|
|
| (aminooxy)acetic acid |
|
| CHEBI:40823 |
|
| A member of the class of hydroxylamines that is acetic acid substituted at postion 2 by an aminooxy group. It is a compound which inhibits aminobutyrate aminotransferase activity in vivo, resulting in increased levels of γ-aminobutyric acid in tissues. |
|
This entity has been manually annotated by the ChEBI Team.
|
|
| ChemicalBook:CB31248204, eMolecules:972365, ZINC000004689151 |
|
|
Molfile
XML
SDF
|
|
|
more structures >>
|
|
call loadScript javascripts\jsmol\core\package.js call loadScript javascripts\jsmol\core\core.z.js -- required by ClazzNode call loadScript javascripts\jsmol\J\awtjs2d\WebOutputChannel.js Jmol JavaScript applet jmolApplet0_object__2275794987451847__ initializing getValue debug = null getValue logLevel = null getValue allowjavascript = null AppletRegistry.checkIn(jmolApplet0_object__2275794987451847__) call loadScript javascripts\jsmol\core\corestate.z.js viewerOptions: { "name":"jmolApplet0_object","applet":true,"documentBase":"https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:40823","platform":"J.awtjs2d.Platform","fullName":"jmolApplet0_object__2275794987451847__","display":"jmolApplet0_canvas2d","signedApplet":"true","appletReadyCallback":"Jmol._readyCallback","statusListener":"[J.appletjs.Jmol.MyStatusListener object]","codeBase":"https://www.ebi.ac.uk/chebi/javascripts/jsmol/","syncId":"2275794987451847","bgcolor":"#000" } (C) 2012 Jmol Development Jmol Version: 13.2.7 $Date: 2013-10-01 11:35:15 -0500 (Tue, 01 Oct 2013) $ java.vendor: j2s java.version: 0.0 os.name: j2s Access: ALL memory: 0.0/0.0 processors available: 1 useCommandThread: false appletId:jmolApplet0_object (signed) starting HoverWatcher_1 getValue emulate = null defaults = "Jmol" getValue boxbgcolor = null getValue bgcolor = #000 backgroundColor = "#000" getValue ANIMFRAMECallback = null getValue APPLETREADYCallback = Jmol._readyCallback APPLETREADYCallback = "Jmol._readyCallback" getValue ATOMMOVEDCallback = null getValue CLICKCallback = null getValue ECHOCallback = null getValue ERRORCallback = null getValue EVALCallback = null getValue HOVERCallback = null getValue LOADSTRUCTCallback = null getValue MEASURECallback = null getValue MESSAGECallback = null getValue MINIMIZATIONCallback = null getValue PICKCallback = null getValue RESIZECallback = null getValue SCRIPTCallback = null getValue SYNCCallback = null getValue STRUCTUREMODIFIEDCallback = null getValue doTranslate = null language=en_US getValue popupMenu = null getValue script = null Jmol applet jmolApplet0_object__2275794987451847__ ready call loadScript javascripts\jsmol\core\corescript.z.js call loadScript javascripts\jsmol\J\script\FileLoadThread.js starting QueueThread0_2 script 1 started starting HoverWatcher_3 starting HoverWatcher_4 The Resolver thinks Mol Marvin 09130717243D starting HoverWatcher_5 Time for openFile( Marvin 09130717243D 11 10 0 0 0 0 999 V2000 -0.6120 -0.0220 0.3220 C 0 0 0 0 0 0 0 0 0 0 0 0 -0.2540 -0.0380 2.6160 N 0 0 0 0 0 0 0 0 0 0 0 0 0.4140 -0.0150 1.3150 O 0 0 0 0 0 0 0 0 0 0 0 0 0.0130 0.0000 -1.0480 C 0 0 0 0 0 0 0 0 0 0 0 0 -0.7640 -0.0010 -2.1420 O 0 0 0 0 0 0 0 0 0 0 0 0 1.2160 0.0190 -1.1620 O 0 0 0 0 0 0 0 0 0 0 0 0 0.4720 -0.0330 3.3160 H 0 0 0 0 0 0 0 0 0 0 0 0 -0.7470 0.8380 2.7030 H 0 0 0 0 0 0 0 0 0 0 0 0 -1.2170 -0.9220 0.4300 H 0 0 0 0 0 0 0 0 0 0 0 0 -1.2440 0.8570 0.4470 H 0 0 0 0 0 0 0 0 0 0 0 0 -0.3620 0.0120 -3.0210 H 0 0 0 0 0 0 0 0 0 0 0 0 1 3 1 0 0 0 0 1 4 1 0 0 0 0 1 9 1 0 0 0 0 1 10 1 0 0 0 0 2 3 1 0 0 0 0 2 7 1 0 0 0 0 2 8 1 0 0 0 0 4 5 1 0 0 0 0 4 6 2 0 0 0 0 5 11 1 0 0 0 0 M END): 15 ms reading 11 atoms ModelSet: haveSymmetry:false haveUnitcells:false haveFractionalCoord:false 1 model in this collection. Use getProperty "modelInfo" or getProperty "auxiliaryInfo" to inspect them. Default Van der Waals type for model set to Babel 11 atoms created ModelSet: not autobonding; use forceAutobond=true to force automatic bond creation Script completed Jmol script terminated
|
| 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 enzymes (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 lesions of the striatum, similar to Huntington's disease, 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, seizures, and psychosis 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. |
|
Read full article at Wikipedia
|
| InChI=1S/C2H5NO3/c3-6-1-2(4)5/h1,3H2,(H,4,5) |
| NQRKYASMKDDGHT-UHFFFAOYSA-N |
|
|
Bronsted base
A molecular entity capable of accepting a hydron from a donor (Bronsted acid).
(via organic amino compound )
Bronsted acid
A molecular entity capable of donating a hydron to an acceptor (Bronsted base).
