Aminooxyacetic acid

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Aminooxyacetic acid
Aminooxyacetic Acid.svg
Names
Preferred IUPAC name
(Aminooxy)acetic acid
Other names
Carboxymethoxylamine
Hydroxylamineacetic acid
U-7524
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
DrugBank
MeSH Aminooxyacetic+Acid
PubChem CID
UNII
  • InChI=1S/C2H5NO3/c3-6-1-2(4)5/h1,3H2,(H,4,5) Yes check.svgY
    Key: NQRKYASMKDDGHT-UHFFFAOYSA-N Yes check.svgY
  • InChI=1/C2H5NO3/c3-6-1-2(4)5/h1,3H2,(H,4,5)
    Key: NQRKYASMKDDGHT-UHFFFAOYAB
  • O=C(O)CON
  • NOCC(O)=O
Properties
C2H5NO3
Molar mass 91.066
Density 1.375 g/cm3
Melting point 138 °C (280 °F; 411 K)
Boiling point 326.7 °C (620.1 °F; 599.8 K)
Hazards
Flash point 151 °C (304 °F; 424 K)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
X mark.svgN (what is  Yes check.svgYX mark.svgN ?)

Aminooxyacetic acid, often abbreviated AOA or AOAA, is a compound that inhibits 4-aminobutyrate aminotransferase (GABA-T) activity in vitro and in vivo , leading to less gamma-aminobutyric acid (GABA) being broken down. [1] Subsequently, the level of GABA is increased in tissues. At concentrations high enough to fully inhibit 4-aminobutyrate aminotransferase activity, aminooxyacetic acid is indicated as a useful tool to study regional GABA turnover in rats. [2]

Aminooxyacetic acid is a general inhibitor of pyridoxal phosphate (PLP)-dependent enzymes (this includes GABA-T). [3] It functions as an inhibitor by attacking the Schiff base linkage between PLP and the enzyme, forming oxime type complexes. [3]

Aminooxyacetic acid inhibits aspartate aminotransferase, another PLP-dependent enzyme, which is an essential part of the malate-aspartate shuttle. [4] The inhibition of the malate-aspartate shuttle prevents the reoxidation of cytosolic NADH by the mitochondria in nerve terminals. [4] Also in the nerve terminals, aminooxyacetic acid prevents the mitochondria from utilizing pyruvate generated from glycolysis, thus leading to a bioenergetic state similar to that of hypoglycemia. [4] Aminooxyacetic acid has been shown to cause excitotoxic lesions of the striatum, similar to Huntington's disease, potentially due to its impairment of mitochondrial energy metabolism. [5] Aminooxyacetic acid was previously used in a clinical trial to reduce symptoms of Huntington's disease by increasing GABA levels in the brain. [6] However, the patients who received the aminooxyacetic acid treatment failed to show clinical improvement and suffered from side effects such as drowsiness, ataxia, seizures, and psychosis when the dosage was increased beyond 2 mg per kilogram per day. [6] Also, the inhibition of aspartate aminotransferase by aminooxyacetic acid has clinical implications for the treatment of breast cancer, since a decrease in glycolysis disrupts breast adenocarcinoma cells more than normal cells. [7]

Moreover, selective inhibition of aspartate aminotransferase with aminooxyacetic acid ameliorated experimental autoimmune encephalomyelitis in a therapeutic mouse model by reprograming the differentiation of pro-inflammatory T helper 17 cells, that boost the immune system, towards induced anti-inflammatory regulatory T cells. [8]

Aminooxyacetic acid has been studied as a treatment for tinnitus. [9] [10] [11] One study showed that about 20% of patients with tinnitus had a decrease in its severity when treated with aminooxyacetic acid. [11] However, about 70% of those patients reported side effects, mostly nausea and disequilibrium. [11] Thus, the investigators of the study concluded that the incidence of the side effects makes aminooxyacetic acid unsuitable to treat tinnitus. [11]

Aminooxyacetic acid also has anticonvulsant properties. [12] At high dosages, it can act as a convulsant agent in mice and rats. [13]

Aminooxyacetic acid can also inhibit 1-aminocyclopropane-1-carboxylate synthase preventing ethylene synthesis, which can increase the vase life of cut flowers. [14]

