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Pathway Description
GABA-Transaminase Deficiency
Rattus norvegicus
Category:
Metabolite Pathway
Sub-Category:
Disease
Created: 2018-09-10
Last Updated: 2019-09-15
GABA-transaminase deficiency, also known as gamma-amino butyric acid transaminase (GABA-T) deficiency, is an extremely rare autosomal recessive inborn error of metabolism (IEM) that is caused by a defect in the ABAT gene, which codes for 4-aminobutyrate (GABA) aminotransferase. This enzyme is present in several tissues in addition to brain and is most active in liver, and it catalyzes the conversion of GABA and 2-oxoglutarate into succinic semialdehyde and L-glutamate, and when it is deficient, GABA levels in the body, specifically the cerebrospinal fluid, are elevated. GABA is a neurotransmitter found in the nervous system that inhibits neurons from firing, and also affects the development of the brain, as well as regulating muscle tone. GABA-T can also convert beta-alanine and oxoglutaric acid to L-glutamic acid and malonic semialdehyde as part of the beta-alanine metabolism pathway, and when it is mutated, leads to an accumulation of beta-alanine within the cell. GABA-T deficiency is characterized by an increase of GABA levels in the cerebrospinal fluid. Symptoms of this disorder include low muscle tone and psychomotor retardation, as well as potential epilepsy and excessive sleeping. Treatment with Flumanezil, sold as Anexate, Lanexat, Mazicon or Romazicon, a GABA-A antagonist, has been tested and may be beneficial in some cases, and potentially more effective if started at a young age. It is estimated that GABA-T deficiency affects less than 1 in 1,000,000 individuals, as only five cases have been reported in literature as of 2017.
References
GABA-Transaminase Deficiency References
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beta-Alanine Metabolism References
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Pubmed: 16641100
Wyborski RJ, Bond RW, Gottlieb DI: Characterization of a cDNA coding for rat glutamic acid decarboxylase. Brain Res Mol Brain Res. 1990 Aug;8(3):193-8. doi: 10.1016/0169-328x(90)90016-7.
Pubmed: 2170798
Julien JF, Samama P, Mallet J: Rat brain glutamic acid decarboxylase sequence deduced from a cloned cDNA. J Neurochem. 1990 Feb;54(2):703-5. doi: 10.1111/j.1471-4159.1990.tb01928.x.
Pubmed: 2299361
Michelsen BK, Petersen JS, Boel E, Moldrup A, Dyrberg T, Madsen OD: Cloning, characterization, and autoimmune recognition of rat islet glutamic acid decarboxylase in insulin-dependent diabetes mellitus. Proc Natl Acad Sci U S A. 1991 Oct 1;88(19):8754-8. doi: 10.1073/pnas.88.19.8754.
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Kvalnes-Krick KL, Traut TW: Cloning, sequencing, and expression of a cDNA encoding beta-alanine synthase from rat liver. J Biol Chem. 1993 Mar 15;268(8):5686-93.
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Pubmed: 1536562
Matsuda K, Sakata S, Kaneko M, Hamajima N, Nonaka M, Sasaki M, Tamaki N: Molecular cloning and sequencing of a cDNA encoding dihydropyrimidinase from the rat liver. Biochim Biophys Acta. 1996 Jun 7;1307(2):140-4. doi: 10.1016/0167-4781(96)00056-5.
Pubmed: 8679696
Kimura M, Sakata SF, Matoba Y, Matsuda K, Kontani Y, Kaneko M, Tamaki N: Cloning of rat dihydropyrimidine dehydrogenase and correlation of its mRNA increase in the rat liver with age. J Nutr Sci Vitaminol (Tokyo). 1998 Aug;44(4):537-46.
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Medina-Kauwe LK, Tillakaratne NJ, Wu JY, Tobin AJ: A rat brain cDNA encodes enzymatically active GABA transaminase and provides a molecular probe for GABA-catabolizing cells. J Neurochem. 1994 Apr;62(4):1267-75. doi: 10.1046/j.1471-4159.1994.62041267.x.
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Kontani Y, Sakata SF, Matsuda K, Ohyama T, Sano K, Tamaki N: The mature size of rat 4-aminobutyrate aminotransferase is different in liver and brain. Eur J Biochem. 1999 Aug;264(1):218-22. doi: 10.1046/j.1432-1327.1999.00612.x.
Pubmed: 10447691
Tamaki N, Sakata SF, Matsuda K: Purification, properties, and sequencing of aminoisobutyrate aminotransferases from rat liver. Methods Enzymol. 2000;324:376-89. doi: 10.1016/s0076-6879(00)24247-x.
Pubmed: 10989446
Kedishvili NY, Popov KM, Rougraff PM, Zhao Y, Crabb DW, Harris RA: CoA-dependent methylmalonate-semialdehyde dehydrogenase, a unique member of the aldehyde dehydrogenase superfamily. cDNA cloning, evolutionary relationships, and tissue distribution. J Biol Chem. 1992 Sep 25;267(27):19724-9.
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Goodwin GW, Rougraff PM, Davis EJ, Harris RA: Purification and characterization of methylmalonate-semialdehyde dehydrogenase from rat liver. Identity to malonate-semialdehyde dehydrogenase. J Biol Chem. 1989 Sep 5;264(25):14965-71.
Pubmed: 2768248
Kedishvili NY, Popov KM, Harris RA: The effect of ligand binding on the proteolytic pattern of methylmalonate semialdehyde dehydrogenase. Arch Biochem Biophys. 1991 Oct;290(1):21-6. doi: 10.1016/0003-9861(91)90586-8.
Pubmed: 1898092
Farres J, Guan KL, Weiner H: Primary structures of rat and bovine liver mitochondrial aldehyde dehydrogenases deduced from cDNA sequences. Eur J Biochem. 1989 Mar 1;180(1):67-74. doi: 10.1111/j.1432-1033.1989.tb14616.x.
Pubmed: 2540003
Farres J, Guan KL, Weiner H: Sequence of the signal peptide for rat liver mitochondrial aldehyde dehydrogenase. Biochem Biophys Res Commun. 1988 Feb 15;150(3):1083-7. doi: 10.1016/0006-291x(88)90740-1.
Pubmed: 3342060
Ochiai Y, Itoh K, Sakurai E, Tanaka Y: Molecular cloning and characterization of rat semicarbazide-sensitive amine oxidase. Biol Pharm Bull. 2005 Mar;28(3):413-8. doi: 10.1248/bpb.28.413.
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Morris NJ, Ducret A, Aebersold R, Ross SA, Keller SR, Lienhard GE: Membrane amine oxidase cloning and identification as a major protein in the adipocyte plasma membrane. J Biol Chem. 1997 Apr 4;272(14):9388-92. doi: 10.1074/jbc.272.14.9388.
Pubmed: 9083076
This pathway was propagated using PathWhiz -
Pon, A. et al. Pathways with PathWhiz (2015) Nucleic Acids Res. 43(Web Server issue): W552–W559.
Propagated from SMP0000351
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