(via oxoacid )
|
|
|
EC 4.2.1.22 (cystathionine beta-synthase) inhibitor
An EC 4.2.1.* (hydro-lyases) inhibitor that interferes with the action of cystathionine beta-synthase (EC 4.2.1.22).
EC 2.6.1.19 (4-aminobutyrate--2-oxoglutarate transaminase) inhibitor
An EC 2.6.1.* (transaminase) inhibitor that interferes with the action of 4-aminobutyrate2-oxoglutarate transaminase (EC 2.6.1.19).
|
|
|
nootropic agent
Any compound that improves mental functions such as cognition, memory, intelligence, motivation, attention, and concentration.
anticonvulsant
A drug used to prevent seizures or reduce their severity.
|
|
View more via ChEBI Ontology
|
(carboxymethoxy)amine
|
ChemIDplus
|
|
(O-carboxymethyl)hydroxylamine
|
ChemIDplus
|
|
2-(aminooxy)acetic acid
|
IUPAC
|
|
2-aminooxyethanoic acid
|
PDBeChem
|
|
aminooxyacetic acid
|
ChemIDplus
|
AOA
 Note: (2020-10-15) Used as an abbreviation. |
|
ChEBI
|
AOAA
| Note: (2020-10-15) Used as an abbreviation. |
|
ChemIDplus
|
|
carboxymethoxyamine
|
DrugBank
|
|
U-7524
|
DrugBank
|
|
645-88-5
|
CAS Registry Number
|
ChemIDplus
|
|
878238
|
Reaxys Registry Number
|
Reaxys
|
Mei S, Huang Y, Li N, Xu Z, Xu J, Dai Q, Wu J, Kijlstra A, Yang P, Hou S (2020)
Aminooxy-Acetic Acid Inhibits Experimental Autoimmune Uveitis by Modulating the Balance between Effector and Regulatory Lymphocyte Subsets.
Current molecular medicine 20, 624-632 [PubMed:32072910]
[show Abstract]
PurposeA small molecular compound, aminooxy-acetic acid (AOA), has been shown to modulate experimental autoimmune encephalomyelitis (EAE). The current study was designed to investigate whether AOA has a similar effect on the development of experimental autoimmune uveitis (EAU) and to further explore underlying mechanisms of this drug.MethodsEAU was induced in C57BL/6J mice by immunization with interphotoreceptor retinoid-binding protein peptide 651-670 (IRBP 651-670). AOA (500μg or 750μg) or vehicle was administered by intraperitoneal injection from day 10 to 14 after EAU induction. The severity was assessed by clinical and histological scores. The integrity of the blood retinal barrier was detected with Evans Blue. Frequencies of splenic Th1, Th17 and Foxp3+ Treg cells were examined by flow cytometry. The production of cytokines was tested by ELISA. The mRNA expression of IL-17, IFN-γ and IL-10 was detected by RT-PCR. The expression of p-Stat1 and NF-κB was detected by Western Blotting.ResultsAOA was found to markedly inhibit the severity of EAU, as determined by clinical and histopathological examinations. AOA can relieve the leakage of blood retinal barrier (BRB). Functional studies found a decreased frequency of Th1 and Th17 cells and an increased frequency of Treg cells in EAU mice as compared with controls. Further studies showed that AOA not only downregulated the production of the proinflammatory cytokines including IFN-γ and IL-17 but also upregulated the expression of an anti-inflammatory cytokine such as IL-10, which might be caused by inhibiting the expressions of p-Stat1 and NF-κB.ConclusionThis study shows that AOA inhibits the severity and development of EAU by modulating the balance between regulatory and pathogenic lymphocyte subsets. | Yue T, Zuo S, Bu D, Zhu J, Chen S, Ma Y, Ma J, Guo S, Wen L, Zhang X, Hu J, Wang Y, Yao Z, Chen G, Wang X, Pan Y, Wang P, Liu Y (2020)
Aminooxyacetic acid (AOAA) sensitizes colon cancer cells to oxaliplatin via exaggerating apoptosis induced by ROS.
Journal of Cancer 11, 1828-1838 [PubMed:32194794]
[show Abstract]
Background: As the third confirmed gaseous transmitter, the role of hydrogen sulfide (H2S) in the pathogenesis of multiple types of cancer has been attracting increasing attention. Increased expression of cystathionine β-synthase (CBS) and H2S in colon cancer tissue samples has been validated and tumor-derived H2S, mainly produced by CBS, stimulates bioenergetics, cell proliferation, and angiogenesis in colon cancer. Recently, the therapeutic manipulation of H2S has been proposed as a promising anticancer approach. However, the effect of aminooxyacetic acid (AOAA), which has been widely used as an inhibitor of CBS dependent synthesis of H2S, on the chemotherapeutic effect of oxaliplatin (OXA) and the underlying mechanisms remain to be illustrated. Methods: We examined the expression of CBS in human colorectal cancer specimens and matched normal mucosa by immunohistochemistry. The effect of AOAA on the sensitivity of colon cancer cells to OXA and the level of apoptosis induced by caspase cascade was investigated in both HCT116 and HT29 cell lines utilizing CCK-8 assays, flow cytometry analysis and western blot analysis. The endogenous levels of reactive oxygen species (ROS) were detected fluorescently by DCF-DA, and glutathione (GSH) levels were measured by a Total GSH Detection Kit. Tumor bearing xenograft mouse models and in vivo imaging systems were further used to investigate the effect of AOAA in vivo and immunohistochemistry (IHC) and TUNEL analysis were performed. Results: In the current study, we confirmed CBS, the main target of AOAA, is overexpressed in human colorectal cancer by immunohistochemistry. The inhibitory effect of AOAA on the synthesis of H2S was validated utilizing fluorescent probe and specific electrode. AOAA significantly reduced the IC50 values of OXA in both colon cancer cell lines. Co-incubation with AOAA elicited increased apoptosis induced by OXA, featured by increased activation of caspase cascade. Besides, AOAA further increased the levels of ROS induced by OXA and attenuated the synthesis of glutathione (GSH), which is a vital antioxidant. Besides, the results of in vivo imaging and following IHC and TUNEL analysis were in accordance with cellular experiments, indicating that AOAA sensitizes colon cancer cells to OXA via exaggerating intrinsic apoptosis. Conclusion: The results suggested that CBS is overexpressed in colorectal cancer tissues and AOAA sensitizes colon cancer cells to OXA via exaggerating apoptosis both in vitro and in vivo. Decreasing the endogenous level of GSH and consequently impaired detoxification of ROS might be one of the mechanisms underlying the effect of AOAA. | Zhao P, Zhou W, Zhang Y, Li J, Zhao Y, Pan L, Shen Z, Chen W, Hui J (2020)
Aminooxyacetic acid attenuates post-infarct cardiac dysfunction by balancing macrophage polarization through modulating macrophage metabolism in mice.
