Inhibition of aminoacylase 3 protects rat brain cortex neuronal cells from the toxicity of 4-hydroxy-2-nonenal mercapturate and 4-hydroxy-2-nonenal.
Inhibition of aminoacylase 3 protects rat brain cortex neuronal cells from the toxicity of 4-hydroxy-2-nonenal mercapturate and 4-hydroxy-2-nonenal.
复制标题
抗氨基酶3的抑制作用可保护大鼠脑皮质神经元细胞免受4-羟基-2-非胃胃酸盐和4-羟基-2-非纳纳纳尔的毒性。
DOI：
10.1016/j.taap.2012.07.002
复制
发表时间：
2012-09-15
影响因子：
3.8
通讯作者：
Pushkin A
中科院分区：
文献类型：
--
作者：
Tsirulnikov K;Abuladze N;Bragin A;Faull K;Cascio D;Damoiseaux R;Schibler MJ;Pushkin A
4-羟基-2-壬烯醛（HNE）和丙烯醛是脂质过氧化的高反应性神经毒性产物，其在阿尔茨海默病和帕金森病脑中积累，并与这些神经系统疾病的发病机制和进展有关。与谷胱甘肽（GSH）结合启动HNE和丙烯醛解毒途径，其产生可被排泄的HNE和丙烯醛的巯基尿酸盐。先前的工作已经表明，卤代烯烃衍生的巯基尿酸盐的GSH依赖性肾解毒的效率在其脱乙酰化后显著降低。此外，脱乙酰化产物通过β-裂解酶迅速转化为导致巯基尿酸盐肾毒性的毒性化合物。由于GSH结合途径的酶和β-裂解酶在脑中表达，因此我们假设HNE和丙烯醛巯基尿酸盐的脱乙酰化可能在脑中引发类似的毒性机制。进行本研究以鉴定参与HNE和丙烯醛巯基尿酸盐脱乙酰化的酶，表征该酶的脑表达，并确定其抑制是否降低HNE和HNE巯基尿酸盐在神经元中的毒性。我们证明，已知的两个候选酶脱乙酰巯基尿酸，氨基酰化酶1（AA 1）和3（AA 3），只有AA 3有效地脱乙酰HNE和丙烯醛巯基尿酸。AA 3进一步定位于神经元和血管。使用小分子筛选，我们进一步产生高亲和力AA 3抑制剂。其中两个完全保护大鼠大脑皮层神经元表达AA 3的毒性HNE硫醇。结果提示，AA 3介导的HNE巯基尿酸酯的脱乙酰化可能参与了HNE的神经毒性。
4-Hydroxy-2-nonenal (HNE) and acrolein are highly reactive neurotoxic products of lipid peroxidation that accumulate in Alzheimer’s and Parkinson’s disease brain and are implicated in the pathogenesis and progression of these neurological diseases. Conjugation with glutathione (GSH) initiates the HNE and acrolein detoxification pathway, which generates the mercapturates of HNE and acrolein that can be excreted. Prior work has shown that the efficiency of the GSH-dependent renal detoxification of haloalkene derived mercapturates is significantly decreased upon their deacetylation. Moreover the deacetylated products are rapidly transformed via β-lyases into toxic compounds responsible for the nephrotoxicity of the mercapturates. Because the enzymes of the GSH-conjugation pathway and β-lyases are expressed in brain, we hypothesized that a similar toxicity mechanism may be initiated in brain by the deacetylation of HNE and acrolein mercapturates. The present study was performed to identify an enzyme(s) involved in HNE and acrolein mercapturate deacetylation, characterize the brain expression of this enzyme and determine whether its inhibition decreases HNE and HNE mercapturate toxicity in neurons. We demonstrated that of two candidate enzymes known to deacetylate mercapturic acids, aminoacylases 1 (AA1) and 3 (AA3), only AA3 efficiently deacetylates both HNE and acrolein mercapturates. AA3 was further localized to neurons and blood vessels. Using a small molecule screen we further generated high-affinity AA3 inhibitors. Two of them completely protected rat brain cortex neurons expressing AA3 from the toxicity of HNE mercapturate. The results suggest that AA3 mediated deacetylation of HNE mercapturate may be involved in the neurotoxicity of HNE.
登录
查看更多内容
DOI：
10.1016/j.bbalip.2010.02.005
发表时间：
2010-08
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Butterfield DA;Bader Lange ML;Sultana R
通讯作者：
Sultana R
影响因子：
9.9
作者：
Gao, Xiang;Chen, Honglei;Ascherio, Alberto
通讯作者：
Ascherio, Alberto
DOI：
10.1073/pnas.1006687107
发表时间：
2010-10-19
影响因子：
11.1
作者：
Hsieh, Jennifer M.;Tsirulnikov, Kirill;Pushkin, Alexander
通讯作者：
Pushkin, Alexander
影响因子：
4.2
作者：
Huang, Quanzhen;Aluise, Christopher D.;Butterfield, D. Allan
通讯作者：
Butterfield, D. Allan
影响因子：
2.9
作者：
Humphries, KM;Yoo, Y;Szweda, LI
通讯作者：
Szweda, LI