4-aminobutyrate transaminase

{{infobox enzyme

| Name = 4-aminobutyrate transaminase

| EC_number = 2.6.1.19

| CAS_number = 9037-67-6

| GO_code = 0003867

| image = 1ohv.jpg

| width = 270

| caption = 4-Aminobutyrate transaminase homodimer, Pig

}}

{{infobox protein

|Name=4-aminobutyrate transaminase

|caption=

|image=

|width=

|HGNCid=23

|Symbol=ABAT

|AltSymbols=

|EntrezGene=18

|OMIM=137150

|RefSeq=NM_020686

|UniProt=P80404

|PDB=

|ECnumber=

|Chromosome=16

|Arm=p

|Band=13.2

|LocusSupplementaryData=

}}

In enzymology, 4-aminobutyrate transaminase ({{EC number|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 $\rightleftharpoons$ 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).{{Cite web|title=4-aminobutyrate aminotransferase - Identical Protein Groups - NCBI|url=https://www.ncbi.nlm.nih.gov/ipg/?term=4-aminobutyrate+aminotransferase|access-date=2020-09-29|website=www.ncbi.nlm.nih.gov}} Pigs have often been used when studying how this protein may work in humans.{{Cite journal|vauthors=Iftikhar H, Batool S, Deep A, Narasimhan B, Sharma PC, Malhotra M|date=February 2017|title=In silico analysis of the inhibitory activities of GABA derivatives on 4-aminobutyrate transaminase|journal=Arabian Journal of Chemistry|volume=10|pages=S1267–75|doi=10.1016/j.arabjc.2013.03.007|doi-access=free}}

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.{{Cite web|title=BRENDA - Information on EC 2.6.1.19 - 4-aminobutyrate-2-oxoglutarate transaminase|url=https://www.brenda-enzymes.org/enzyme.php?ecno=2.6.1.19|access-date=2020-09-24|website=www.brenda-enzymes.org}} 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.{{cite book|title=Neurotransmitter Enzymes|vauthors=Tunnicliff G|year=1986|isbn=0-89603-079-2|veditors=Boulton AA, Baker GB, Yu PH|pages=389–420|chapter=4-Aminobutyrate Transaminase|volume=5|doi=10.1385/0-89603-079-2:389}}{{cite journal|vauthors=Shelp BJ, Bown AW, Zarei A|date=2017|title=4-Aminobutyrate (GABA): a metabolite and signal with practical significance|url=https://www.researchgate.net/publication/320088803|journal=Botany|volume=95|issue=11|pages=1015–32|doi=10.1139/cjb-2017-0135|hdl=1807/79639|hdl-access=free}}{{cite journal | vauthors = Cao J, Barbosa JM, Singh N, Locy RD | title = GABA transaminases from Saccharomyces cerevisiae and Arabidopsis thaliana complement function in cytosol and mitochondria | journal = Yeast | volume = 30 | issue = 7 | pages = 279–89 | date = July 2013 | pmid = 23740823 | doi = 10.1002/yea.2962 | s2cid = 1303165 }} This produces succinate semialdehyde and L-glutamate. In plants, pyruvate and glyoxylate can be used in the place of 2-oxoglutarate.{{cite journal | vauthors = Fait A, Fromm H, Walter D, Galili G, Fernie AR | title = Highway or byway: the metabolic role of the GABA shunt in plants | journal = Trends in Plant Science | volume = 13 | issue = 1 | pages = 14–9 | date = January 2008 | pmid = 18155636 | doi = 10.1016/j.tplants.2007.10.005 | bibcode = 2008TPS....13...14F }} catalyzed by the enzyme 4-aminobutyrate—pyruvate transaminase:

:(1) 4-aminobutanoate (GABA) + pyruvate {{eqm}} succinate semialdehyde + L-alanine

: (2) 4-aminobutanoate (GABA) + glyoxylate {{eqm}} succinate semialdehyde + glycine

Cellular and metabolic role

The primary role of GABA-T is to break down GABA as part of the GABA-Shunt. 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.{{cite journal | vauthors = Bown AW, Shelp BJ | title = The Metabolism and Functions of [gamma]-Aminobutyric Acid | journal = Plant Physiology | volume = 115 | issue = 1 | pages = 1–5 | date = September 1997 | pmid = 12223787 | pmc = 158453 | doi = 10.1104/pp.115.1.1 }} 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.