Journal of cellular and molecular medicine 24, 2593-2609 [PubMed:31930778]
[show Abstract]
Excessive activation of pro-inflammatory M1 macrophages following acute myocardial infarction (MI) aggravates adverse cardiac remodelling and heart dysfunction. There are two break points in the tricarboxylic acid cycle of M1 macrophages, and aspartate-arginosuccinate shunt compensates them. Aminooxyacetic acid (AOAA) is an inhibitor of aspartate aminotransferase in the aspartate-arginosuccinate shunt. Previous studies showed that manipulating macrophage metabolism may control macrophage polarization and inflammatory response. In this study, we aimed to clarify the effects of AOAA on macrophage metabolism and polarization and heart function after MI. In vitro, AOAA inhibited lactic acid and glycolysis and enhanced ATP levels in classically activated M1 macrophages. Besides, AOAA restrained pro-inflammatory M1 macrophages and promoted anti-inflammatory M2 phenotype. In vivo, MI mice were treated with AOAA or saline for three consecutive days. Remarkably, AOAA administration effectively inhibited the proportion of M1 macrophages and boosted M2-like phenotype, which subsequently attenuated infarct size as well as improved post-MI cardiac function. Additionally, AOAA attenuated NLRP3-Caspase1/IL-1β activation and decreased the release of IL-6 and TNF-α pro-inflammatory cytokines and reciprocally increased IL-10 anti-inflammatory cytokine level in both ischaemic myocardium and M1 macrophages. In conclusion, short-term AOAA treatment significantly improves cardiac function in mice with MI by balancing macrophage polarization through modulating macrophage metabolism and inhibiting NLRP3-Caspase1/IL-1β pathway. | Kovaleva LV, Zakharova EV, Timofeeva GV, Andreev IM, Golivanov YY, Bogoutdinova LR, Baranova EN, Khaliluev MR (2020)
Aminooxyacetic acid (АОА), inhibitor of 1-aminocyclopropane-1-carboxilic acid (AСС) synthesis, suppresses self-incompatibility-induced programmed cell death in self-incompatible Petunia hybrida L. pollen tubes.
Protoplasma 257, 213-227 [PubMed:31410589]
[show Abstract]
Self-incompatibility (SI) is genetically determined reproductive barrier preventing inbreeding and thereby providing the maintenance of plant species diversity. At present, active studies of molecular bases of SI mechanisms are underway. S-RNAse-based SI in Petunia hybrida L. is a self-/non-self recognition system that allows the pistil to reject self pollen and to accept non-self pollen for outcrossing. In the present work, using fluorescent methods including the TUNEL method allowed us to reveal the presence of markers of programmed cell death (PCD), such as DNA fragmentation, in growing in vivo petunia pollen tubes during the passage of the SI reaction. The results of statistical analysis reliably proved that PCD is the factor of S-RNAse-based SI. It was found that preliminary treatment before self-pollination of stigmas of petunia self-incompatible line with aminooxyacetic acid (AOA), inhibitor of ACC synthesis, led to stimulation of pollen tubes growth when the latter did not exhibit any hallmarks of PCD. These data argue in favor of assumption that ethylene controls the passage of PCD in incompatible pollen tubes in the course of S-RNAse-based SI functioning. The involvement of the hormonal regulation in SI mechanism in P. hybrida L. is the finding observed by us for the first time. | Du A, Dai X, Dong J, Liu J, Zhang Y, Fu P, Qin H, Li R, Zhang R (2019)
Effects of aminooxyacetic acid on hippocampal mitochondria in rats with chronic alcoholism: the analysis of learning and memory-related genes.
Journal of integrative neuroscience 18, 451-462 [PubMed:31912705]
[show Abstract]
The incidence of chronic alcoholism leading to central and peripheral nervous system damage has been increasing year-to-year. The purpose of this study is to explore the effects of aminooxyacetic acid on hippocampus mitochondria in rats with chronic alcoholism and analyze learning and memory-related genes. Sixty male Sprague Dawley rats were randomly divided into three groups. Except for the control group, each group was fed with the water containing (v/v) 6% alcohol for 28 days. After 14 days, rats in the treatment group were intraperitoneally injected daily for 14 days with aminooxyacetic acid. High throughput sequencing was combined and tested for learning and memory abilities, Hydrogen sulfide content, catalase activity in mitochondria, and the expression of F-actin in the hippocampus of the rats in each group. Compared with the control group, the learning and memory abilities of rats with chronic alcoholism were significantly impaired, mitochondria contained vacuoles, hydrogen sulfide increased, but catalase activity and F-actin content were significantly decreased, After treatment with aminooxyacetic acid, mitochondrial morphology improved, hydrogen sulfide content was decreased, while catalase activity and F-actin expression of in hippocampus were increased. This indicates that aminooxyacetic acid may improve learning and memory in rats with chronic alcoholism, and the mechanism is related to decreased hydrogen sulfide content and an increase of both catalase activity and F-actin level in the hippocampus, thereby reducing the damage of alcohol to mitochondria and neurons. | Du AL, Qin HZ, Jiang HB, Fu PY, Lou K, Xu YM (2018)
Aminooxyacetic acid improves learning and memory in a rat model of chronic alcoholism.
