MetaCyc Pathway: 4-aminobutanoate degradation III
Inferred from experiment

Enzyme View:

Pathway diagram: 4-aminobutanoate degradation III

This view shows enzymes only for those organisms listed below, in the list of taxa known to possess the pathway. If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.

Synonyms: γ-amino-butyrate shunt, GABA degradation

Superclasses: Degradation/Utilization/AssimilationAmines and Polyamines Degradation4-Aminobutanoate Degradation

Some taxa known to possess this pathway include : Pseudomonas aeruginosa, Pseudomonas fluorescens, Ralstonia eutropha H16, Saccharomyces cerevisiae, Streptomyces griseus

Expected Taxonomic Range: Bacteria , Fungi

General Background

4-aminobutanoate (GABA) is the major inhibitory neurotransmitter in the mammalian brain. Recent findings suggest that GABA has a role as a signal molecule in plants as well [Bouche04]. In animals and plants GABA is produced by the cytosolic enzyme glutamate decarboxylase.

The most common path for GABA degradation involves transamination to succinate semialdehyde, followed by oxidation to succinate. Diiferent variants of both enzymes are known. The amino-group acceptor for the transamination can be either 2-oxoglutarate (e.g. in mammalian brain [Bessman53]) or pyruvate (e.g. in the plant Arabidopsis thaliana ler [Van02]). Different variants of the second enzyme, succinate semialdehyde dehydrogenase, were shown to possess different cofactor requirement, for either NAD+, NADP+, or NAD(P)+.

The action of glutamate decarboxylase, γ-aminobutyrate aminotransferase and succinate semialdehyde dehydrogenase, combined, defines a short pathway known as the "GABA shunt", since it can channel glutamate into the TCA cycle I (prokaryotic), bypassing two steps of that cycle.

While there is no evidence for a special role for GABA in bacteria, the capabillity to degrade it exists in many strains. GABA is present in the environment as a product of plant and animal tissue decay, and many bacteria can synthesize GABA as an intermediate in the degradation of putrescine (see putrescine degradation). The first indication for a bacterial pathway for GABA degradation was found in Pseudomonas fluorescens [Scott59, Jakoby59]. While some organisms, like Pseudomonas fluorescens, can grow on GABA as the sole carbon and nitrogen source, others, such as Bacillus subtilis, can grow on it only as a nitrogen source [Ferson96, Belitsky02].

About This Pathway

This variant of the pathway includes a 2-oxoglutarate-dependent 4-aminobutyrate transaminase and an NAD(P)+-dependent dehydrogenase. This combination of enzymes has been documented in the bacterium Ralstonia eutropha H16 [Mayer09] and in Baker's yeast Saccharomyces cerevisiae [Ramos85]. Another study of Cupriavidus necator (Ralstonia eutropha) showed that the bacterium posseses two different dehydrogenases - an NAD(P)-specific one, and an NADP-specific one [LutkeEversloh99].

In Saccharomyces cerevisiae GABA plays an important role in nitrogen utilization and oxidative stress tolerance [Coleman01, Ramos85]. GABA accumulates in Saccharomyces cerevisiae either through permease-mediated uptake (by Uga4p, Put4p, and Gap1p), or by intracellular production via L-glutamate degradation, catalyzed by the glutamate decarboxylase Gad1p [Coleman01, Ramos85] (see L-glutamate degradation IX (via 4-aminobutanoate)).

The presence of GABA causes an increase in expression of the genes UGA1 and UGA2, which encode the enzymes responsible for degrading GABA into succinate [Ramos85]. This GABA-induced upregulation is mediated by the transcriptional activators Uga3p and Uga35p/Dal81p [Vissers89]. These transcription factors bind to upstream activation sites in the promoters of GABA-regulated genes known as the UAS-GABA [Idicula02, Vissers89]. The level of UGA2 transcript is also upregulated under conditions of oxidative stress [Coleman01]. Saccharomyces cerevisiae cells in which GABA degradation is blocked are more sensitive to oxidative stress and can no longer grow on GABA as their sole nitrogen source [Coleman01, Ramos85].

An alternative route for GABA catabolism in Saccharomyces cerevisiae has been proposed [Bach09]. that pathway involves the reduction of succinate-semialdehyde into 4-hydroxybutanoate and its polymerization to form poly-(3-hydroxybutyric acid-co-4-hydroxybutyric acid).