History

Aminooxyacetic acid was first described by Werner in 1893, and was prepared by the hydrolysis of ethylbenzhydroximinoacetic acid. [15] [16] [17] [18] In 1936, Anchel and Shoenheimer used aminooxyacetic acid to isolate ketones from natural sources. [17] Also in 1936, Kitagawa and Takani described the preparation of aminooxyacetic acid by the condensation of benzhydroxamic acid and ethyl bromoacetate, followed by hydrolysis by hydrochloric acid. [19]

Related Research Articles

γ-Aminobutyric acid Main inhibitory neurotransmitter in the mammalian brain

γ-Aminobutyric acid, or GABA, is the chief inhibitory neurotransmitter in the developmentally mature mammalian central nervous system. Its principal role is reducing neuronal excitability throughout the nervous system.

<span class="mw-page-title-main">Pyridoxal phosphate</span> Active form of vitamin B6

Pyridoxal phosphate (PLP, pyridoxal 5'-phosphate, P5P), the active form of vitamin B6, is a coenzyme in a variety of enzymatic reactions. The International Union of Biochemistry and Molecular Biology has catalogued more than 140 PLP-dependent activities, corresponding to ~4% of all classified activities. The versatility of PLP arises from its ability to covalently bind the substrate, and then to act as an electrophilic catalyst, thereby stabilizing different types of carbanionic reaction intermediates.

<span class="mw-page-title-main">Aspartate transaminase</span> Enzyme involved in amino acid metabolism

Aspartate transaminase (AST) or aspartate aminotransferase, also known as AspAT/ASAT/AAT or (serum) glutamic oxaloacetic transaminase, is a pyridoxal phosphate (PLP)-dependent transaminase enzyme that was first described by Arthur Karmen and colleagues in 1954. AST catalyzes the reversible transfer of an α-amino group between aspartate and glutamate and, as such, is an important enzyme in amino acid metabolism. AST is found in the liver, heart, skeletal muscle, kidneys, brain, red blood cells and gall bladder. Serum AST level, serum ALT level, and their ratio are commonly measured clinically as biomarkers for liver health. The tests are part of blood panels.

<span class="mw-page-title-main">Malate dehydrogenase</span> Class of enzymes

Malate dehydrogenase (EC 1.1.1.37) (MDH) is an enzyme that reversibly catalyzes the oxidation of malate to oxaloacetate using the reduction of NAD+ to NADH. This reaction is part of many metabolic pathways, including the citric acid cycle. Other malate dehydrogenases, which have other EC numbers and catalyze other reactions oxidizing malate, have qualified names like malate dehydrogenase (NADP+).

<span class="mw-page-title-main">Glutamate decarboxylase</span> Enzyme

Glutamate decarboxylase or glutamic acid decarboxylase (GAD) is an enzyme that catalyzes the decarboxylation of glutamate to gamma-aminobutyric acid (GABA) and carbon dioxide. GAD uses pyridoxal-phosphate (PLP) as a cofactor. The reaction proceeds as follows:

The GABAA-rho receptor is a subclass of GABAA receptors composed entirely of rho (ρ) subunits. GABAA receptors including those of the ρ-subclass are ligand-gated ion channels responsible for mediating the effects of gamma-amino butyric acid (GABA), the major inhibitory neurotransmitter in the brain. The GABAA-ρ receptor, like other GABAA receptors, is expressed in many areas of the brain, but in contrast to other GABAA receptors, the GABAA-ρ receptor has especially high expression in the retina.

<span class="mw-page-title-main">Malate–aspartate shuttle</span> Biochemical system for transporting electrons produced during glycolysis

The malate–aspartate shuttle is a biochemical system for translocating electrons produced during glycolysis across the semipermeable inner membrane of the mitochondrion for oxidative phosphorylation in eukaryotes. These electrons enter the electron transport chain of the mitochondria via reduction equivalents to generate ATP. The shuttle system is required because the mitochondrial inner membrane is impermeable to NADH, the primary reducing equivalent of the electron transport chain. To circumvent this, malate carries the reducing equivalents across the membrane.

