Aminooxyacetic acid, often abbreviated AOA or AOAA, is a compound that inhibits

4-aminobutyrate aminotransferase In enzymology, 4-aminobutyrate transaminase (), also called GABA transaminase or 4-aminobutyrate aminotransferase, or GABA-T, is an enzyme that catalyzes the chemical reaction: :4-aminobutanoate + 2-oxoglutarate \rightleftharpoons succinate semi ...

(GABA-T) activity ''

in vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology an ...

'' and ''

in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...

'', leading to less gamma-aminobutyric acid (GABA) being broken down. 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 Rats are various medium-sized, long-tailed rodents. Species of rats are found throughout the order Rodentia, but stereotypical rats are found in the genus ''Rattus''. Other rat genera include ''Neotoma'' (pack rats), ''Bandicota'' (bandicoot ...

. Aminooxyacetic acid is a general inhibitor of

pyridoxal phosphate 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 ac ...

(PLP)-dependent

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...

s (this includes GABA-T). It functions as an inhibitor by attacking the Schiff base linkage between PLP and the enzyme, forming oxime type complexes. Aminooxyacetic acid inhibits aspartate aminotransferase, another PLP-dependent enzyme, which is an essential part of the

malate-aspartate shuttle The malate-aspartate shuttle (sometimes simply the malate shuttle) is a biochemical system for translocating electrons produced during glycolysis across the semipermeable inner membrane of the mitochondrion for oxidative phosphorylation in eukaryo ...

. The inhibition of the malate-aspartate shuttle prevents the reoxidation of cytosolic NADH by the

mitochondria A mitochondrion (; ) is an organelle found in the Cell (biology), cells of most Eukaryotes, such as animals, plants and Fungus, fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosi ...

in nerve terminals. Also in the nerve terminals, aminooxyacetic acid prevents the mitochondria from utilizing

pyruvate Pyruvic acid (CH3COCOOH) is the simplest of the alpha-keto acids, with a carboxylic acid and a ketone functional group. Pyruvate, the conjugate base, CH3COCOO−, is an intermediate in several metabolic pathways throughout the cell. Pyruvic aci ...

generated from

glycolysis Glycolysis is the metabolic pathway that converts glucose () into pyruvate (). The free energy released in this process is used to form the high-energy molecules adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide (NADH ...

, thus leading to a bioenergetic state similar to that of

hypoglycemia Hypoglycemia, also called low blood sugar, is a fall in blood sugar to levels below normal, typically below 70 mg/dL (3.9 mmol/L). Whipple's triad is used to properly identify hypoglycemic episodes. It is defined as blood glucose belo ...

. Aminooxyacetic acid has been shown to cause excitotoxic

lesion A lesion is any damage or abnormal change in the tissue of an organism, usually caused by disease or trauma. ''Lesion'' is derived from the Latin "injury". Lesions may occur in plants as well as animals. Types There is no designated classifi ...

s of the

striatum The striatum, or corpus striatum (also called the striate nucleus), is a nucleus (a cluster of neurons) in the subcortical basal ganglia of the forebrain. The striatum is a critical component of the motor and reward systems; receives glutamate ...

, similar to

Huntington's disease Huntington's disease (HD), also known as Huntington's chorea, is a neurodegenerative disease that is mostly inherited. The earliest symptoms are often subtle problems with mood or mental abilities. A general lack of coordination and an unst ...

, potentially due to its impairment of mitochondrial energy metabolism. Aminooxyacetic acid was previously used in a clinical trial to reduce symptoms of Huntington's disease by increasing GABA levels in the brain. However, the patients who received the aminooxyacetic acid treatment failed to show clinical improvement and suffered from side effects such as drowsiness,

ataxia Ataxia is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in eye movements. Ataxia is a clinical manifestation indicating dysfunction of ...

seizure An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much of the body with los ...

s, and psychotic behavior when the dosage was increased beyond 2 mg per kilogram per day. Also, the inhibition of aspartate aminotransferase by aminooxyacetic acid has clinical implications for the treatment of

breast cancer Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or a re ...

, since a decrease in glycolysis disrupts breast

adenocarcinoma Adenocarcinoma (; plural adenocarcinomas or adenocarcinomata ) (AC) is a type of cancerous tumor that can occur in several parts of the body. It is defined as neoplasia of epithelial tissue that has glandular origin, glandular characteristics, or ...

cells more than normal cells. 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 cell T helper 17 cells (Th17) are a subset of pro-inflammatory T helper cells defined by their production of interleukin 17 (IL-17). They are related to T regulatory cells and the signals that cause Th17s to differentiate actually inhibit Treg different ...

s, that boost the immune system, towards induced anti-inflammatory regulatory T cells. Aminooxyacetic acid has been studied as a treatment for tinnitus. One study showed that about 20% of patients with tinnitus had a decrease in its severity when treated with aminooxyacetic acid. However, about 70% of those patients reported side effects, mostly

nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the ...

and disequilibrium. Thus, the investigators of the study concluded that the incidence of the side effects makes aminooxyacetic acid unsuitable to treat tinnitus. Aminooxyacetic acid also has

anticonvulsant Anticonvulsants (also known as antiepileptic drugs or recently as antiseizure drugs) are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of b ...

properties. At high dosages, it can act as a

convulsant A convulsant is a drug which induces convulsions and/or epileptic seizures, the opposite of an anticonvulsant. These drugs generally act as stimulants at low doses, but are not used for this purpose due to the risk of convulsions and consequent exc ...

agent in mice and rats. Aminooxyacetic acid can also inhibit 1-aminocyclopropane-1-carboxylate synthase preventing

ethylene Ethylene (IUPAC name: ethene) is a hydrocarbon which has the formula or . It is a colourless, flammable gas with a faint "sweet and musky" odour when pure. It is the simplest alkene (a hydrocarbon with carbon-carbon double bonds). Ethylene i ...

synthesis, which can increase the

vase life Vase life is the period during which a cut flower or cut foliage retains its appearance in a vase. This is a major consideration in identifying plant species suitable for use in floristry, plants with a long vase life being far more desirable than ...

of cut flowers.

History

Aminooxyacetic acid was first described by Werner in 1893, and was prepared by the hydrolysis of ethylbenzhydroximinoacetic acid. In 1936, Anchel and Shoenheimer used aminooxyacetic acid to isolate

ketone In organic chemistry, a ketone is a functional group with the structure R–C(=O)–R', where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group –C(=O)– (which contains a carbon-oxygen double bo ...

s from natural sources. Also in 1936, Kitagawa and Takani described the preparation of aminooxyacetic acid by the condensation of benzhydroxamic acid and

ethyl bromoacetate Ethyl bromoacetate is the chemical compound with the formula CH2BrCO2C2H5. It is the ethyl ester of bromoacetic acid and is prepared in two steps from acetic acid. It is a lachrymator and has a fruity, pungent odor. It is also a highly toxic alky ...

, followed by hydrolysis by

hydrochloric acid Hydrochloric acid, also known as muriatic acid, is an aqueous solution of hydrogen chloride. It is a colorless solution with a distinctive pungent smell. It is classified as a strong acid Acid strength is the tendency of an acid, symbol ...

References

{{Glutamate metabolism and transport modulators GABA transaminase inhibitors Glutamate decarboxylase inhibitors