Neural regeneration research 13, 1568-1574 [PubMed:30127117]
[show Abstract]
Chronic alcoholism seriously damages the central nervous system and leads to impaired learning and memory. Cell damage in chronic alcoholism is strongly associated with elevated levels of hydrogen sulfide (H2S) and calcium ion overload. Aminooxyacetic acid is a cystathionine-β-synthase activity inhibitor that can reduce H2S formation in the brain. This study sought to observe the effect of aminooxyacetic acid on learning and memory in a chronic alcoholism rat model. Rats were randomly divided into three groups. Rats in the control group were given pure water for 28 days. Rats in the model group were given 6% alcohol for 28 days to establish an alcoholism rat model. Rats in the aminooxyacetic acid remedy group were also given 6% alcohol for 28 days and were also intraperitoneally injected daily with aminooxyacetic acid (5 mg/kg) from day 15 to day 28. Learning and memory was tested using the Morris water maze test. The ultrastructure of mitochondria in the hippocampus was observed by electron microscopy. H2S levels in the hippocampus were measured indirectly by spectrophotometry, and ATPase activity was measured using a commercial kit. The expression of myelin basic protein was determined by immunohistochemistry and western blotting. Compared with the control group, latency and swimming distance were prolonged in the navigation test on days 2, 3, and 4 in the model group. In the spatial probe test on day 5, the number of platform crosses was reduced in the model group. Cristae cracks, swelling or deformation of mitochondria appeared in the hippocampus, the hippocampal H2S level was increased, the mitochondrial ATPase activity was decreased, and the expression of myelin basic protein in the hippocampus was down-regulated in the model group compared with the control group. All the above indexes were ameliorated in the aminooxyacetic acid remedy group compared with the model group. These findings indicate that aminooxyacetic acid can improve learning and memory in a chronic alcoholism rat model, which may be associated with reduction of hippocampal H2S level and mitochondrial ATPase activity, and up-regulation of myelin basic protein levels in the hippocampus. | Qin HZ, Jiang HB, Dai X, Huang YD, Luo XQ, Zhang RL, Du AL (2018)
[Effects of aminooxyacetic acid on the learning and memory ability and its possible mechanism in rats with chronic alcoholism].
Zhongguo ying yong sheng li xue za zhi = Zhongguo yingyong shenglixue zazhi = Chinese journal of applied physiology 34, 485-489 [PubMed:31032581]
[show Abstract]
ObjectiveTo investigate the effects of aminooxyacetic acid (AOAA) on learning and memory ability and possible mechanisms in rats with chronic alcoholism.MethodsSixty SD male rats were randomly divided into three groups on average.The model group rats and the remedy group rats were fed with the water containing (v/v) 6% alcohol for 28 days.After 14 days, the remedy group rats were treated with AOAA (5 mg/kg·d) by intraperitoneal injection once a day for 14 days and the other two group rats were treated with the equal amount of saline by intraperitoneal injection every day.Five days before the end of the experiment, the water maze test was carried out to test the learning and memory ability of rats for 5 days.Subsequently, the content of H2S, the activity of ATP enzyme and the expression of 5-HT in hippocampus were measured.ResultsCompared with the rats in the control group, the latency and the swimming distance of the 2nd to the 4th day, the content of H2S in hippocampus of rats in the model group were all increased, the mitochondrial ATP enzyme activity in hippocampus and the positive expression of 5-HT in hippocampus CA1 and CA3 of rats in the model group were decreased (P<0.01).Compared with the rats in the model group, the latency and the swimming distance of the 2nd to the 4th day, the content of H2S in hippocampus of the rats in the remedy group were decreased, the mitochondrial ATP enzyme activity in hippocampus and the positive expression of 5-HT in hippocampus CA1 and CA3 of rats in the model group were increased (P<0.01).ConclusionsAOAA could alleviate the symptoms of chronic alcoholism rats, which may be related to the effects of AOAA on the content of H2S, the mitochondrial enzyme activity and the expression of 5-HT in hippocampus. | Shang W, Wei X, Ying W (2017)
Malate-aspartate shuttle inhibitor aminooxyacetic acid blocks lipopolysaccharides-induced activation of BV2 microglia.
International journal of physiology, pathophysiology and pharmacology 9, 58-63 [PubMed:28533892]
[show Abstract]
NADH shuttles, including malate-aspartate shuttle (MAS) and glycerol-3-phosphate shuttle, mediate the transfer of the reducing equivalents of cytosolic NADH into mitochondria. In our current study, we used BV2 microglia as a cellular model to determine the roles of NADH shuttles in lipopolysaccharides (LPS)-induced microglial activation. We found that aminooxyacetic acid (AOAA), a widely used MAS inhibitor, significantly attenuated LPS-induced increases in the levels of nitric oxide-a hallmarker of microglial activation. Our Western Blot assays also showed that AOAA blocked the LPS-induced increases in the protein levels of iNOS, TNF-α and COX-2. Furthermore, we found that AOAA decreased LPS-induced nuclear translocation of NF-κB. Collectively, our study has suggested that AOAA may be a new agent for inhibiting microglial activation. Our study has also suggested that MAS may be a novel target for modulating microglial activation under pathological conditions. | Wang C, Chen H, Zhang M, Zhang J, Wei X, Ying W (2016)
Malate-aspartate shuttle inhibitor aminooxyacetic acid leads to decreased intracellular ATP levels and altered cell cycle of C6 glioma cells by inhibiting glycolysis.
