4-Aminobutyrate transaminase

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 group from 2-oxoglutarate to GABA. This produces succinate semialdehyde and L-glutamate. In plants, pyruvate and glyoxylate can be used in the place of 2-oxoglutarate. catalyzed by the enzyme 4-aminobutyrate—pyruvate transaminase:

:(1) 4-aminobutanoate (GABA) + pyruvate succinate semialdehyde + L-alanine : (2) 4-aminobutanoate (GABA) + glyoxylate 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, resulting in succinate. This succinate will then enter mitochondrion and become part of the citric acid cycle. The critic acid cycle can then produce 2-oxoglutarate (α-ketoglutarate), which can be used to make glutamate, which can in turn be converted back into GABA, continuing the cycle.

GABA is a very important neurotransmitter in animal brains, and a low concentration of GABA in mammalian brains has been linked to several neurological disorders, including Alzheimer's disease 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 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 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

Main article: GABA transaminase inhibitor

• Aminooxyacetic acid
• Gabaculine
• Phenelzine
• Phenylethylidenehydrazine (PEH)
• Rosmarinic acid
• Valproic acid
• Vigabatrin

References

References

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11. "GABA-TRANSAMINASE DEFICIENCY".
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16. (August 2009). "Bioassay-guided fractionation of lemon balm (Melissa officinalis L.) using an in vitro measure of GABA transaminase activity". Phytotherapy Research.