Aminooxyacetic acid
Encyclopedia
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. 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
.
Aminooxyacetic acid is a general inhibitor of pyridoxal phosphate (PLP)-dependent enzyme
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 inhibition of the malate-aspartate shuttle prevents the reoxidation of cytosolic NADH
by the mitochondria
in nerve terminals. 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
. Aminooxyacetic acid has been shown to cause excitotoxic
lesion
s of the striatum
, similar to Huntington's disease
, potentially due to its impairment of mitochondrial energy metabolism. Interestingly, 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 effect
s such as drowsiness, ataxia
, seizure
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
, since a decrease in glycolysis disrupts breast adenocarcinoma
cells more than normal 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
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
properties. At high dosages, it can act as a convulsant
agent in mice and rats.
Aminooxyacetic acid can also inhibit 1-aminocyclopropane-1-carboxylate synthase
preventing ethylene
synthesis, which can increase the vase life
of cut flowers.
in 1893, and was prepared by the hydrolysis of ethylbenzhydroximinoacetic acid. In 1936, Anchel and Shoenheimer
used aminooxyacetic acid to isolate ketone
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
, followed by hydrolysis by hydrochloric acid
.
4-aminobutyrate aminotransferase
4-aminobutyrate aminotransferase is an enzyme which catalyzes the conversion of 4-aminobutanoic acid and 2-oxoglutarate into succinic semialdehyde and glutamate.-Inhibitors:* Aminooxyacetic acid* Gabaculine* Phenelzine...
(GABA-T) activity in vitro
In vitro
In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...
and in vivo
In vivo
In vivo is experimentation using a whole, living organism as opposed to a partial or dead organism, or an in vitro controlled environment. Animal testing and clinical trials are two forms of in vivo research...
, leading to less gamma-aminobutyric acid (GABA)
Gamma-aminobutyric acid
γ-Aminobutyric acid is the chief inhibitory neurotransmitter in the mammalian central nervous system. It plays a role in regulating neuronal excitability throughout the nervous system...
being broken down. Subsequently, the level of GABA is increased in tissues
Tissue (biology)
Tissue is a cellular organizational level intermediate between cells and a complete organism. A tissue is an ensemble of cells, not necessarily identical, but from the same origin, that together carry out a specific function. These are called tissues because of their identical functioning...
. 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
Laboratory rat
A laboratory rat is a rat of the species Rattus norvegicus which is bred and kept for scientific research. Laboratory rats have served as an important animal model for research in psychology, medicine, and other fields.- Origins :...
.
Aminooxyacetic acid is a general inhibitor of pyridoxal phosphate (PLP)-dependent enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
s (this includes GABA-T). It functions as an inhibitor by attacking the Schiff base
Schiff base
A Schiff base, named after Hugo Schiff, is a compound with a functional group that contains a carbon-nitrogen double bond with the nitrogen atom connected to an aryl or alkyl group, not hydrogen....
linkage between PLP and the enzyme, forming oxime
Oxime
An oxime is a chemical compound belonging to the imines, with the general formula R1R2C=NOH, where R1 is an organic side chain and R2 may be hydrogen, forming an aldoxime, or another organic group, forming a ketoxime. O-substituted oximes form a closely related family of compounds...
type complexes.
Aminooxyacetic acid inhibits aspartate aminotransferase, another PLP-dependent enzyme, which is an essential part of the malate-aspartate shuttle
Malate-aspartate shuttle
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...
. The inhibition of the malate-aspartate shuttle prevents the reoxidation of cytosolic NADH
Nicotinamide adenine dinucleotide
Nicotinamide adenine dinucleotide, abbreviated NAD, is a coenzyme found in all living cells. The compound is a dinucleotide, since it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an adenine base and the other nicotinamide.In metabolism, NAD is involved...
by the mitochondria
Mitochondrion
In cell biology, a mitochondrion is a membrane-enclosed organelle found in most eukaryotic cells. These organelles range from 0.5 to 1.0 micrometers in diameter...
in nerve terminals. Also in the nerve terminals, aminooxyacetic acid prevents the mitochondria from utilizing pyruvate generated from glycolysis
Glycolysis
Glycolysis is the metabolic pathway that converts glucose C6H12O6, into pyruvate, CH3COCOO− + H+...
, thus leading to a bioenergetic
Bioenergetics
Bioenergetics is the subject of a field of biochemistry that concerns energy flow through living systems. This is an active area of biological research that includes the study of thousands of different cellular processes such as cellular respiration and the many other metabolic processes that can...
state similar to that of hypoglycemia
Hypoglycemia
Hypoglycemia or hypoglycæmia is the medical term for a state produced by a lower than normal level of blood glucose. The term literally means "under-sweet blood"...
