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4-aminobutyrate transaminase

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4-aminobutyrate transaminase
4-Aminobutyrate transaminase homodimer, Pig
Identifiers
EC no.2.6.1.19
CAS no.9037-67-6
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO
Search
PMCarticles
PubMedarticles
NCBIproteins
4-aminobutyrate transaminase
Identifiers
SymbolABAT
NCBI gene18
HGNC23
OMIM137150
RefSeqNM_020686
UniProtP80404
Other data
LocusChr. 16 p13.2
Search for
StructuresSwiss-model
DomainsInterPro

In enzymology, 4-aminobutyrate transaminase (EC 2.6.1.19), also called GABA transaminase or 4-aminobutyrate aminotransferase, or GABA-T, is an enzyme that catalyzes the chemical reaction:

4-aminobutanoate + 2-oxoglutarate succinate semialdehyde + L-glutamate

Thus, the two substrates of this enzyme are 4-aminobutanoate (GABA) and 2-oxoglutarate. The two products are succinate semialdehyde and L-glutamate.

This enzyme belongs to the family of transferases, specifically the transaminases, 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, beta-alanine metabolism, propanoate metabolism, and butanoate metabolism. It employs one cofactor, pyridoxal phosphate.

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

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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

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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:

(1) 4-aminobutanoate (GABA) + pyruvate ⇌ succinate semialdehyde + L-alanine
(2) 4-aminobutanoate (GABA) + glyoxylate ⇌ succinate semialdehyde + glycine

Cellular and metabolic role

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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

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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

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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]

Inhibitors

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Main article: GABA transaminase inhibitor

References

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  1. ^ "4-aminobutyrate aminotransferase - Identical Protein Groups - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2020-09-29.
  2. ^ a b Iftikhar H, Batool S, Deep A, Narasimhan B, Sharma PC, Malhotra M (February 2017). "In silico analysis of the inhibitory activities of GABA derivatives on 4-aminobutyrate transaminase". Arabian Journal of Chemistry. 10: S1267–75. doi:10.1016/j.arabjc.2013.03.007.
  3. ^ "BRENDA - Information on EC 2.6.1.19 - 4-aminobutyrate-2-oxoglutarate transaminase". www.brenda-enzymes.org. Retrieved 2020-09-24.
  4. ^ a b Tunnicliff G (1986). "4-Aminobutyrate Transaminase". In Boulton AA, Baker GB, Yu PH (eds.). Neurotransmitter Enzymes. Vol. 5. pp. 389–420. doi:10.1385/0-89603-079-2:389. ISBN 0-89603-079-2.
  5. ^ a b c Shelp BJ, Bown AW, Zarei A (2017). "4-Aminobutyrate (GABA): a metabolite and signal with practical significance". Botany. 95 (11): 1015–32. doi:10.1139/cjb-2017-0135. hdl:1807/79639.
  6. ^ 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. PMID 23740823. S2CID 1303165.
  7. ^ 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. Bibcode:2008TPS....13...14F. doi:10.1016/j.tplants.2007.10.005. PMID 18155636.
  8. ^ a b Bown AW, Shelp BJ (September 1997). "The Metabolism and Functions of [gamma]-Aminobutyric Acid". Plant Physiology. 115 (1): 1–5. doi:10.1104/pp.115.1.1. PMC 158453. PMID 12223787.
  9. ^ a b Ricci 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. PMID 16540097.
  10. ^ 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. PMID 7628073.
  11. ^ "GABA-TRANSAMINASE DEFICIENCY". www.omim.org. Retrieved 2020-10-18.
  12. ^ 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. Bibcode:2008TPS....13...14F. doi:10.1016/j.tplants.2007.10.005. PMID 18155636.
  13. ^ a b Bönnighausen J, Gebhard D, Kröger C, Hadeler B, Tumforde T, Lieberei R, et al. (December 2015). "Disruption of the GABA shunt affects mitochondrial respiration and virulence in the cereal pathogen Fusarium graminearum". Molecular Microbiology. 98 (6): 1115–32. doi:10.1111/mmi.13203. PMID 26305050. S2CID 45755014.
  14. ^ Liu W, Peterson PE, Carter RJ, Zhou X, Langston JA, Fisher AJ, Toney MD (August 2004). "Crystal structures of unbound and aminooxyacetate-bound Escherichia coli gamma-aminobutyrate aminotransferase". Biochemistry. 43 (34): 10896–905. doi:10.1021/bi049218e. PMID 15323550.
  15. ^ a b Storici P, De Biase D, Bossa F, Bruno S, Mozzarelli A, Peneff C, et al. (January 2004). "Structures of gamma-aminobutyric acid (GABA) aminotransferase, a pyridoxal 5'-phosphate, and [2Fe-2S] cluster-containing enzyme, complexed with gamma-ethynyl-GABA and with the antiepilepsy drug vigabatrin". The Journal of Biological Chemistry. 279 (1): 363–73. doi:10.1074/jbc.M305884200. PMID 14534310. S2CID 42918710.
  16. ^ 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. PMID 19165747. S2CID 23127112.

Further reading

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