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4-aminobutyrate transaminase
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, 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]

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 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] 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.[10]

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.[11]

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.[12] There is also experimental evidence that the breakdown of GABA by GABA-T plays a role in managing oxidative stress in fungi.[12]

Structure

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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.[13]

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.[14] This site will also bind with a pyridoxal 5'􏰌- phosphate co-enzyme.[14]

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. pp. 389–420. doi:10.1385/0-89603-079-2:389.
  5. ^ a b c Shelp BJ, Bown AW, Zarei A (2017). "4-Aminobutyrate (GABA): a metabolite and signal with practical significance" (PDF). Botany. 95 (11): 1015–32.
  6. ^ Cao, Juxiang; Barbosa, Jose M.; Singh, Narendra; Locy, Robert D. (2013). "GABA transaminases from Saccharomyces cerevisiae and Arabidopsis thaliana complement function in cytosol and mitochondria". Yeast. 30 (7): 279–289. doi:10.1002/yea.2962. ISSN 1097-0061.
  7. ^ Fait, Aaron; Fromm, Hillel; Walter, Dirk; Galili, Gad; Fernie, Alisdair R. (2008-01-01). "Highway or byway: the metabolic role of the GABA shunt in plants". Trends in Plant Science. 13 (1): 14–19. doi:10.1016/j.tplants.2007.10.005. ISSN 1360-1385.
  8. ^ a b Bown, Alan W.; Shelp, Barry J. (1997). "The Metabolism and and Functions of y-Aminobutyric Acid" (PDF). Plant Physiology. 115: 1–5.
  9. ^ a b Ricci, Lorenzo; Frosini, Maria; Gaggelli, Nicola; Valensin, Gianni; Machetti, Fabrizio; Sgaragli, Giampietro; Valoti, Massimo (2006-05-14). "Inhibition of rabbit brain 4-aminobutyrate transaminase by some taurine analogues: A kinetic analysis". Biochemical Pharmacology. 71 (10): 1510–1519. doi:10.1016/j.bcp.2006.02.007. ISSN 0006-2952.
  10. ^ "GABA-TRANSAMINASE DEFICIENCY". www.omim.org. Retrieved 2020-10-18.{{cite web}}: CS1 maint: url-status (link)
  11. ^ Fait, Aaron; Fromm, Hillel; Walter, Dirk; Galili, Gad; Fernie, Alisdair R. (2008-01-01). "Highway or byway: the metabolic role of the GABA shunt in plants". Trends in Plant Science. 13 (1): 14–19. doi:10.1016/j.tplants.2007.10.005. ISSN 1360-1385.
  12. ^ a b Bönnighausen, Jakob; Gebhard, Daniel; Kröger, Cathrin; Hadeler, Birgit; Tumforde, Thomas; Lieberei, Reinhard; Bergemann, Jörg; Schäfer, Wilhelm; Bormann, Jörg (2015). "Disruption of the GABA shunt affects mitochondrial respiration and virulence in the cereal pathogen Fusarium graminearum". Molecular Microbiology. 98 (6): 1115–1132. doi:10.1111/mmi.13203. ISSN 1365-2958.
  13. ^ Liu, Wenshe; Peterson, Peter E.; Carter, Richard J.; Zhou, Xianzhi; Langston, James A.; Fisher, Andrew J.; Toney, Michael D. (2004). "Crystal Structures of Unbound and Aminooxyacetate-Bound Escherichia coli γ-Aminobutyrate Aminotransferase" (PDF). Biochemistry. 43: 10896–10905.
  14. ^ 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.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  15. ^ 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.

Further reading

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Category:EC 2.6.1 Category:Pyridoxal phosphate enzymes Category:Enzymes of known structure Category:GABA Category:Glutamate (neurotransmitter)

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