Variants: 4-aminobutanoate degradation I, 4-aminobutanoate degradation II, 4-aminobutanoate degradation IV, 4-aminobutanoate degradation V, GABA shunt, superpathway of 4-aminobutanoate degradation

Created 23-Jun-2010 by Caspi R, SRI International


Bach09: Bach B, Meudec E, Lepoutre JP, Rossignol T, Blondin B, Dequin S, Camarasa C (2009). "New insights into {gamma}-aminobutyric acid catabolism: Evidence for {gamma}-hydroxybutyric acid and polyhydroxybutyrate synthesis in Saccharomyces cerevisiae." Appl Environ Microbiol 75(13);4231-9. PMID: 19411412

Belitsky02: Belitsky BR, Sonenshein AL (2002). "GabR, a member of a novel protein family, regulates the utilization of gamma-aminobutyrate in Bacillus subtilis." Mol Microbiol 45(2);569-83. PMID: 12123465

Bessman53: Bessman SP, Rossen J, Layne EC (1953). "Gamma-Aminobutyric acid-glutamic acid transamination in brain." J Biol Chem 201(1);385-91. PMID: 13044808

Bouche04: Bouche N, Fromm H (2004). "GABA in plants: just a metabolite?." Trends Plant Sci 9(3);110-5. PMID: 15003233

Coleman01: Coleman ST, Fang TK, Rovinsky SA, Turano FJ, Moye-Rowley WS (2001). "Expression of a glutamate decarboxylase homologue is required for normal oxidative stress tolerance in Saccharomyces cerevisiae." J Biol Chem 276(1);244-50. PMID: 11031268

Dover72: Dover S, Halpern YS (1972). "Utilization of -aminobutyric acid as the sole carbon and nitrogen source by Escherichia coli K-12 mutants." J Bacteriol 1972;109(2);835-43. PMID: 4550821

Ferson96: Ferson AE, Wray LV, Fisher SH (1996). "Expression of the Bacillus subtilis gabP gene is regulated independently in response to nitrogen and amino acid availability." Mol Microbiol 22(4);693-701. PMID: 8951816

Idicula02: Idicula AM, Blatch GL, Cooper TG, Dorrington RA (2002). "Binding and activation by the zinc cluster transcription factors of Saccharomyces cerevisiae. Redefining the UASGABA and its interaction with Uga3p." J Biol Chem 277(48);45977-83. PMID: 12235130

Jakoby59: Jakoby WB, Scott EM (1959). "Aldehyde oxidation. III. Succinic semialdehyde dehydrogenase." J Biol Chem 234(4);937-40. PMID: 13654295

LutkeEversloh99: Lutke-Eversloh T, Steinbuchel A (1999). "Biochemical and molecular characterization of a succinate semialdehyde dehydrogenase involved in the catabolism of 4-hydroxybutyric acid in Ralstonia eutropha." FEMS Microbiol Lett 181(1);63-71. PMID: 10564790

Mayer09: Mayer J, Cook AM (2009). "Homotaurine Metabolized to 3-Sulfopropanoate in Cupriavidus necator H16: Enzymes and Genes in a Patchwork Pathway." J Bacteriol. PMID: 19648235

Ramos85: Ramos F, el Guezzar M, Grenson M, Wiame JM (1985). "Mutations affecting the enzymes involved in the utilization of 4-aminobutyric acid as nitrogen source by the yeast Saccharomyces cerevisiae." Eur J Biochem 149(2);401-4. PMID: 3888627

Scott59: Scott EM, Jakoby WB (1959). "Soluble gamma-aminobutyric-glutamic transaminase from Pseudomonas fluorescens." J Biol Chem 234(4);932-6. PMID: 13654294

Van02: Van Cauwenberghe, Owen R., Makhmoudova, Amina, McLean, Michael D., Clark, Shawn M., Shelp, Barry J. "Plant Pyruvate-dependent gamma-aminobutyrate transaminase: identification of an Arabidopsis cDNA and its expression in Escherichia coli." Can J. Bot. (2002) 80: 933-941.

Vissers89: Vissers S, Andre B, Muyldermans F, Grenson M (1989). "Positive and negative regulatory elements control the expression of the UGA4 gene coding for the inducible 4-aminobutyric-acid-specific permease in Saccharomyces cerevisiae." Eur J Biochem 181(2);357-61. PMID: 2653828

Other References Related to Enzymes, Genes, Subpathways, and Substrates of this Pathway

Andersen07: Andersen G, Andersen B, Dobritzsch D, Schnackerz KD, Piskur J (2007). "A gene duplication led to specialized gamma-aminobutyrate and beta-alanine aminotransferase in yeast." FEBS J 274(7);1804-17. PMID: 17355287

Andre90: Andre B, Jauniaux JC (1990). "Nucleotide sequence of the yeast UGA1 gene encoding GABA transaminase." Nucleic Acids Res 18(10);3049. PMID: 2190186

Bartsch90: Bartsch K, Dichmann R, Schmitt P, Uhlmann E, Schulz A (1990). "Stereospecific production of the herbicide phosphinothricin (glufosinate) by transamination: cloning, characterization, and overexpression of the gene encoding a phosphinothricin-specific transaminase from Escherichia coli." Appl Environ Microbiol 1990;56(1);7-12. PMID: 2178553

Bartsch90a: Bartsch K, von Johnn-Marteville A, Schulz A (1990). "Molecular analysis of two genes of the Escherichia coli gab cluster: nucleotide sequence of the glutamate:succinic semialdehyde transaminase gene (gabT) and characterization of the succinic semialdehyde dehydrogenase gene (gabD)." J Bacteriol 1990;172(12);7035-42. PMID: 2254272

BRENDA14: BRENDA team (2014). Imported from BRENDA version existing on Aug 2014.