. Aminooxyacetic acid has been shown to cause excitotoxic
Excitotoxicity
Excitotoxicity is the pathological process by which nerve cells are damaged and killed by excessive stimulation by neurotransmitters such as glutamate and similar substances. This occurs when receptors for the excitatory neurotransmitter glutamate such as the NMDA receptor and AMPA receptor are...
lesion
Lesion
A lesion is any abnormality in the tissue of an organism , usually caused by disease or trauma. Lesion is derived from the Latin word laesio which means injury.- Types :...
s of the striatum
Striatum
The striatum, also known as the neostriatum or striate nucleus, is a subcortical part of the forebrain. It is the major input station of the basal ganglia system. The striatum, in turn, gets input from the cerebral cortex...
, similar to Huntington's disease
Huntington's disease
Huntington's disease, chorea, or disorder , is a neurodegenerative genetic disorder that affects muscle coordination and leads to cognitive decline and dementia. It typically becomes noticeable in middle age. HD is the most common genetic cause of abnormal involuntary writhing movements called chorea...
, potentially due to its impairment of mitochondrial energy metabolism. Interestingly, 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 effect
Side effect
In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequences of the use of a drug.Occasionally, drugs are...
s such as drowsiness, ataxia
Ataxia
Ataxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
, seizure
Seizure
An epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...
s, and psychotic behavior
Psychosis
Psychosis means abnormal condition of the mind, and is a generic psychiatric term for a mental state often described as involving a "loss of contact with reality"...
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
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
, since a decrease in glycolysis disrupts breast adenocarcinoma
Adenocarcinoma
Adenocarcinoma is a cancer of an epithelium that originates in glandular tissue. Epithelial tissue includes, but is not limited to, the surface layer of skin, glands and a variety of other tissue that lines the cavities and organs of the body. Epithelium can be derived embryologically from...
cells more than normal cells.
Aminooxyacetic acid has been studied as a treatment for tinnitus
Tinnitus
Tinnitus |ringing]]") is the perception of sound within the human ear in the absence of corresponding external sound.Tinnitus is not a disease, but a symptom that can result from a wide range of underlying causes: abnormally loud sounds in the ear canal for even the briefest period , ear...
. 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
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
and disequilibrium
Disequilibrium (medicine)
In medicine, disequilibrium refers to an impaired sense of equilibrioception.It is one of the causes of dizziness.It is caused by the lesioof the vestibulocerebellar tract.-References:Otology...
. 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
Anticonvulsant
The anticonvulsants are a diverse group of pharmaceuticals used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of bipolar disorder, since many seem to act as mood stabilizers, and in the treatment of neuropathic pain. The goal of an...
properties. At high dosages, it can act as a convulsant
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 excitotoxicity...
agent in mice and rats.
Aminooxyacetic acid can also inhibit 1-aminocyclopropane-1-carboxylate synthase
1-aminocyclopropane-1-carboxylate synthase
In enzymology, a 1-aminocyclopropane-1-carboxylate synthase is an enzyme that catalyzes the chemical reactionHence, this enzyme has one substrate, S-adenosyl-L-methionine, and two products, 1-aminocyclopropane-1-carboxylate and methylthioadenosine....
preventing ethylene
Ethylene
Ethylene is a gaseous organic compound with the formula . It is the simplest alkene . Because it contains a carbon-carbon double bond, ethylene is classified as an unsaturated hydrocarbon. Ethylene is widely used in industry and is also a plant hormone...
synthesis, which can increase the vase life
Vase life
Vase life is the period of time 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 the cut flower industry, plants with a long vase life being far more desirable than those with a short vase life....
of cut flowers.
History
Aminooxyacetic acid was first described by WernerAlfred Werner
Alfred Werner was a Swiss chemist who was a student at ETH Zurich and a professor at the University of Zurich. He won the Nobel Prize in Chemistry in 1913 for proposing the octahedral configuration of transition metal complexes. Werner developed the basis for modern coordination chemistry...
in 1893, and was prepared by the hydrolysis of ethylbenzhydroximinoacetic acid. In 1936, Anchel and Shoenheimer
Rudolph Schoenheimer
-Bibliography:*[Anon.] "Schoenheimer, Rudolf", Encyclopaedia Britannica, Deluxe CDROM edition...
used aminooxyacetic acid to isolate ketone
Ketone
In organic chemistry, a ketone is an organic compound with the structure RCR', where R and R' can be a variety of atoms and groups of atoms. It features a carbonyl group bonded to two other carbon atoms. Many ketones are known and many are of great importance in industry and in biology...
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
Ethyl 2-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.-Applications:...
, followed by hydrolysis by hydrochloric acid
Hydrochloric acid
Hydrochloric acid is a solution of hydrogen chloride in water, that is a highly corrosive, strong mineral acid with many industrial uses. It is found naturally in gastric acid....
.