645-88-5 NQRKYASMKDDGHT-UHFFFAOYSA-N NQRKYASMKDDGHT-UHFFFAOYSA-N Aminooxyacetic acid DTXSID50214756 Aminooxyacetic acid 2019-06-14T09:57:02 2019-06-14T09:57:02 S-(4-Carboxybutyl)-D,L-homocysteine; 5-(3-Amino-3-carboxypropyl)sulfanyl-pentanoic acid 2019-06-14T09:57:40 2019-06-14T09:57:40 CBS inhibition Molecular AOPWiki 2019-06-14T09:39:28 2019-06-14T09:39:28 Homocysteine increases Cellular AOPWiki 2019-06-14T09:45:38 2019-06-14T09:45:38 Plasma HCY level Tissue AOPWiki 2019-07-03T05:31:44 2019-07-03T05:31:44 dysfunction of microcirculation Organ AOPWiki 2019-07-03T05:34:31 2019-07-03T05:34:31 anterior-posterior axis development Individual AOPWiki 2019-07-03T05:35:53 2019-07-03T05:35:53 AOPWiki 2019-06-14T09:53:51 2019-06-14T09:53:51 AOPWiki 2019-07-03T05:37:06 2019-07-03T05:37:06 AOPWiki 2019-07-03T05:37:31 2019-07-03T05:37:31 AOPWiki 2019-07-03T05:37:55 2019-07-03T05:37:55 Homocysteine, anterior-posterior axis Young Jun Kim <p><strong>Chang Seon Ryu¹, Kichul Choe¹, Baeckkyoung Sung¹, Seungyun Baik¹, Sang Kyum Kim² and Young Jun Kim¹</strong></p> <p><strong><em>¹</em></strong><em>Environmental Safety Group, Korea Institute of Science and Technology (KIST) Europe, Campus E 7.1, Saarbruecken, Germany</em></p> <p><em>²</em><em>College of Pharmacy, Chungnam National University, daehakro 99, daejeon, Republic of Korea</em></p> BY-SA 2.0 <div> <table align="left" cellpadding="0" cellspacing="0"> <tbody> <tr> <td> <p>This AOP describes an adverse outcome that results from the inhibition of homocysteine (Hcy) catabolism. &nbsp;Hcy is a non-proteinogenic intermediary amino acid formed by the conversion of methionine to cysteine. &nbsp;Hcy is metabolized via two major pathways that remethylated via two remethylation pathway methionine synthase (MS) and betaine homocysteine methyltransferase (BHMT) and transsulfuration pathway enzyme, cystathionine beta-synthase (CBS). Impairment of re-methylation inhibition and/or transsulfuration lead to increment systemic concentration as known as hyperhomocysteinemia. &nbsp;CBS is responsible for 50% of Hcy clearance (Noga et al. 2003), together CBS is responsible for the generation of hydrogen sulfide (H₂S) from cysteine (Carter and Morton, 2016). &nbsp;&nbsp;&nbsp;Hyperhomocysteinemia leads to increment in Hcy to the neuronal system.&nbsp; CBS gene was expressed in liver and kidney, skeletal, cardiac and nervous systems (Robert et al. 2003;&nbsp; Namekata et al. 2004). Genetic deficiency of CBS in fish is critical for axis development (Prabhudesai et al. 2018), but there is not enough evidence in early neuronal development impairment in fish by chemical inhibition. Aminooxyacetic acid is a widely used CBS inhibitor that can reduce Hcy clearance and H₂S formation in the brain, has not only inhibition of CBS but also cystathione gamma-lyase. So far no selective pharmacological SBS inhibitor is currently available (Asimakopoulou et al. 2013).</p> </td> </tr> </tbody> </table> <div>&nbsp;</div> </div> <div>&nbsp;</div> <table align="left" cellpadding="0" cellspacing="0"> <tbody> <tr> <td> <p>Several observations indicate the involvement of hyperhomocysteinemia in neurodegeneration. Hcy levels may play a role in neuronal death via stimulation of glutamate receptors. Homocysteine is an agonist for metabotropic glutamate receptors as well as for NMDA (N-methyl-D-aspartate, as a partial antagonist) and AMPA (amino-3-hydroxy-5-methyl-4-isoxazolepropionate)/Kainate ionotropic glutamate receptors (Lazarewicz et al. 2003; Poddar and Paul 2009). Hcy further mediated subsequent