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
excitotoxiclesions 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]
Aminooxyacetic acid has been studied as a treatment for
tinnitus.[8][9][10] One study showed that about 20% of patients with tinnitus had a decrease in its severity when treated with aminooxyacetic acid.[10] However, about 70% of those patients reported side effects, mostly
nausea and
disequilibrium.[10] Thus, the investigators of the study concluded that the incidence of the side effects makes aminooxyacetic acid unsuitable to treat tinnitus.[10]
Aminooxyacetic acid also has
anticonvulsant properties.[11] At high dosages, it can act as a
convulsant agent in mice and rats.[12]
Aminooxyacetic acid was first described by
Werner in 1893, and was prepared by the hydrolysis of ethylbenzhydroximinoacetic acid.[14][15][16][17] In 1936, Anchel and
Shoenheimer used aminooxyacetic acid to isolate
ketones from natural sources.[16] 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.[18]
References
^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.
PMID13782815.
^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.
PMID2809589.
S2CID39248295.
^
abcRisto 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.
PMID3620514.
^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.
PMID1830613.
S2CID27982816.
^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.
PMID2415097.
^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.
PMID3734755.
^
abcdGuth, 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.
PMID1688487.
S2CID7789128.
^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.
PMID13883717.
^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.
^Borek, E.; Clarke, H. T. (1936). "Carboxymethoxylamine". Journal of the American Chemical Society. 58 (10): 2020–2021.
doi:
10.1021/ja01301a058.
^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.