De95: De Biase D, Barra D, Simmaco M, John RA, Bossa F (1995). "Primary structure and tissue distribution of human 4-aminobutyrate aminotransferase." Eur J Biochem 227(1-2);476-80. PMID: 7851425

deBittencourt94: de Bittencourt PR, Mazer S, Marcourakis T, Bigarella MM, Ferreira ZS, Mumford JP (1994). "Vigabatrin: clinical evidence supporting rational polytherapy in management of uncontrolled seizures." Epilepsia 35(2);373-80. PMID: 8156960

Dover72a: Dover S, Halpern YS (1972). "Control of the pathway of -aminobutyrate breakdown in Escherichia coli K-12." J Bacteriol 110(1);165-70. PMID: 4552985

Feldmann94: Feldmann H, Aigle M, Aljinovic G, Andre B, Baclet MC, Barthe C, Baur A, Becam AM, Biteau N, Boles E (1994). "Complete DNA sequence of yeast chromosome II." EMBO J 13(24);5795-809. PMID: 7813418

Kurihara05: Kurihara S, Oda S, Kato K, Kim HG, Koyanagi T, Kumagai H, Suzuki H (2005). "A novel putrescine utilization pathway involves gamma-glutamylated intermediates of Escherichia coli K-12." J Biol Chem 280(6);4602-8. PMID: 15590624

Kurihara10: Kurihara S, Kato K, Asada K, Kumagai H, Suzuki H (2010). "A putrescine-inducible pathway comprising PuuE-YneI in which gamma-aminobutyrate is degraded into succinate in Escherichia coli K-12." J Bacteriol 192(18);4582-91. PMID: 20639325

Lal14: Lal PB, Schneider BL, Vu K, Reitzer L (2014). "The redundant aminotransferases in lysine and arginine synthesis and the extent of aminotransferase redundancy in Escherichia coli." Mol Microbiol 94(4);843-56. PMID: 25243376

Latendresse13: Latendresse M. (2013). "Computing Gibbs Free Energy of Compounds and Reactions in MetaCyc."

Liu05: Liu W, Peterson PE, Langston JA, Jin X, Zhou X, Fisher AJ, Toney MD (2005). "Kinetic and crystallographic analysis of active site mutants of Escherichia coli gamma-aminobutyrate aminotransferase." Biochemistry 44(8);2982-92. PMID: 15723541

Metzer79: Metzer E, Levitz R, Halpern YS (1979). "Isolation and properties of Escherichia coli K-12 mutants impaired in the utilization of gamma-aminobutyrate." J Bacteriol 137(3);1111-8. PMID: 374339

Metzer90: Metzer E, Halpern YS (1990). "In vivo cloning and characterization of the gabCTDP gene cluster of Escherichia coli K-12." J Bacteriol 172(6);3250-6. PMID: 2188954

Paulsen05: Paulsen IT, Press CM, Ravel J, Kobayashi DY, Myers GS, Mavrodi DV, DeBoy RT, Seshadri R, Ren Q, Madupu R, Dodson RJ, Durkin AS, Brinkac LM, Daugherty SC, Sullivan SA, Rosovitz MJ, Gwinn ML, Zhou L, Schneider DJ, Cartinhour SW, Nelson WC, Weidman J, Watkins K, Tran K, Khouri H, Pierson EA, Pierson LS, Thomashow LS, Loper JE (2005). "Complete genome sequence of the plant commensal Pseudomonas fluorescens Pf-5." Nat Biotechnol 23(7);873-8. PMID: 15980861

Schulz90: Schulz A, Taggeselle P, Tripier D, Bartsch K (1990). "Stereospecific production of the herbicide phosphinothricin (glufosinate) by transamination: isolation and characterization of a phosphinothricin-specific transaminase from Escherichia coli." Appl Environ Microbiol 1990;56(1);1-6. PMID: 2178550

Steward49: Steward, F.C., Thosmpson, J.F., Dent, C.E. (1949). "γ-aminobutyric acid: a constituent of the potato tuber?." Science 110 (2861):439-440.

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Please cite the following article in publications resulting from the use of MetaCyc: Caspi et al, Nucleic Acids Research 42:D459-D471 2014
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