This enzyme is found in prokaryotes, plants, fungi, and animals (including humans).[1] Pigs have often been used when studying how this protein may work in humans.[2]
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.[3] 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.[4][5][6] This produces succinate semialdehyde and L-glutamate.[4] In plants, pyruvate and glyoxylate can be used in the place of 2-oxoglutarate.[7] catalyzed by the enzyme 4-aminobutyrate—pyruvate transaminase:
The primary role of GABA-T is to break down GABA as part of the GABA-Shunt.[2] 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.[8] 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.[8]
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.[9][10] Because GABA-T degrades GABA, the inhibition of this enzyme has been the target of many medical studies.[9] 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.[11]
In plants, GABA can be produced as a stress response.[5] Plants also use GABA to for internal signaling and for interactions with other organisms near the plant.[5] 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.[12]
In fungi, the breakdown of GABA in the GABA shunt is key in ensuring a high level of activity in the critic acid cycle.[13] There is also experimental evidence that the breakdown of GABA by GABA-T plays a role in managing oxidative stress in fungi.[13]
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: 1OHV, 1OHW, 1OHY, 1SF2, and at least 4 such structures have been solved in Escherichia coli: 1SFF, 1SZK, 1SZS, 1SZU. 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.[14]
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.[15] This site will also bind with a pyridoxal 5'- phosphate co-enzyme.[15]
^Cao J, Barbosa JM, Singh N, Locy RD (July 2013). "GABA transaminases from Saccharomyces cerevisiae and Arabidopsis thaliana complement function in cytosol and mitochondria". Yeast. 30 (7): 279–89. doi:10.1002/yea.2962. PMID23740823. S2CID1303165.
^Fait A, Fromm H, Walter D, Galili G, Fernie AR (January 2008). "Highway or byway: the metabolic role of the GABA shunt in plants". Trends in Plant Science. 13 (1): 14–9. doi:10.1016/j.tplants.2007.10.005. PMID18155636.
^ abRicci L, Frosini M, Gaggelli N, Valensin G, Machetti F, Sgaragli G, Valoti M (May 2006). "Inhibition of rabbit brain 4-aminobutyrate transaminase by some taurine analogues: a kinetic analysis". Biochemical Pharmacology. 71 (10): 1510–9. doi:10.1016/j.bcp.2006.02.007. PMID16540097.
^Sherif FM, Ahmed SS (April 1995). "Basic aspects of GABA-transaminase in neuropsychiatric disorders". Clinical Biochemistry. 28 (2): 145–54. doi:10.1016/0009-9120(94)00074-6. PMID7628073.
^Awad R, Muhammad A, Durst T, Trudeau VL, Arnason JT (August 2009). "Bioassay-guided fractionation of lemon balm (Melissa officinalis L.) using an in vitro measure of GABA transaminase activity". Phytotherapy Research. 23 (8): 1075–81. doi:10.1002/ptr.2712. PMID19165747. S2CID23127112.
Aurich H (October 1961). "[On the beta-alanine-alpha-ketoglutarate transaminase from Neurospora crassa]" [On the beta-alanine-alpha-ketoglutarate transaminase from Neurospora crassa]. Hoppe-Seyler's Zeitschrift für Physiologische Chemie (in German). 326: 25–33. doi:10.1515/bchm2.1961.326.1.25. PMID13863304.
Schousboe A, Wu JY, Roberts E (July 1973). "Purification and characterization of the 4-aminobutyrate--2,ketoglutarate transaminase from mouse brain". Biochemistry. 12 (15): 2868–73. doi:10.1021/bi00739a015. PMID4719123.