Cancer letters 378, 1-7 [PubMed:27157912]
[show Abstract]
NADH shuttles, including malate-aspartate shuttle (MAS) and glycerol-3-phosphate shuttle, can shuttle the reducing equivalents of cytosolic NADH into mitochondria. It is widely accepted that the major function of NADH shuttles is to increase mitochondrial energy production. Our study tested the hypothesis that the novel major function of NADH shuttles in cancer cells is to maintain glycolysis by decreasing cytosolic NADH/NAD(+) ratios. We found that AOAA, a widely used MAS inhibitor, led to decreased intracellular ATP levels, altered cell cycle and increased apoptosis and necrosis of C6 glioma cells, without affecting the survival of primary astrocyte cultures. AOAA also decreased the glycolytic rate and the levels of extracellular lactate and pyruvate, without affecting the mitochondrial membrane potential of C6 cells. Moreover, the toxic effects of AOAA were completely prevented by pyruvate treatment. Collectively, our study has suggested that AOAA may be used to selectively decrease glioma cell survival, and the major function of MAS in cancer cells may be profoundly different from its major function in normal cells: The major function of MAS in cancer cells is to maintain glycolysis, instead of increasing mitochondrial energy metabolism. | Chao C, Zatarain JR, Ding Y, Coletta C, Mrazek AA, Druzhyna N, Johnson P, Chen H, Hellmich JL, Asimakopoulou A, Yanagi K, Olah G, Szoleczky P, Törö G, Bohanon FJ, Cheema M, Lewis R, Eckelbarger D, Ahmad A, Módis K, Untereiner A, Szczesny B, Papapetropoulos A, Zhou J, Hellmich MR, Szabo C (2016)
Cystathionine-beta-synthase inhibition for colon cancer: Enhancement of the efficacy of aminooxyacetic acid via the prodrug approach.
Molecular medicine (Cambridge, Mass.) 22, 361-379 [PubMed:27257787]
[show Abstract]
Colon cancer cells contain high levels of cystathionine-beta-synthase (CBS). Its product, hydrogen sulfide (H2S) promotes the growth and proliferation of colorectal tumor cells. In order to improve the antitumor efficacy of the prototypical CBS inhibitor aminooxyacetic acid (AOAA), we have designed and synthesized YD0171, a methyl ester derivative of AOAA. The antiproliferative effect of YD0171 exceeded the antiproliferative potency of AOAA in HCT116 human colon cancer cells. The esterase inhibitor paraoxon prevented the cellular inhibition of CBS activity by YD0171. YD0171 suppressed mitochondrial respiration and glycolytic function and induced G0/G1 arrest, but did not induce tumor cell apoptosis or necrosis. Metabolomic analysis in HCT116 cells showed that YD0171 affects multiple pathways of cell metabolism. The efficacy of YD0171 as an inhibitor of tumor growth was also tested in nude mice bearing subcutaneous HCT116 cancer cell xenografts. Animals were treated via subcutaneous injection of vehicle, AOAA (1, 3 or 9 mg/kg/day) or YD0171 (0.1, 0.5 or 1 mg/kg/day) for 3 weeks. Tumor growth was significantly reduced by 9 mg/kg/day AOAA, but not at the lower doses. YD0171 was more potent: tumor volume was significantly inhibited at 0.5 and 1 mg/kg/day. Thus, the in vivo efficacy of YD0171 is 9-times higher than that of AOAA. YD0171 (1 mg/kg/day) attenuated tumor growth and metastasis formation in the intracecal HCT116 tumor model. YD0171 (3 mg/kg/day) also reduced tumor growth in patient-derived tumor xenograft (PDTX) bearing athymic mice. YD0171 (3 mg/kg/day) induced the regression of established HCT116 tumors in vivo. A 5-day safety study in mice demonstrated that YD0171 at 20 mg/kg/day (given in two divided doses) does not increase plasma markers of organ injury, nor does it induce histological alterations in the liver or kidney. YD0171 caused a slight elevation in plasma homocysteine levels. In conclusion, the prodrug approach improves the pharmacological profile of AOAA; YD0171 represents a prototype for CBS inhibitory anticancer prodrugs. By targeting colorectal cancer bioenergetics, an emerging important hallmark of cancer, the approach exemplified herein may offer direct translational opportunities. | Ahmad A, Szabo C (2016)
Both the H2S biosynthesis inhibitor aminooxyacetic acid and the mitochondrially targeted H2S donor AP39 exert protective effects in a mouse model of burn injury.
Pharmacological research 113, 348-355 [PubMed:27639598]
[show Abstract]
Hydrogen sulfide (H2S) exerts beneficial as well as deleterious effects in various models of critical illness. Here we tested the effect of two different pharmacological interventions: (a) inhibition of H2S biosynthesis using the cystathionine-beta-synthase (CBS)/cystathionine-gamma-lyase (CSE) inhibitor aminooxyacetic acid (AOAA) and the mitochondrially targeted H2S donor [10-oxo-10-[4-(3-thioxo-3H-1,2-dithiol-5-yl)phenoxy]decyl]triphenyl-phosphonium (AP39). A 30% body surface area burn injury was induced in anesthetized mice; animals were treated with vehicle, AOAA (10mg/kg i.p. once or once a day for 6days), or AP39 (0.3mg/kg/day once or once a day for 6days). In two separate groups, animals were sacrificed, at 24h post-burn or on Day 7 post-burn, blood and lungs were collected and the following parameters were evaluated: myeloperoxidase (MPO) and malondialdehyde (MDA) in lung homogenates, plasma cytokines (Luminex analysis) and circulating indicators of organ dysfunction (Vetscan analysis). Lung MPO levels (an index of neutrophil infiltration) and MDA levels (an index of oxidative stress) were significantly increased in response to burn injury both at 24h and at 7days; both AOAA and AP39 attenuated these increases. From a panel of inflammatory cytokines (TNFα, IL-1β, IL-6, IL-10, MCP-1, MIP-2, VEGF and IFNγ) in the plasma, IL-6 and IL-10 levels were markedly elevated at 24h and VEGF was slightly elevated. IL-6 remained highly elevated at 7days post-burn while IL-10 levels decreased, but remained slightly elevated over baseline 7days post-burn. The changes in cytokine levels were attenuated both by AP39 and AOAA at both time points studied. The burn-induced increases in the organ injury markers ALP and ALT, amylase and creatinine were reduced by both AOAA and AP39. We conclude that both H2S biosynthesis inhibition (using AOAA) and H2S donation (using AP39) suppresses inflammatory mediator production and reduces multi-organ injury in a murine model of burn injury, both at an early time point (when systemic H2S levels are elevated) and at a later time point (at which time systemic H2S levels have returned to baseline). These findings point to the complex pathogenetic role of H2S in burns. | Koshio A, Hasegawa T, Okada R, Takeno K (2015)
Endogenous factors regulating poor-nutrition stress-induced flowering in pharbitis: The involvement of metabolic pathways regulated by aminooxyacetic acid.