<i>N</i>-Acetylaspartylglutamic acid Peptide neurotransmitter

N-Acetylaspartylglutamic acid is a peptide neurotransmitter and the third-most-prevalent neurotransmitter in the mammalian nervous system. NAAG consists of N-acetylaspartic acid (NAA) and glutamic acid coupled via a peptide bond.

<span class="mw-page-title-main">Branched-chain amino acid aminotransferase</span> Aminotransferase enzyme

Branched-chain amino acid aminotransferase (BCAT), also known as branched-chain amino acid transaminase, is an aminotransferase enzyme (EC 2.6.1.42) which acts upon branched-chain amino acids (BCAAs). It is encoded by the BCAT2 gene in humans. The BCAT enzyme catalyzes the conversion of BCAAs and α-ketoglutarate into branched chain α-keto acids and glutamate.

<span class="mw-page-title-main">4-aminobutyrate transaminase</span> Class of enzymes

In enzymology, 4-aminobutyrate transaminase, also called GABA transaminase or 4-aminobutyrate aminotransferase, or GABA-T, is an enzyme that catalyzes the chemical reaction:

<span class="mw-page-title-main">GOT2</span> Mitochondrial enzyme involved in amino acid metabolism

Aspartate aminotransferase, mitochondrial is an enzyme that in humans is encoded by the GOT2 gene. Glutamic-oxaloacetic transaminase is a pyridoxal phosphate-dependent enzyme which exists in cytoplasmic and inner-membrane mitochondrial forms, GOT1 and GOT2, respectively. GOT plays a role in amino acid metabolism and the urea and Kreb's cycle. Also, GOT2 is a major participant in the malate-aspartate shuttle, which is a passage from the cytosol to the mitochondria. The two enzymes are homodimeric and show close homology. GOT2 has been seen to have a role in cell proliferation, especially in terms of tumor growth.

Glutaminolysis (glutamine + -lysis) is a series of biochemical reactions by which the amino acid glutamine is lysed to glutamate, aspartate, CO2, pyruvate, lactate, alanine and citrate.

<span class="mw-page-title-main">Malate dehydrogenase 2</span> Enzyme that oxidizes malate to oxaloacetate in Krebs cycle

Malate dehydrogenase, mitochondrial also known as malate dehydrogenase 2 is an enzyme that in humans is encoded by the MDH2 gene.

<span class="mw-page-title-main">Reuptake inhibitor</span> Type of drug

A reuptake inhibitor (RI) is a type of drug known as a reuptake modulator that inhibits the plasmalemmal transporter-mediated reuptake of a neurotransmitter from the synapse into the pre-synaptic neuron. This leads to an increase in extracellular concentrations of the neurotransmitter and an increase in neurotransmission. Various drugs exert their psychological and physiological effects through reuptake inhibition, including many antidepressants and psychostimulants.

<span class="mw-page-title-main">Gabaculine</span> Chemical compound

Gabaculine is a naturally occurring neurotoxin first isolated from the bacteria Streptomyces toyacaensis, which acts as a potent and irreversible GABA transaminase inhibitor, and also a GABA reuptake inhibitor. Gabaculine is also known as 3-amino-2,3-dihydrobenzoic acid hydrochloride and 5-amino cyclohexa-1,3 dienyl carboxylic acid. Gabaculine increased GABA levels in the brain and had an effect on convulsivity in mice.

<span class="mw-page-title-main">GABA reuptake inhibitor</span> Drug class

A GABA reuptake inhibitor (GRI) is a type of drug which acts as a reuptake inhibitor for the neurotransmitter gamma-Aminobutyric acid (GABA) by blocking the action of the gamma-Aminobutyric acid transporters (GATs). This in turn leads to increased extracellular concentrations of GABA and therefore an increase in GABAergic neurotransmission.

<span class="mw-page-title-main">Cartazolate</span> Chemical compound

Cartazolate (SQ-65,396) is a drug of the pyrazolopyridine class. It acts as a GABAA receptor positive allosteric modulator at the barbiturate binding site of the complex and has anxiolytic effects in animals. It is also known to act as an adenosine antagonist at the A1 and A2 subtypes and as a phosphodiesterase inhibitor. Cartazolate was tested in human clinical trials and was found to be efficacious for anxiety but was never marketed. It was developed by a team at E.R. Squibb and Sons in the 1970s.