Ca2+ efflux to biphasic activation of p38 &nbsp;mitogen-activated protein kinase&nbsp; (MAPK) (poddar and Paul 2013). Second possible mechanism of Hcy toxicity is free radical species production, and downregulation of antioxidant enzymes such as superoxide dismutase and peroxidase (Moat et al. 2000; Liu et al. 2013) &nbsp;Hcy has also been reported to modulate the expression of pro-inflammatory molecules, C-reactive protein in vascular smooth muscle cells (Pang et al. 2014). Moreover, Hcy is able to inhibit neurogenesis in the hippocampus and subventricular zone of the murine adult brain (Wang et al. 2012; Rabaneda et al. 2008). &nbsp;&nbsp; Hyperhomocysteinemia accelerates the dopaminergic cell death, probably due to the fact that hyperhomocysteinemia could cause a severe reduction in dopamine turnover in the striatum (De Lau et al. 2005).</p> <p><strong>Acknowledgements</strong>:&nbsp;This research was supported by the National Research Council of Science &amp; Technology(NST) grant by the Korea&nbsp;government (MSIP) (No. CAP-17-01-KIST Europe)</p> </td> </tr> </tbody> </table> <div>&nbsp;</div> adjacent Low High adjacent Moderate High adjacent Low Moderate adjacent Low Moderate Moderate Mixed High Birth to < 1 month <p>This AOP is under development supported by the National Research Council of Science &amp; Technology (NST) grant by the Korea government (MSIP) (No. CAP-17-01-KIST Europe).</p> <p>&nbsp;</p> <table border="1" cellpadding="0" cellspacing="0" style="width:841px"> <tbody> <tr> <td colspan="2" style="height:17px; width:463px"> <p><strong><u>To do</u></strong></p> </td> <td style="height:17px; width:97px"> <p><strong><u>Expected duration</u></strong></p> </td> </tr> <tr> <td rowspan="2" style="height:16px; width:168px"> <p>Building the AOP frame</p> </td> <td style="height:16px; width:294px"> <p>Development of KEs</p> </td> <td style="height:16px; width:97px"> <p>3 month</p> </td> </tr> <tr> <td style="height:17px; width:294px"> <p>Production of experimental data</p> </td> <td style="height:17px; width:97px"> <p>18 month</p> </td> </tr> <tr> <td rowspan="5" style="height:16px; width:168px"> <p>Overall assessment of the AOP</p> </td> <td style="height:16px; width:294px"> <p>Biological domain of applicability</p> </td> <td style="height:16px; width:97px"> <p>3 month</p> </td> </tr> <tr> <td style="height:17px; width:294px"> <p>Essentiality of all KEs</p> </td> <td style="height:17px; width:97px"> <p>3 month</p> </td> </tr> <tr> <td style="height:16px; width:294px"> <p>Evidence supporting all KERs</p> </td> <td style="height:16px; width:97px"> <p>5 month</p> </td> </tr> <tr> <td style="height:17px; width:294px"> <p>Quantitative WoE considerations</p> </td> <td style="height:17px; width:97px"> <p>5 month</p> </td> </tr> <tr> <td style="height:17px; width:294px"> <p>Quantitative understanding for each KER</p> </td> <td style="height:17px; width:97px"> <p>6 month</p> </td> </tr> </tbody> </table> <p>FIsh</p> <p>This AOP is designed to detect changes of Hcy concentration in early developmental condition including fish larvae by chemical inhibition of CBS.&nbsp; Accumulation of neuronal damage in fish is the should be measured together in <em>in vivo</em> experiment for clarifing&nbsp;the adverse outcome. In addition, screening of selective potential chemical inhibitor of CBS will be performed in <em>in vitro</em> cell-based assay in different species.