, specifically the
transaminases Transaminases or aminotransferases are enzymes that catalyze a transamination reaction between an amino acid and an α-keto acid. They are important in the synthesis of amino acids, which form proteins. Function and mechanism An amino acid co ...
, which transfer nitrogenous groups. The systematic name of this enzyme class is 4-aminobutanoate:2-oxoglutarate aminotransferase. This enzyme participates in 5 metabolic pathways: alanine and aspartate metabolism,
glutamate metabolism Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can synt ...
, beta-alanine metabolism, propanoate metabolism, and butanoate metabolism. It employs one cofactor, pyridoxal phosphate. This enzyme is found in
prokaryotes A prokaryote () is a single-celled organism that lacks a nucleus and other membrane-bound organelles. The word ''prokaryote'' comes from the Greek πρό (, 'before') and κάρυον (, 'nut' or 'kernel').Campbell, N. "Biology:Concepts & Connec ...
, plants, fungi, and animals (including humans). Pigs have often been used when studying how this protein may work in humans.


Enzyme Commission number

GABA-T is Enzyme Commission number 2.6.1.19. This means that it is in the transferase class of enzymes, the nitrogenous transferase sub-class and the transaminase sub-subclass. As a nitrogenous transferase, its role is to transfer nitrogenous groups from one molecule to another. As a transaminase, GABA-T's role is to move functional groups from an amino acid and a α-keto acid, and vice versa. In the case of GABA-T, it takes a nitrogen group from GABA and uses it to create L-glutamate.


Reaction pathway

In animals, fungi, and bacteria, GABA-T helps facilitate a reaction that moves an amine group from GABA to 2-oxoglutarate, and a
ketone In organic chemistry, a ketone is a functional group with the structure R–C(=O)–R', where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group –C(=O)– (which contains a carbon-oxygen double bo ...
group from 2-oxoglutarate to GABA. This produces succinate semialdehyde and L-glutamate. In plants,
pyruvate Pyruvic acid (CH3COCOOH) is the simplest of the alpha-keto acids, with a carboxylic acid and a ketone functional group. Pyruvate, the conjugate base, CH3COCOO−, is an intermediate in several metabolic pathways throughout the cell. Pyruvic aci ...
and
glyoxylate Glyoxylic acid or oxoacetic acid is an organic compound. Together with acetic acid, glycolic acid, and oxalic acid, glyoxylic acid is one of the C2 carboxylic acids. It is a colourless solid that occurs naturally and is useful industrially. Str ...
can be used in the place of 2-oxoglutarate. catalyzed by the enzyme 4-aminobutyrate—pyruvate transaminase: :(1) 4-aminobutanoate (GABA) +
pyruvate Pyruvic acid (CH3COCOOH) is the simplest of the alpha-keto acids, with a carboxylic acid and a ketone functional group. Pyruvate, the conjugate base, CH3COCOO−, is an intermediate in several metabolic pathways throughout the cell. Pyruvic aci ...
succinate semialdehyde Succinic semialdehyde (SSA) is a GABA metabolite. It is formed from GABA by the action of GABA transaminase and further oxidised to become succinic acid, which enters TCA cycle. See also * Succinic semialdehyde dehydrogenase deficiency Succin ...
+ L- alanine : (2) 4-aminobutanoate (GABA) +
glyoxylate Glyoxylic acid or oxoacetic acid is an organic compound. Together with acetic acid, glycolic acid, and oxalic acid, glyoxylic acid is one of the C2 carboxylic acids. It is a colourless solid that occurs naturally and is useful industrially. Str ...
succinate semialdehyde + glycine


