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abat

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Official Full Name
4-aminobutyrate aminotransferase
Background
4-aminobutyrate aminotransferase (ABAT) is responsible for catabolism of gamma-aminobutyric acid (GABA), an important, mostly inhibitory neurotransmitter in the central nervous system, into succinic semialdehyde. The active enzyme is a homodimer of 50-kD subunits complexed to pyridoxal-5-phosphate. The protein sequence is over 95% similar to the pig protein. GABA is estimated to be present in nearly one-third of human synapses. ABAT in liver and brain is controlled by 2 codominant alleles with a frequency in a Caucasian population of 0.56 and 0.44. The ABAT deficiency phenotype includes psychomotor retardation, hypotonia, hyperreflexia, lethargy, refractory seizures, and EEG abnormalities. Multiple alternatively spliced transcript variants encoding the same protein isoform have been found for this gene.
Synonyms
ABAT; 4-aminobutyrate aminotransferase; 4-aminobutyrate aminotransferase, mitochondrial; 4 aminobutyrate transaminase; GABAT; mitochondrial; (S) 3 amino 2 methylpropionate transaminase; (S)-3-amino-2-methylpropionate transaminase; 4 aminobutyrate aminotransferase; 4 aminobutyrate aminotransferase, mitochondrial; FLJ17813; FLJ30272; GABA aminotransferase; GABA AT; GABA T; GABA transaminase; GABA transferase; GABA-AT; GABA-T; GABT_HUMAN; Gamma amino N butyrate transaminase; Gamma-amino-N-butyrate transaminase; hCG1984265; L AIBAT; L-AIBAT; LAIBAT; NPD009; 4-aminobutyrate transaminase; I54; X61497; AI255750; 9630038C02Rik; Abat
 cb880; fj82a01; wu:fj82a01

Gamma-aminobutyric acid (GABA) is the most important inhibitory transmitter in the central nervous system and inhibits the stimulatory effects of beta-adrenergic neurotransmitters epinephrine and norepinephrine. In recent years, there is increasing evidence that GABA metabolism-related genes, the 4-aminobutyrate aminotransferase (ABAT) gene, is closely linked to many diseases of the nervous system and play an important role in other diseases such as digestive, neoplastic, and hematological diseases.

The ABAT gene is located at 16p13.2, is 56 kb in length, and encodes a protein of GABAT. ABAT gene has three co-dominant alleles, ABAT1, ABAT2, and ABAT3, respectively. ABAT gene expression in different tissues is inconsistent, and the corresponding ABAT mRNA expression levels from high to low are liver, pancreas, brain, kidney, heart, and placenta, and lung is difficult to detect. The activities of GABAT in different tissues are also different. The activities of brain and spinal cord are the highest, followed by peripheral tissues. From high to low are liver, kidney, lung, heart, stomach and peripheral platelets, respectively. ABAT gene expression levels and enzyme activity Inconsistency suggests that there may be differences in the regulation of enzyme activity in different tissues.

The function of the ABAT gene is mainly to encode GABAT and participate in the catabolism of GABA. In addition, ABAT gene also participates in the salvage synthesis pathway of mitochondrial nucleotides and promotes the conversion of deoxyribonucleoside diphosphates into deoxyribonucleoside triphosphates. Moreover, it maintains mitochondrial membrane function and mitochondrial respiratory chain complex activity.

The Progress of ABAT Gene in Neuropsychiatric Diseases

Emotional disorders

Wegerer et al. initiated a prospective high-risk study (Munich Vulnerability Study) with 83 patients with list/bipolar disorder in 12 families to discover the molecular biology of affective disorders, wanted to find susceptibility indicators in the molecular biology of affective disorders. Of these, 69 patients consented to electroencephalography, genotyping, psychiatric investigations, and somatosensory evoked potential acquisition procedures, followed by screening for genes encoding important substances in the 5-hydroxytryptamine, GABAergic, and substance P systems. Among the 25 candidate genes related to affective disorders, 176 SNPs were found in these candidate genes. Further analysis revealed that only 4 SNP sites in the 3′-UTR region of ABAT gene, rs2270288, rs3743798, rs3743801, and rs7205816, are strongest associated with disease, suggesting that the single nucleotide variation of the ABAT gene can be used as a susceptibility indicator of affective disorders.