Journal of plant physiology 173, 82-88 [PubMed:25462081]
[show Abstract]
The short-day plant pharbitis (also called Japanese morning glory), Ipomoea nil (formerly Pharbitis nil), was induced to flower by poor-nutrition stress. This stress-induced flowering was inhibited by aminooxyacetic acid (AOA), which is a known inhibitor of phenylalanine ammonia-lyase (PAL) and the synthesis of indole-3-acetic acid (IAA) and 1-aminocycropropane-1-carboxylic acid (ACC) and thus regulates endogenous levels of salicylic acid (SA), IAA and polyamine (PA). Stress treatment increased PAL activity in cotyledons, and AOA suppressed this increase. The observed PAL activity and flowering response correlate positively, indicating that AOA functions as a PAL inhibitor. The inhibition of stress-induced flowering by AOA was also overcome by IAA. An antiauxin, 4-chlorophenoxy isobutyric acid, inhibited stress-induced flowering. Both SA and IAA promoted flowering induced by stress. PA also promoted flowering, and the effective PA was found to be putrescine (Put). These results suggest that all of the pathways leading to the synthesis of SA, IAA and Put are responsive to the flowering inhibition by AOA and that these endogenous factors may be involved in the regulation of stress-induced flowering. However, as none of them induced flowering under non-stress conditions, they may function cooperatively to promote flowering. | Djordjevic S, Zhang X, Bartlam M, Ye S, Rao Z, Danpure CJ (2010)
Structural implications of a G170R mutation of alanine:glyoxylate aminotransferase that is associated with peroxisome-to-mitochondrion mistargeting.
Acta crystallographica. Section F, Structural biology and crystallization communications 66, 233-236 [PubMed:20208150]
[show Abstract]
In a subset of patients with the hereditary kidney-stone disease primary hyperoxaluria type 1 (PH1), the liver-specific enzyme alanine:glyoxylate aminotransferase (AGT) is mistargeted from peroxisomes to mitochondria. This is a consequence of the combined presence of the common P11L polymorphism and a disease-specific G170R mutation. In this paper, the crystal structure of mutant human AGT containing the G170R replacement determined at a resolution of 2.6 A is reported. The crystal structure of AGT consists of an intimate dimer in which an extended N-terminal segment of 21 amino acids from one subunit wraps as an elongated irregular coil around the outside of the crystallographic symmetry-related subunit. In addition to the N-terminal segment, the monomer structure contains a large domain of 261 amino acids and a small C-terminal domain of 110 amino acids. Comparison of the mutant AGT structure and that of wild-type normal AGT shows that the two structures are almost identical, with a backbone-atom r.m.s. deviation of 0.34 A. However, evidence of significant local structural changes in the vicinity of the G170R mutation might be linked to the apparent decrease in protein stability. | Campos-Sepúlveda AE, Martínez Enríquez ME, Rodríguez Arellanes R, Peláez LE, Rodríguez Amézquita AL, Cadena Razo A (2009)
Neonatal monosodium glutamate administration increases aminooxyacetic acid (AOA) susceptibility effects in adult mice.
Proceedings of the Western Pharmacology Society 52, 72-74 [PubMed:22128428]
[show Abstract]
Neonatal administration of monosodium glutamate (MSG) to mice causes neurotoxicity of the CNS resulting in endocrine, metabolic and behavioral abnormalities. Aminooxyacetic acid (AOAA) is a potent inhibitor of GABA-transaminase and increases GABA levels in the brain. In this work, we studied the effect of neonatal treatment of CFW mice with MSG (2 mg/g sc on the 2nd and 4th days after birth followed by 4 mg/g on days 6, 8 and 10) on AOAA- (100 to 250 mg/kg ip) induced hypothermia, hypnosis and lethality after six months of treatment. The control group was vehicle-treated only. MSG treatment significantly increased susceptibility to the hypothermic, hypnotic and lethal effect of AOAA acutely administered. The increased susceptibility to the depressor effects of AOAA may occur as a consequence of changes in neural excitability, up regulation of GABA-receptors or might be related to pharmacokinetic modifications induced by neonatal treatment with MSG. | Dever JT, Elfarra AA (2008)
L-methionine-dl-sulfoxide metabolism and toxicity in freshly isolated mouse hepatocytes: gender differences and inhibition with aminooxyacetic acid.