4-aminobutyrate---pyruvate transaminase is an enzyme with systematic name 4-aminobutanoate:pyruvate aminotransferase. This enzyme is a type of GABA transaminase, which degrades the neurotransmitter GABA. The enzyme catalyses the following chemical reaction

<span class="mw-page-title-main">ABAT</span> Protein-coding gene in the species Homo sapiens

4-Aminobutyrate aminotransferase is a protein that in humans is encoded by the ABAT gene. This gene is located in chromosome 16 at position of 13.2. This gene goes by a number of names, including, GABA transaminase, GABAT, 4-aminobutyrate transaminase, NPD009 etc. This gene is mainly and abundant located in neuronal tissues. 4-Aminobutyrate aminotransferase belongs to group of pyridoxal 5-phosphate-dependent enzyme which activates a large portion giving reaction to amino acids. ABAT is made up of two monomers of enzymes where each subunit has a molecular weight of 50kDa. It is identified that almost tierce of human synapses have GABA. GABA is a neurotransmitter that has different roles in different regions of the central and peripheral nervous systems. It can be found also in some tissues that do not have neurons. In addition, GAD and GABA-AT are responsible in regulating the concentration of GABA.

Fernando Garcia de Mello is a renowned neurochemist from Brazil. He obtained his degree in Biochemistry in 1968 from the State University of Rio de Janeiro. Fernando Mello started his scientific training as an undergraduate student at the Brazilian National Institute of Cancer, and later at the Institute of Biophysics from the Federal University of Rio de Janeiro, being mentored by dr. Firmino de Castro, which greatly influenced him to have a more humanistic approach towards the students that he would train. It was only during his post-doc period (1973-1976) at the National Institutes of Health under supervision of dr. Marshall Warren Nirenberg that Mello began his research in Neurochemistry, using the embryonary Retina as a model for his investigations.