Cellular and metabolic role

The primary role of GABA-T is to break down GABA as part of the GABA-Shunt. In the next step of the shunt, the semialdehyde produced by GABA-T will be oxidized to succinic acid by
succinate-semialdehyde dehydrogenase In enzymology, a succinate-semialdehyde dehydrogenase (SSADH) () is an enzyme that catalyzes the chemical reaction :succinate semialdehyde + NAD+ + H2O succinate + NADH + 2 H+ The 3 substrates of this enzyme are succinate semialdehyde, NAD ...
, resulting in succinate. This succinate will then enter
mitochondrion A mitochondrion (; ) is an organelle found in the cells of most Eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is used ...
and become part of the citric acid cycle. The critic acid cycle can then produce 2-oxoglutarate, which can be used to make glutamate, which can in turn be made into GABA, continuing the cycle. GABA is a very important
neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell. Neuro ...
in animal brains, and a low concentration of GABA in mammalian brains has been linked to several neurological disorders, including
Alzheimer's disease Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...
and Parkinson's disease. Because GABA-T degrades GABA, the inhibition of this enzyme has been the target of many medical studies. The goal of these studies is to find a way to inhibit GABA-T activity, which would reduce the rate that GABA and 2-oxoglutarate are converted to semialdehyde and L-glutamate, thus raising GABA concentration in the brain. There is also a genetic disorder in humans which can lead to a deficiency in GABA-T. This can lead to developmental impairment or mortality in extreme cases. In plants, GABA can be produced as a stress response. Plants also use GABA to for internal signaling and for interactions with other organisms near the plant. In all of these intra-plant pathways, GABA-T will take on the role of degrading GABA. It has also been demonstrated that the succinate produced in the GABA shunt makes up a significant proportion of the succinate needed by the mitochondrion. In fungi, the breakdown of GABA in the GABA shunt is key in ensuring maintaining a high level of activity in the critic acid cycle. There is also experimental evidence that the breakdown of GABA by GABA-T plays a role in managing oxidative stress in fungi.


Structural Studies

There have been several structures solved for this class of enzymes, given PDB accession codes, and published in peer reviewed journals. At least 4 such structures have been solved using pig enzymes: , , , , and at least 4 such structures have been solved in '' Escherichia coli'': , , , . There are actually some differences between the enzyme structure for these organisms. ''E. coli'' enzymes of GABA-T lack an iron-sulfur cluster that is found in the pig model.


Active sites

Amino acid residues found in the
active site In biology and biochemistry, the active site is the region of an enzyme where substrate molecules bind and undergo a chemical reaction. The active site consists of amino acid residues that form temporary bonds with the substrate (binding site) a ...
of 4-aminobutyrate transaminase include Lys-329, which are found on each of the two subunits of the enzyme. This site will also bind with a pyridoxal 5'􏰌- phosphate co-enzyme.


Inhibitors

*
Aminooxyacetic acid Aminooxyacetic acid, often abbreviated AOA or AOAA, is a compound that inhibits 4-aminobutyrate aminotransferase (GABA-T) activity ''in vitro'' and ''in vivo'', leading to less gamma-aminobutyric acid (GABA) being broken down. Subsequently, the le ...
*
Gabaculine Gabaculine is a naturally occurring neurotoxin first isolated from the bacteria ''Streptomyces toyacaensis'', which acts as a potent and irreversible GABA transaminase inhibitor, and also a GABA reuptake inhibitor. Gabaculine is also known as 3-am ...
* Phenelzine *
Phenylethylidenehydrazine Phenylethylidenehydrazine (PEH), also known as 2-phenylethylhydrazone or β-phenylethylidenehydrazine, is an inhibitor of the enzyme GABA transaminase (GABA-T). It is a metabolite of the antidepressant phenelzine and is responsible for its eleva ...
(PEH) * Rosmarinic acid * Valproic acid *
Vigabatrin Vigabatrin, brand name Sabril, is a medication used to treat epilepsy. It became available as a generic medication in 2019. It works by inhibiting the breakdown of γ-aminobutyric acid (GABA). It is also known as γ-vinyl-GABA, and is a stru ...


References


Further reading

* * * *


External links

* * {{Portal bar, Biology, border=no EC 2.6.1 Pyridoxal phosphate enzymes Enzymes of known structure GABA Glutamate (neurotransmitter)