Biology:4-aminobutyrate transaminase
| 4-aminobutyrate transaminase | |||||||||
|---|---|---|---|---|---|---|---|---|---|
 4-Aminobutyrate transaminase homodimer, Pig | |||||||||
| Identifiers | |||||||||
| EC number | 2.6.1.19 | ||||||||
| CAS number | 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 | ||||||||
| |||||||||
| 4-aminobutyrate transaminase | |
|---|---|
| Identifiers | |
| Symbol | ABAT |
| NCBI gene | 18 |
| HGNC | 23 |
| OMIM | 137150 |
| RefSeq | NM_020686 |
| UniProt | P80404 |
| Other data | |
| Locus | Chr. 16 p13.2 |
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 [math]\displaystyle{ \rightleftharpoons }[/math] 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
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:
- (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.[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]
Inhibitors
- Aminooxyacetic acid
- Gabaculine
- Phenelzine
- Phenylethylidenehydrazine (PEH)
- Rosmarinic acid[16]
- Valproic acid
- Vigabatrin
References
- ↑ "4-aminobutyrate aminotransferase - Identical Protein Groups - NCBI". https://www.ncbi.nlm.nih.gov/ipg/?term=4-aminobutyrate+aminotransferase.
- ↑ 2.0 2.1 "In silico analysis of the inhibitory activities of GABA derivatives on 4-aminobutyrate transaminase". Arabian Journal of Chemistry 10: S1267–75. February 2017. doi:10.1016/j.arabjc.2013.03.007.
- ↑ "BRENDA - Information on EC 2.6.1.19 - 4-aminobutyrate-2-oxoglutarate transaminase". https://www.brenda-enzymes.org/enzyme.php?ecno=2.6.1.19.
- ↑ 4.0 4.1 "4-Aminobutyrate Transaminase". Neurotransmitter Enzymes. 5. 1986. pp. 389–420. doi:10.1385/0-89603-079-2:389. ISBN 0-89603-079-2.
- ↑ 5.0 5.1 5.2 "4-Aminobutyrate (GABA): a metabolite and signal with practical significance". Botany 95 (11): 1015–32. 2017. doi:10.1139/cjb-2017-0135. https://www.researchgate.net/publication/320088803.
- ↑ "GABA transaminases from Saccharomyces cerevisiae and Arabidopsis thaliana complement function in cytosol and mitochondria". Yeast 30 (7): 279–89. July 2013. doi:10.1002/yea.2962. PMID 23740823.
- ↑ "Highway or byway: the metabolic role of the GABA shunt in plants". Trends in Plant Science 13 (1): 14–9. January 2008. doi:10.1016/j.tplants.2007.10.005. PMID 18155636.
- ↑ 8.0 8.1 "The Metabolism and Functions of [gamma-Aminobutyric Acid"]. Plant Physiology 115 (1): 1–5. September 1997. doi:10.1104/pp.115.1.1. PMID 12223787.
- ↑ 9.0 9.1 "Inhibition of rabbit brain 4-aminobutyrate transaminase by some taurine analogues: a kinetic analysis". Biochemical Pharmacology 71 (10): 1510–9. May 2006. doi:10.1016/j.bcp.2006.02.007. PMID 16540097.
- ↑ "Basic aspects of GABA-transaminase in neuropsychiatric disorders". Clinical Biochemistry 28 (2): 145–54. April 1995. doi:10.1016/0009-9120(94)00074-6. PMID 7628073.
- ↑ "GABA-TRANSAMINASE DEFICIENCY" (in en-us). https://www.omim.org/entry/613163?search=GABA%20transaminase&highlight=gaba%20transaminase#4.
- ↑ "Highway or byway: the metabolic role of the GABA shunt in plants". Trends in Plant Science 13 (1): 14–9. January 2008. doi:10.1016/j.tplants.2007.10.005. PMID 18155636. http://www.sciencedirect.com/science/article/pii/S1360138507003032.
- ↑ 13.0 13.1 "Disruption of the GABA shunt affects mitochondrial respiration and virulence in the cereal pathogen Fusarium graminearum". Molecular Microbiology 98 (6): 1115–32. December 2015. doi:10.1111/mmi.13203. PMID 26305050.
- ↑ "Crystal structures of unbound and aminooxyacetate-bound Escherichia coli gamma-aminobutyrate aminotransferase". Biochemistry 43 (34): 10896–905. August 2004. doi:10.1021/bi049218e. PMID 15323550. https://www.researchgate.net/publication/8387667.
- ↑ 15.0 15.1 "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. January 2004. doi:10.1074/jbc.M305884200. PMID 14534310.
- ↑ "Bioassay-guided fractionation of lemon balm (Melissa officinalis L.) using an in vitro measure of GABA transaminase activity". Phytotherapy Research 23 (8): 1075–81. August 2009. doi:10.1002/ptr.2712. PMID 19165747.
Further reading
- "Soluble gamma-aminobutyric-glutamic transaminase from Pseudomonas fluorescens". The Journal of Biological Chemistry 234 (4): 932–6. April 1959. doi:10.1016/S0021-9258(18)70206-8. PMID 13654294. http://www.jbc.org/cgi/pmidlookup?view=long&pmid=13654294.
- "[On the beta-alanine-alpha-ketoglutarate transaminase from Neurospora crassa]" (in de). Hoppe-Seyler's Zeitschrift für Physiologische Chemie 326: 25–33. October 1961. doi:10.1515/bchm2.1961.326.1.25. PMID 13863304.
- "Purification and characterization of the 4-aminobutyrate--2,ketoglutarate transaminase from mouse brain". Biochemistry 12 (15): 2868–73. July 1973. doi:10.1021/bi00739a015. PMID 4719123.
- "Disorders of GABA metabolism: SSADH and GABA-transaminase deficiencies". Journal of Pediatric Epilepsy 3 (4): 217–227. November 2014. doi:10.3233/PEP-14097. PMID 25485164. PMC 4256671. https://dash.harvard.edu/bitstream/handle/1/29361684/PARVIZ_MAHSA_GABA2014JPED_nihms-615766.pdf?sequence=1.
External links
- 4-Aminobutyrate+Transaminase at the US National Library of Medicine Medical Subject Headings (MeSH)
- "GABA-transaminase deficiency". MedLink Neurology. 2015. http://medlink.com/article/gaba-transaminase_deficiency.
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