4-aminobutyrate transaminase

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4-aminobutyrate transaminase
ExPASy
NiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO
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PMCarticles
PubMedarticles
NCBIproteins
4-aminobutyrate transaminase
Identifiers
SymbolABAT
Chr. 16 p13.2
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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

L-glutamate
.

This enzyme belongs to the family of

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

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)
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

Main article: GABA transaminase inhibitor

References

  1. ^ "4-aminobutyrate aminotransferase - Identical Protein Groups - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2020-09-29.
  2. ^
    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. ^
    ISBN 0-89603-079-2
    .
  5. ^
    hdl:1807/79639
    .
  6. S2CID 1303165
    .
  7. PMID 18155636
    .
  8. ^
    PMID 12223787
    .
  9. ^
    PMID 16540097
    .
  10. PMID 7628073
    .
  11. ^ "GABA-TRANSAMINASE DEFICIENCY". www.omim.org. Retrieved 2020-10-18.
  12. PMID 18155636
    .
  13. ^
    S2CID 45755014
    .
  14. PMID 15323550
    .
  15. ^
    S2CID 42918710
    .
  16. S2CID 23127112
    .

Further reading

External links

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