Drug metabolism and disposition: the biological fate of chemicals 36, 2252-2260 [PubMed:18687801]
[show Abstract]
L-methionine-dl-sulfoxide (MetO) is an L-methionine (Met) metabolite, but its role in Met metabolism and toxicity is not clear. In this study, MetO uptake, metabolism to Met, cytotoxicity, and glutathione (GSH) and glutathione disulfide (GSSG) status were characterized in freshly isolated mouse hepatocytes incubated at 37 degrees C with 0 to 30 mM MetO for 0 to 5 h. In male hepatocytes, dose-dependent cytotoxicity concomitant with GSH depletion without GSSG formation occurred after exposure to 20 or 30 mM MetO but not after exposure to 10 mM MetO. Interestingly, female hepatocytes exposed to 30 mM MetO showed no cytotoxicity and exhibited increased intracellular GSH levels compared with control hepatocytes. Male hepatocytes had approximately 2-fold higher levels of intracellular Met-d-O or Met-l-O after MetO (30 mM) exposure for 0 to 1.5 h compared with female hepatocytes. In hepatocytes of both genders, Met-l-O was detected at nearly 5-fold higher levels than Met-d-O, and no significant increase in cellular Met levels was detected. Addition of aminooxyacetic acid (AOAA), an inhibitor of transamination reactions, to MetO-exposed male hepatocytes resulted in higher cellular Met-d-O and Met-l-O levels and decreased the cytotoxicity of MetO. Interestingly, exposure of control male hepatocytes to AOAA selectively increased cellular Met-d-O levels to levels similar to those observed after exposure to MetO (30 mM). Analysis of MetO transamination activity by glutamine transaminase K in mouse liver cytosol revealed similar rates of MetO transamination in cytosol of both genders. Taken together, these results provide evidence for stereoselective oxidation of Met to Met-d-O under physiological conditions and suggest a major role for MetO transamination in MetO metabolism and toxicity. | Nakai T, Nakagawa N, Maoka N, Masui R, Kuramitsu S, Kamiya N (2005)
Structure of P-protein of the glycine cleavage system: implications for nonketotic hyperglycinemia.
The EMBO journal 24, 1523-1536 [PubMed:15791207]
[show Abstract]
The crystal structure of the P-protein of the glycine cleavage system from Thermus thermophilus HB8 has been determined. This is the first reported crystal structure of a P-protein, and it reveals that P-proteins do not involve the alpha(2)-type active dimer universally observed in the evolutionarily related pyridoxal 5'-phosphate (PLP)-dependent enzymes. Instead, novel alphabeta-type dimers associate to form an alpha(2)beta(2) tetramer, where the alpha- and beta-subunits are structurally similar and appear to have arisen by gene duplication and subsequent divergence with a loss of one active site. The binding of PLP to the apoenzyme induces large open-closed conformational changes, with residues moving up to 13.5 A. The structure of the complex formed by the holoenzyme bound to an inhibitor, (aminooxy)acetate, suggests residues that may be responsible for substrate recognition. The molecular surface around the lipoamide-binding channel shows conservation of positively charged residues, which are possibly involved in complex formation with the H-protein. These results provide insights into the molecular basis of nonketotic hyperglycinemia. | Kaźmierczak A (2004)
Aminooxyacetic acid inhibits antheridiogenesis and development of Anemia phyllitidis gametophytes.
Plant cell reports 23, 203-210 [PubMed:15480681]
[show Abstract]
Cytomorphological studies of the development of young fern gametophytes (Anemia phyllitidis) have been used to investigate combined effects of gibberellic acid and ethylene on male sex expression. ACC (the key by-product in ethylene biosynthesis pathway) was found to exert a synergetic effect on the gibberellic acid-induced antheridia formation, and this phenomenon could be related with the specific stimulation of cell growth and activity of their differentiation. To complete and verify those observations male sex expression in the fern gametophytes treated with ACC-biosynthesis inhibitor was reinvestigated. Aminooxyacetic acid (AOA) restrained antheridia formation via inhibition of cell divisions. AOA influenced the arrangement and flexibility of cellulose microfibrils in the antheridial zone cells, thus affecting cell expansion. On the other hand, the level of DNA synthesis was not reduced. Transient increase in the number of S-phase cells, followed by the accumulation of G2-phase cells led to the enhancement of cell polyploidization. All these findings correspond with the previous observations and support participation of ethylene in gibberellic acid-induced male sex expression in ferns. | Zhang X, Roe SM, Hou Y, Bartlam M, Rao Z, Pearl LH, Danpure CJ (2003)
Crystal structure of alanine:glyoxylate aminotransferase and the relationship between genotype and enzymatic phenotype in primary hyperoxaluria type 1.
Journal of molecular biology 331, 643-652 [PubMed:12899834]
[show Abstract]
A deficiency of the liver-specific enzyme alanine:glyoxylate aminotransferase (AGT) is responsible for the potentially lethal hereditary kidney stone disease primary hyperoxaluria type 1 (PH1). Many of the mutations in the gene encoding AGT are associated with specific enzymatic phenotypes such as accelerated proteolysis (Ser205Pro), intra-peroxisomal aggregation (Gly41Arg), inhibition of pyridoxal phosphate binding and loss of catalytic activity (Gly82Glu), and peroxisome-to-mitochondrion mistargeting (Gly170Arg). Several mutations, including that responsible for AGT mistargeting, co-segregate and interact synergistically with a Pro11Leu polymorphism found at high frequency in the normal population. In order to gain further insights into the mechanistic link between genotype and enzymatic phenotype in PH1, we have determined the crystal structure of normal human AGT complexed to the competitive inhibitor amino-oxyacetic acid to 2.5A. Analysis of this structure allows the effects of these mutations and polymorphism to be rationalised in terms of AGT tertiary and quaternary conformation, and in particular it provides a possible explanation for the Pro11Leu-Gly170Arg synergism that leads to AGT mistargeting. | Eisenhauer BM, Hecht SM (2002)
Site-specific incorporation of (aminooxy)acetic acid into proteins.