Autosomal recessive mitochondrial depletion syndrome

Besse et al. found that the ABAT gene is involved in the salvage synthesis pathway of mitochondrial nucleotides. SUCLG1, SUCLG2, SUCLA2, and NDPK function as interactors of the GABAT protein regulate mitochondrial nucleotide metabolism. ABAT gene mutations can cause autosomal recessive mitochondrial depletion syndrome. In this study, homozygous missense mutations in the ABAT gene (613C>T) were detected in exon in one of the patients, but no mutation was found in 61,486 normal controls. In another patient, Sanger sequencing revealed homozygous mutations in the ABAT gene and proved to be inherited implicitly—their parents were heterozygous (carriers). Missense mutations in the ABAT gene can cause decreased mitochondrial DNA levels in myofibroblasts, reduced mitochondrial respiratory chain complex activity, and decreased mitochondrial membrane function in these patients, causing neurometabolic disorders including autosomal recessive mitochondrial depletion syndrome. The authors further knocked out the ABAT gene in human normal embryonic fibroblast cell lines and found that GABAT deficiency, elevated GABA content, decreased mitochondrial copy number, and decreased mitochondrial membrane function can be caused. The above situation was also seen in the aminoquenoic acid with the inhibitor of GABAT, confirming the conclusion of this study.

Figure 1. ABAT in mitochondrial nucleoside metabolism. (Besse, et al. 2015).

The Progress of ABAT Gene in Tumor Diseases

The mutation rate of the ABAT gene is very low, and most studies have focused on GABA and its receptors. GABA binds to its A or B receptor and participates in tumor proliferation and apoptosis through various signaling pathways, such as gastric cancer, breast cancer, and pancreatic cancer. Wang et al. found that in the blood system, peripheral blood mononuclear cells express GABAA receptors on the surface, and mononuclear cells in the bone marrow highly express GABAA receptors and participate in the development of acute lymphoblastic leukemia. Mutation or abnormal methylation of the ABAT gene increases GABA content and is one of the possible pathogenic mechanisms. Budczies et al. confirmed that β-alanine was elevated and GABAT expression was decreased in ER-breast cancer patients. A β-alanine level was negatively correlated with GABAT content. The low expression of ABAT gene was closely related to the poor prognosis of breast cancer. Studies confirmed a positive correlation between GABAT levels and ABAT gene mRNA levels. Jansen et al. studied the association between the low expression of ABAT gene and the poor prognosis of breast cancer. The results of the study showed that high gene scores and low expression of ABAT and STC2 were associated with progression-free survival (PFS), indicating that these three indicators could serve as prognostic indicators for breast cancer.

References:

  1. Besse, Arnaud, Wu, et al. The GABA Transaminase, ABAT, Is Essential for Mitochondrial Nucleoside Metabolism. Cell Metabolism, 2015, 21(3):417-427.
  2. Wegerer M, Adena S, Pfennig A, et al. Variants within the GABA transaminase (ABAT) gene region are associated with somatosensory evoked EEG potentials in families at high risk for affective disorders. Psychological Medicine, 2013, 43(6):1207-17.
  3. Budczies J, Brockmöller S F, Müller B M, et al. Comparative metabolomics of estrogen receptor positive and estrogen receptor negative breast cancer: alterations in glutamine and beta-alanine metabolism. Journal of Proteomics, 2013, 94(20):279-288.
  4. Jansen M P H M, Sas L, Sieuwerts A M, et al. Decreased expression of ABAT, and STC2, hallmarks ER-positive inflammatory breast cancer and endocrine therapy resistance in advanced disease. Molecular Oncology, 2015, 9(6):1218.
  5. Tian H, Wu JX, Shan FX, et al. Gamma-aminobutyric acid induces tumor cells apoptosis via GABABR1·β-arrestins·JNKs signaling module. Cell Biochemistry & Biophysics, 2015, 71(2):679-88.
  6. Wang H, Dai Y, Chen L, et al. Up-regulation of GABA-GABAAR signaling system in leukemic cells of childhood acute lymphocytic leukemia. 2014.