Discovery of a series of aromatic lactones as ALDH1/2-directed inhibitors.
Discovery of a series of aromatic lactones as ALDH1/2-directed inhibitors.
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DOI：
10.1016/j.cbi.2014.12.038
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发表时间：
2015-06-05
影响因子：
5.1
通讯作者：
Hurley, Thomas D.
中科院分区：
文献类型：
--
作者：
Buchman, Cameron D.;Mahalingan, Krishna K.;Hurley, Thomas D.
在人类中，醛脱氢酶超家族由19种同工酶组成，主要催化醛的NAD（P）+依赖性氧化。这些同工酶中的许多具有重叠的底物特异性，因此它们的潜在生理功能可能重叠。因此，开发新的同工酶选择性探针将能够更好地描绘单一同工酶的功能及其对特定底物代谢的个体贡献。这项特定的研究旨在寻找ALDH 2的新调节剂，ALDH 2是一种线粒体ALDH同工酶，因其在乙醛氧化中的作用而闻名。通过高通量酯酶筛选，从63，000种化合物的文库中初步鉴定出53种化合物调节ALDH 2的活性。在这些最初的53种化合物中，发现12种也调节ALDH 2对丙醛的氧化。使用ALDH 1A 1、ALDH 1A 2、ALDH 1A 3、ALDH 2、ALDH 1B 1、ALDH 3A 1、ALDH 4A 1和/或ALDH 5A 1在10 μM化合物下进行单一浓度测量，以确定这12种化合物对ALDH 2的选择性。1/2个化合物中的4个具有芳香内酯结构，并且被发现是ALDH 1/2同工酶的有效抑制剂，但对ALDH 3A 1、ALDH 4A 1或ALDH 5A 1没有抑制作用。两种芳香族内酯在ALDH 1/2类中显示出选择性，与所有其他测试的同工酶相比，一种似乎对ALDH 2具有选择性。
In humans, the aldehyde dehydrogenase superfamily consists of 19 isoenzymes which mostly catalyze the NAD(P)+-dependent oxidation of aldehydes. Many of these isoenzymes have overlapping substrate specificities and therefore their potential physiological functions may overlap. Thus the development of new isoenyzme-selective probes would be able to better delineate the function of a single isoenyzme and its individual contribution to the metabolism of a particular substrate. This specific study was designed to find a novel modulator of ALDH2, a mitochondrial ALDH isoenzyme most well-known for its role in acetaldehyde oxidation. 53 compounds were initially identified to modulate the activity of ALDH2 by a high-throughput esterase screen from a library of 63,000 compounds. Of these initial 53 compounds, 12 were found to also modulate the oxidation of propionaldehyde by ALDH2. Single concentration measurements at 10 μM compound were performed using ALDH1A1, ALDH1A2, ALDH1A3, ALDH2, ALDH1B1, ALDH3A1, ALDH4A1, and/or ALDH5A1 to determine the selectivity of these 12 compounds towards ALDH2. Four of the twelve compounds shared an aromatic lactone structure and were found to be potent inhibitors of the ALDH1/2 isoenzymes, but have no inhibitory effect on ALDH3A1, ALDH4A1 or ALDH5A1. Two of the aromatic lactones show selectivity within the ALDH1/2 class, and one appears to be selective for ALDH2 compared to all other isoenzymes tested.
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影响因子：
7.3
作者：
Kimble-Hill AC;Parajuli B;Chen CH;Mochly-Rosen D;Hurley TD
通讯作者：
Hurley TD
影响因子：
3.2
作者：
Parajuli, Bibek;Georgiadis, Taxiarchis M.;Fishel, Melissa L.;Hurley, Thomas D.
通讯作者：
Hurley, Thomas D.
影响因子：
3
作者：
Moreb, Jan S.;Muhoczy, Dagmara;Zucali, James R.
通讯作者：
Zucali, James R.
影响因子：
2.9
作者：
Klyosov, AA;Rashkovetsky, LG;Keung, WM
通讯作者：
Keung, WM
影响因子：
4.1
作者：
Cheng, G;Shi, YL;Hecht, SS
通讯作者：
Hecht, SS