</p> High High <p>Abbott MH, Folstein SE, Abbey H, Pyeritz RE. (1987) Psychiatric manifestations of homocystinuria due to cystathionine beta-synthase deficiency: prevalence, natural history, and relationship to neurologic impairment and vitamin B6-responsiveness. Am J Med Genet. 1987 Apr; 26(4):959-69.</p> <p>SJ Lee, SH Park, JF Chung, WR Choi, and HK Huh(2017) Homocysteine-induced peripheral microcirculation dysfunction in zebrafish and its attenuation by L-arginine. Oncotarget. 2017 Aug 29; 8(35): 58264&ndash;58271.</p> <p>Noga AA, Stead LM, Zhao Y, Brosnan ME, Brosnan JT, Vance DE (2003) Plasma homocysteine is regulated by phospholipid methylation. J. Biol. Chem. 278, 5952&ndash;5955.</p> <p>Carter RN, Morton NM. &nbsp;(2016) Cysteine and hydrogen sulphide in the regulation of metabolism: insights from genetics and pharmacology &nbsp;J Pathol. 238(2):321-32.</p> <p>Lazarewicz JW1, Ziembowicz A, Matyja E, Stafiej A, Zieminska E (2003) Homocysteine-evoked 45Ca release in the rabbit hippocampus is mediated by both NMDA and group I metabotropic glutamate receptors: in vivo microdialysis study. &nbsp;Neurochem Res. 28(2):259-69.</p> <p>Poddar R, Paul S. (2009) Homocysteine-NMDA receptor-mediated activation of extracellular signal-regulated kinase leads to neuronal cell death. J Neurochem. 110(3):1095-106</p> <p>Pang X, Liu J, Zhao J, Mao J, Zhang X, Feng L (2014) Homocysteine induces the expression of C-reactive protein via NMDAr-ROS-MAPK-NF-KB signal pathway in rat vascular smooth muscle cells. Atherosclerosis. 236:73&ndash;81</p> <p>De Lau LM, Koudstaal PJ, van Meurs JB, Uitterlinden AG, Hofman A, Breteler MM (2005) Methylenterahydrofolate reductase C677T genotype and PD. Annu. Neurol. 57:927&ndash;930.</p> <p>Liu HH, Shih TS, Huang HR, Huang SC, Lee LH, Huang YC. (2013) Plasma homocysteine is associated with increased oxidative stress and antioxidant enzyme activity in welders. ScientificWorldJournal. 370487.</p> <p>Moat SJ, Bonham JR, Cragg RA, Powers HJ.(2000)&nbsp; Elevated plasma homocysteine elicits an increase in antioxidant enzyme activity. &nbsp;Free Radic Res. 2000 Feb;32(2):171-9.</p> <p>Wang J, Bai X, Chen Y, Zhao Y, Liu X. (2012) Homocysteine induces apoptosis of rat hippocampal neurons by inhibiting 14-3-3&epsilon; expression and activating calcineurin. PLoS One. 7(11):e48247.</p> <p>Rabaneda LG1, Carrasco M, L&oacute;pez-Toledano MA, Murillo-Carretero M, Ruiz FA, Estrada C, Castro C. (2008) Homocysteine inhibits proliferation of neuronal precursors in the mouse adult brain by impairing the basic fibroblast growth factor signaling cascade and reducing extracellular regulated kinase 1/2-dependent cyclin E expression. FASEB J. 22(11):3823-35.</p> <p>Prabhudesai et al. (2018) Cystathionine &beta;-Synthase Is Necessary for Axis Development in Vivo. Front Cell Dev Biol. 2018 Feb 16;6:14</p> <p>Asimakopoulou A, Panopoulos P, Chasapis CT, Coletta C, Zhou Z, Cirino G, Giannis A, Szabo C, Spyroulias GA, Papapetropoulos A. (2013) Selectivity of commonly used pharmacological inhibitors for cystathionine &beta; synthase (CBS) and cystathionine &gamma; lyase (CSE). &nbsp;Br J Pharmacol. 169(4):922-32.</p> <p>J Histochem Cytochem. 2003 Mar;51(3):363-71. Expression of the cystathionine beta synthase (CBS) gene during mouse development and immunolocalization in adult brain. Robert K1, Vialard F, Thiery E, Toyama K, Sinet PM, Janel N, London J.</p> <p>J Biol Chem. 2004 Dec 17;279(51):52961-9. Epub 2004 Oct 4. Abnormal lipid metabolism in cystathionine beta-synthase-deficient mice, an animal model for hyperhomocysteinemia. Namekata K1, Enokido Y, Ishii I, Nagai Y, Harada T, Kimura H.</p> AOPWiki 2019-06-14T08:41:37 2023-04-29T16:03:02