References

  1. ↑ Wallach, D. (1961). "Studies on the GABA pathway. I. The inhibition of gamma-aminobutyric acid-alpha-ketoglutaric acid transaminase in vitro and in vivo by U-7524 (amino-oxyacetic acid)". Biochemical Pharmacology. 5 (4): 323–331. doi:10.1016/0006-2952(61)90023-5. PMID   13782815.
  2. ↑ Wolfgang Löscher; Dagmar Hönack; Martina Gramer (1989). "Use of Inhibitors of γ-Aminobutyric Acid (GABA) Transaminase for the Estimation of GABA Turnover in Various Brain Regions of Rats: A Reevaluation of Aminooxyacetic Acid". Journal of Neurochemistry. 53 (6): 1737–1750. doi:10.1111/j.1471-4159.1989.tb09239.x. PMID   2809589. S2CID   39248295.
  3. 1 2 Beeler, T.; Churchich, J. (1976). "Reactivity of the phosphopyridoxal groups of cystathionase". Journal of Biological Chemistry. 251 (17): 5267–5271. doi: 10.1016/S0021-9258(17)33156-3 . PMID   8458.
  4. 1 2 3 Risto A. Kauppinen; Talvinder S. Sihra; David G. Nicholls (1987). "Aminooxyacetic acid inhibits the malate-aspartate shuttle in isolated nerve terminals and prevents the mitochondria from utilizing glycolytic substrates". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 930 (2): 173–178. doi:10.1016/0167-4889(87)90029-2. PMID   3620514.
  5. ↑ Beal, M.; Swartz, K.; Hyman, B.; Storey, E.; Finn, S.; Koroshetz, W. (1991). "Aminooxyacetic acid results in excitotoxin lesions by a novel indirect mechanism". Journal of Neurochemistry. 57 (3): 1068–1073. doi:10.1111/j.1471-4159.1991.tb08258.x. PMID   1830613. S2CID   27982816.
  6. 1 2 Perry, T.; Wright, J.; Hansen, S.; Allan, B.; Baird, P.; MacLeod, P. (1980). "Failure of aminooxyacetic acid therapy in Huntington disease". Neurology. 30 (7 Pt 1): 772–775. doi:10.1212/wnl.30.7.772. PMID   6446691. S2CID   10190223.
  7. ↑ Thornburg, J. M.; Nelson, K. K.; Clem, B. F.; Lane, A. N.; Arumugam, S.; Simmons, A.; Eaton, J. W.; Telang, S.; Chesney, J. (2008). "Targeting aspartate aminotransferase in breast cancer". Breast Cancer Research. 10 (5): R84. doi: 10.1186/bcr2154 . PMC   2614520 . PMID   18922152.
  8. ↑ Xu, T.; Kelly, M.; et al. (2017). "Metabolic control of TH17 and induced Treg cell balance by an epigenetic mechanism". Nature. 548 (7666): 228–233. Bibcode:2017Natur.548..228X. doi:10.1038/nature23475. PMC   6701955 . PMID   28783731.
  9. ↑ Reed, H.; Meltzer, J.; Crews, P.; Norris, C.; Quine, D.; Guth, P. (1985). "Amino-oxyacetic acid as a palliative in tinnitus". Archives of Otolaryngology. 111 (12): 803–805. doi:10.1001/archotol.1985.00800140047008. PMID   2415097.
  10. ↑ Blair, P.; Reed, H. (1986). "Amino-oxyacetic acid: A new drug for the treatment of tinnitus". Journal of the Louisiana State Medical Society. 138 (6): 17–19. PMID   3734755.
  11. 1 2 3 4 Guth, P.; Risey, J.; Briner, W.; Blair, P.; Reed, H.; Bryant, G.; Norris, C.; Housley, G.; Miller, R. (1990). "Evaluation of amino-oxyacetic acid as a palliative in tinnitus". The Annals of Otology, Rhinology, and Laryngology. 99 (1): 74–79. doi:10.1177/000348949009900113. PMID   1688487. S2CID   7789128.
  12. ↑ Davanzo, J.; Greig, M.; Cronin, M. (1961). "Anticonvulsant properties of amino-oxyacetic acid". American Journal of Physiology. 201 (5): 833–837. doi:10.1152/ajplegacy.1961.201.5.833. PMID   13883717.
  13. ↑ Wood, J.; Peesker, S. (1973). "The role of GABA metabolism in the convulsant and anticonvulsant actions of aminooxyacetic acid". Journal of Neurochemistry. 20 (2): 379–387. doi:10.1111/j.1471-4159.1973.tb12137.x. PMID   4698285. S2CID   45193391.
  14. ↑ Broun, R.; Mayak, S. (1981). "Aminooxyacetic acid as an inhibitor of ethylenesynthesis and senescence in carnation flowers". Scientia Horticulturae. 15 (3): 277–282. doi:10.1016/0304-4238(81)90038-8.
  15. ↑ Werner, A. (1893). "Ueber Hydroxylaminessigsäure und Derivate derselben". Berichte der deutschen chemischen Gesellschaft . 26 (2): 1567–1571. doi:10.1002/cber.18930260274.
  16. ↑ Werner, A.; Sonnenfeld, E. (1894). "Ueber Hydroxylaminessigsäure und α-Hydroxylaminpropionsäure". Berichte der Deutschen Chemischen Gesellschaft. 27 (3): 3350–3354. doi:10.1002/cber.189402703141.
  17. 1 2 Anchel, Marjorie; Schoenheimer, Rudolf (1936). "Reagents for the isolation of carbonyl compounds from unsaponifiable material" (PDF). Journal of Biological Chemistry. 114 (2): 539–546. doi: 10.1016/S0021-9258(18)74826-6 . Retrieved 2011-05-20.
  18. ↑ Borek, E.; Clarke, H. T. (1936). "Carboxymethoxylamine". Journal of the American Chemical Society. 58 (10): 2020–2021. doi:10.1021/ja01301a058.
  19. ↑ Kitagawa, Matsunosuke; Takani, A. (1936). "Studies on a Diamino Acid, Canavanin, IV. The Constitution of Canavanin and Canalin". Journal of Biochemistry. 23: 181–185. doi:10.1093/oxfordjournals.jbchem.a125537.
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