Biochemistry 41, 11472-11478 [PubMed:12234190]
[show Abstract]
By employing a general biosynthetic method for the elaboration of proteins containing unnatural amino acid analogues, we incorporated (aminooxy)acetic acid into positions 10 and 27 of Escherichia coli dihydrofolate reductase. Introduction of the modified amino acid into DHFR was accomplished in an in vitro protein biosynthesizing system by readthrough of a nonsense (UAG) codon with a suppressor tRNA that had been activated with (aminooxy)acetic acid. Incorporation of the amino acid proceeded with reasonable efficiency at codon position 10 but less well at position 27. (Aminooxy)acetic acid was also incorporated into position 72 of DNA polymerase beta. Peptides containing (aminooxy)acetic acid have been shown to adopt a preferred conformation involving an eight-membered ring that resembles a gamma-turn. Accordingly, the present study may facilitate the elaboration of proteins containing conformationally biased peptidomimetic motifs at predetermined sites. The present results further extend the examples of ribosomally mediated formation of peptide bond analogues of altered connectivity and provide a conformationally biased linkage at a predetermined site. It has also been shown that the elaborated protein can be cleaved chemically at the site containing the modified amino acid. | Scharfman HE (1996)
Hyperexcitability of entorhinal cortex and hippocampus after application of aminooxyacetic acid (AOAA) to layer III of the rat medial entorhinal cortex in vitro.
Journal of neurophysiology 76, 2986-3001 [PubMed:8930249]
[show Abstract]
1. Injection of aminooxyacetic acid (AOAA) into the entorhinal cortex in vivo produces acute seizures and cell loss in medial entorhinal cortex. To understand these effects, AOAA was applied directly to the medial entorhinal cortex in slices containing both the entorhinal cortex and hippocampus. Extracellular and intracellular recordings were made in both the entorhinal cortex and hippocampus to study responses to angular bundle stimulation and spontaneous activity. 2. AOAA was applied focally by leak from a micropipette or by pressure ejection. Evoked potentials increased gradually within 5 min of application, particularly the late, negative components. Evoked potentials continued to increase for up to 1 h, and these changes persisted for the remainder of the experiment (up to 5 h after drug application). 3. Paired pulse facilitation (100-ms interval) was also enhanced after AOAA application. Increasing stimulus frequency to 1-10 Hz increased evoked potentials further, and after several seconds of such stimulation multiple field potentials occurred. When stimulation was stopped at this point, repetitive field potentials occurred spontaneously for 1-2 min. These recordings, and simultaneous extracellular recordings in different layers, indicated that spontaneous synchronous activity occurred in entorhinal neurons. Intracellularly labeled cortical pyramidal cells depolarized and discharged during spontaneous and evoked field potentials. 4. The effects of AOAA were blocked reversibly by bath application of the N-methyl-D-aspartate (NMDA) receptor antagonist D-amino-5-phosphonovalerate (D-APV; 25 microM) or focal application of D-APV to the medial entorhinal cortex. 5. Simultaneous extracellular recordings from the entorhinal cortex and hippocampus demonstrated that spontaneous synchronous activity in layer III was often followed within several milliseconds by negative field potentials in the terminal zones of the perforant path (stratum moleculare of the dentate gyrus and stratum lacunosum-moleculare of area CA1). The extracellular potentials recorded in the dentate gyrus corresponded to excitatory postsynaptic potentials and action potentials in dentate granule cells. However, extracellular potentials in area CA1 were small and rarely correlated with discharge in CA1 pyramidal cells. 6. The results demonstrate that AOAA application leads to an NMDA-receptor-dependent enhancement of evoked potentials in medial entorhinal cortical neurons, which appears to be irreversible. The potentials can be facilitated by repetitive stimulation, and lead to synchronized discharges of entorhinal neurons. The discharges invade other areas such as the hippocampus, indicating how seizure activity may spread after AOAA injection in vivo. These data suggest that AOAA may be a useful tool to study longlasting changes in NMDA receptor function that lead to epileptiform activity and neurodegeneration. | McCloskey TC, Beshears JF, Halas NA, Commissaris RL (1988)
Potentiation of the anticonflict effects of diazepam, but not pentobarbital and phenobarbital, by aminooxyacetic acid (AOAA).
Pharmacology, biochemistry, and behavior 31, 693-698 [PubMed:3251251]
[show Abstract]
The Conditioned Suppression of Drinking (CSD) paradigm is an "animal model" for anxiety which has been used to study the anticonflict effects of the benzodiazepines. It has been postulated that benzodiazepines produce their effects through interactions with GABA. The present study examined this potential GABA-BZ interaction on CSD behavior. In daily 10-minute sessions, water-deprived rats were trained to drink from a tube which was occasionally electrified (0.5 mA), electrification being signalled by a tone. Within 2-3 weeks control CSD responding had stabilized (16-24 shocks session and 10-14 ml water/session); drug tests were conducted at weekly intervals. As expected, diazepam (0.3-20.0 mg/kg), pentobarbital (0.6-10.0 mg/kg) and phenobarbital (10.0-40.0 mg/kg) alone markedly increased the number of shocks received at doses which did not depress background responding (i.e., water intake). Treatment with the GABA-transaminase inhibitor aminooxyacetic acid (AOAA: 2.5-10.0 mg/kg, 10- or 60-minute pretreatment) alone had no anticonflict effect on CSD behavior. However, pretreatment (60-minute) with 10.0 mg/kg AOAA significantly potentiated the effects of diazepam, as indicated by a significant shift to the left in the diazepam dose-response curve relative to diazepam alone. By contrast, the anticonflict effects of pentobarbital and phenobarbital were unaffected by this AOAA pretreatment. Thus, while increases in GABA transmission alone do not appear to affect CSD behavior, the anticonflict effect of benzodiazepines, but not barbiturates, appear to be potentiated by increases in GABA transmission. |
|