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.{{cite journal | vauthors = Ricci L, Frosini M, Gaggelli N, Valensin G, Machetti F, Sgaragli G, Valoti M | title = Inhibition of rabbit brain 4-aminobutyrate transaminase by some taurine analogues: a kinetic analysis | journal = Biochemical Pharmacology | volume = 71 | issue = 10 | pages = 1510–9 | date = May 2006 | pmid = 16540097 | doi = 10.1016/j.bcp.2006.02.007 }}{{cite journal | vauthors = Sherif FM, Ahmed SS | title = Basic aspects of GABA-transaminase in neuropsychiatric disorders | journal = Clinical Biochemistry | volume = 28 | issue = 2 | pages = 145–54 | date = April 1995 | pmid = 7628073 | doi = 10.1016/0009-9120(94)00074-6 }} Because GABA-T degrades GABA, the inhibition of this enzyme has been the target of many medical studies. 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.{{Cite web|title=GABA-TRANSAMINASE DEFICIENCY|url=https://www.omim.org/entry/613163?search=GABA%20transaminase&highlight=gaba%20transaminase#4|access-date=2020-10-18|website=www.omim.org|language=en-us}}

In plants, GABA can be produced as a stress response. Plants also use GABA to for internal signaling and for interactions with other organisms near the plant. 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.{{cite journal | vauthors = Fait A, Fromm H, Walter D, Galili G, Fernie AR | title = Highway or byway: the metabolic role of the GABA shunt in plants | journal = Trends in Plant Science | volume = 13 | issue = 1 | pages = 14–9 | date = January 2008 | pmid = 18155636 | doi = 10.1016/j.tplants.2007.10.005 | bibcode = 2008TPS....13...14F | url = http://www.sciencedirect.com/science/article/pii/S1360138507003032 | url-access = subscription }}

In fungi, the breakdown of GABA in the GABA shunt is key in ensuring a high level of activity in the critic acid cycle.{{cite journal | vauthors = Bönnighausen J, Gebhard D, Kröger C, Hadeler B, Tumforde T, Lieberei R, Bergemann J, Schäfer W, Bormann J | display-authors = 6 | title = Disruption of the GABA shunt affects mitochondrial respiration and virulence in the cereal pathogen Fusarium graminearum | journal = Molecular Microbiology | volume = 98 | issue = 6 | pages = 1115–32 | date = December 2015 | pmid = 26305050 | doi = 10.1111/mmi.13203 | s2cid = 45755014 | doi-access = free }} There is also experimental evidence that the breakdown of GABA by GABA-T plays a role in managing oxidative stress in fungi.

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: {{PDB link|1OHV}}, {{PDB link|1OHW}}, {{PDB link|1OHY}}, {{PDB link|1SF2}}, and at least 4 such structures have been solved in Escherichia coli: {{PDB link|1SFF}}, {{PDB link|1SZK}}, {{PDB link|1SZS}}, {{PDB link|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.{{cite journal | vauthors = Liu W, Peterson PE, Carter RJ, Zhou X, Langston JA, Fisher AJ, Toney MD | title = Crystal structures of unbound and aminooxyacetate-bound Escherichia coli gamma-aminobutyrate aminotransferase | journal = Biochemistry | volume = 43 | issue = 34 | pages = 10896–905 | date = August 2004 | pmid = 15323550 | doi = 10.1021/bi049218e | url = https://www.researchgate.net/publication/8387667 }}

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.{{cite journal|display-authors=6|vauthors=Storici P, De Biase D, Bossa F, Bruno S, Mozzarelli A, Peneff C, Silverman RB, Schirmer T|date=January 2004|title=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|journal=The Journal of Biological Chemistry|volume=279|issue=1|pages=363–73|doi=10.1074/jbc.M305884200|pmid=14534310|s2cid=42918710|doi-access=free}} This site will also bind with a pyridoxal 5'􏰌- phosphate co-enzyme.

Inhibitors

Aminooxyacetic acid
Gabaculine
Phenelzine
Phenylethylidenehydrazine (PEH)
Rosmarinic acid{{cite journal | vauthors = Awad R, Muhammad A, Durst T, Trudeau VL, Arnason JT | title = Bioassay-guided fractionation of lemon balm (Melissa officinalis L.) using an in vitro measure of GABA transaminase activity | journal = Phytotherapy Research | volume = 23 | issue = 8 | pages = 1075–81 | date = August 2009 | pmid = 19165747 | doi = 10.1002/ptr.2712 | s2cid = 23127112 }}
Valproic acid
Vigabatrin

References

External links

{{MeshName|4-Aminobutyrate+Transaminase}}
{{cite web | vauthors = Pearl PL, Parviz M, Hodgeman R, Gibson KM, Reimschisel T | title = GABA-transaminase deficiency | work = MedLink Neurology | date = 2015 | url = http://medlink.com/article/gaba-transaminase_deficiency }}

Category:EC 2.6.1

Category:Pyridoxal phosphate enzymes

Category:Enzymes of known structure

Category:GABA

Category:Glutamate (neurotransmitter)