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4-aminobutyrate transaminase | |||||||||
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Identifiers | |||||||||
EC no. | 2.6.1.19 | ||||||||
CAS no. | 9037-67-6 | ||||||||
Databases | |||||||||
IntEnz | IntEnz view | ||||||||
BRENDA | BRENDA entry | ||||||||
ExPASy | NiceZyme view | ||||||||
KEGG | KEGG entry | ||||||||
MetaCyc | metabolic pathway | ||||||||
PRIAM | profile | ||||||||
PDB structures | RCSB PDB PDBe PDBsum | ||||||||
Gene Ontology | AmiGO / QuickGO | ||||||||
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4-aminobutyrate transaminase | |||||||
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Identifiers | |||||||
Symbol | ABAT | ||||||
NCBI gene | 18 | ||||||
HGNC | 23 | ||||||
OMIM | 137150 | ||||||
RefSeq | NM_020686 | ||||||
UniProt | P80404 | ||||||
Other data | |||||||
Locus | Chr. 16 p13.2 | ||||||
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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
[edit]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
[edit]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
[edit]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
[edit]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
[edit]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
[edit]- Aminooxyacetic acid
- Gabaculine
- Phenelzine
- Phenylethylidenehydrazine (PEH)
- Rosmarinic acid[15]
- Valproic acid
- Vigabatrin
References
[edit]- ^ "4-aminobutyrate aminotransferase - Identical Protein Groups - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2020-09-29.
- ^ 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.
- ^ "BRENDA - Information on EC 2.6.1.19 - 4-aminobutyrate-2-oxoglutarate transaminase". www.brenda-enzymes.org. Retrieved 2020-09-24.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ a b Bown, Alan W.; Shelp, Barry J. (1997). "The Metabolism and and Functions of y-Aminobutyric Acid" (PDF). Plant Physiology. 115: 1–5.
- ^ 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.
- ^ "GABA-TRANSAMINASE DEFICIENCY". www.omim.org. Retrieved 2020-10-18.
{{cite web}}
: CS1 maint: url-status (link) - ^ 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.
- ^ 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.
- ^ 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.
- ^ 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) - ^ 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
[edit]- Scott EM, Jakoby WB (April 1959). "Soluble gamma-aminobutyric-glutamic transaminase from Pseudomonas fluorescens". The Journal of Biological Chemistry. 234 (4): 932–6. PMID 13654294.
- 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. PMID 13863304.
- 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. PMID 4719123.
- Parviz M, Vogel K, Gibson KM, Pearl PL (November 2014). "Disorders of GABA metabolism: SSADH and GABA-transaminase deficiencies" (PDF). Journal of Pediatric Epilepsy. 3 (4): 217–227. doi:10.3233/PEP-14097. PMC 4256671. PMID 25485164.
- Pearl PL, DiBasco M, Gite J, Gibbson KM, Friedman J. "GABA-transaminase deficiency.". In Reimschisel T (ed.). MedLink Neurology. San Diego, California: MedLink Corporation.
External links
[edit]![](http://upload.wikimedia.org/wikipedia/en/thumb/4/4a/Commons-logo.svg/30px-Commons-logo.svg.png)
- 4-Aminobutyrate+Transaminase at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
Category:EC 2.6.1 Category:Pyridoxal phosphate enzymes Category:Enzymes of known structure Category:GABA Category:Glutamate (neurotransmitter)