Structures of aminoacylase 3 in complex with acetylated substrates
Structures of aminoacylase 3 in complex with acetylated substrates
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DOI：
10.1073/pnas.1006687107
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发表时间：
2010-10-19
影响因子：
11.1
通讯作者：
Pushkin, Alexander
中科院分区：
文献类型：
--
作者：
Hsieh, Jennifer M.;Tsirulnikov, Kirill;Pushkin, Alexander
三氯乙烯（TCE）是一种分布最广泛的环境污染物，其在通过尿液排出体外之前会被代谢为n -乙酰基- s -1,2-二氯乙烯基- l-半胱氨酸（NA-DCVC）。另外，NA-DCVC可以被氨基酰化酶3 （AA3）去乙酰化，这种酶在肾、肝和脑中高度表达。NA-DCVC去乙酰化启动转化为有毒产物，最终导致急性肾功能衰竭。因此，AA3抑制是预防TCE引起的肾毒性的重要靶点。本文报道了重组小鼠AA3 （mAA3）在乙酸副产物和n - α -乙酰基- l-酪氨酸和NA-DCVC两种底物存在下的晶体结构。这些结构结合生化数据表明，AA3通过范德瓦尔斯相互作用介导底物特异性，提供了一个动态的相互作用界面，促进了各种底物的形成。
Trichloroethylene (TCE) is one of the most widespread environmental contaminants, which is metabolized to N-acetyl-S-1,2-dichloro-vinyl-L-cysteine (NA-DCVC) before being excreted in the urine. Alternatively, NA-DCVC can be deacetylated by aminoacylase 3 (AA3), an enzyme that is highly expressed in the kidney, liver, and brain. NA-DCVC deacetylation initiates the transformation into toxic products that ultimately causes acute renal failure. AA3 inhibition is therefore a target of interest to prevent TCE induced nephrotoxicity. Here we report the crystal structure of recombinant mouse AA3 (mAA3) in the presence of its acetate byproduct and two substrates: N-alpha-acetyl-L-tyrosine and NA-DCVC. These structures, in conjunction with biochemical data, indicated that AA3 mediates substrate specificity through van der Waals interactions providing a dynamic interaction interface, which facilitates a diverse range of substrates.