Novel inhibitors of mitochondrial sn-glycerol 3-phosphate dehydrogenase.
Novel inhibitors of mitochondrial sn-glycerol 3-phosphate dehydrogenase.
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DOI：
10.1371/journal.pone.0089938
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Brand MD
中科院分区：
文献类型：
--
作者：
Orr AL;Ashok D;Sarantos MR;Ng R;Shi T;Gerencser AA;Hughes RE;Brand MD
线粒体sn-甘油3-磷酸脱氢酶（mGPDH）是线粒体内膜中的一种泛醌连接酶，最好表征为甘油磷酸穿梭的一部分，其将还原当量从细胞溶质NADH转移到线粒体电子传递链中。尽管mGPDH的广泛表达和mGPDH缺失小鼠的可用性，这种酶的生理作用在许多组织中仍然不清楚，可能是因为NAD+的胞质再生的补偿途径和甘油磷酸代谢的机制。在这里，我们描述了一类新的细胞渗透性小分子抑制剂mGPDH（iGP）发现通过小分子筛选。结构-活性分析鉴定了核心苯并咪唑-苯基-琥珀酰胺结构对于抑制mGPDH是必不可少的，而对苯并咪唑环系统的修饰调节了效力和脱靶效应。活细胞成像提供了iGP穿透细胞膜的证据。对两种化合物（iGP-1和iGP-5）进行了进一步表征，以确定效力和选择性，并发现其为混合抑制剂，IC 50和Ki值在1-15 µM之间。这些新型mGPDH抑制剂是研究甘油3-磷酸代谢在分离和完整系统中的作用的独特工具。
Mitochondrial sn-glycerol 3-phosphate dehydrogenase (mGPDH) is a ubiquinone-linked enzyme in the mitochondrial inner membrane best characterized as part of the glycerol phosphate shuttle that transfers reducing equivalents from cytosolic NADH into the mitochondrial electron transport chain. Despite the widespread expression of mGPDH and the availability of mGPDH-null mice, the physiological role of this enzyme remains poorly defined in many tissues, likely because of compensatory pathways for cytosolic regeneration of NAD+ and mechanisms for glycerol phosphate metabolism. Here we describe a novel class of cell-permeant small-molecule inhibitors of mGPDH (iGP) discovered through small-molecule screening. Structure-activity analysis identified a core benzimidazole-phenyl-succinamide structure as being essential to inhibition of mGPDH while modifications to the benzimidazole ring system modulated both potency and off-target effects. Live-cell imaging provided evidence that iGPs penetrate cellular membranes. Two compounds (iGP-1 and iGP-5) were characterized further to determine potency and selectivity and found to be mixed inhibitors with IC50 and K i values between ∼1–15 µM. These novel mGPDH inhibitors are unique tools to investigate the role of glycerol 3-phosphate metabolism in both isolated and intact systems.
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影响因子：
4.8
作者：
Brown, LJ;Koza, RA;MacDonald, MJ
通讯作者：
MacDonald, MJ
DOI：
10.1016/0006-291x(89)92414-5
发表时间：
1989-02-28
影响因子：
3.1
作者：
BELEZNAI, Z;JANCSIK, V
通讯作者：
JANCSIK, V
DOI：
10.1006/bbrc.1995.1724
发表时间：
1995-05-25
影响因子：
3.1
作者：
DRAHOTA, Z;SAF, P;KALOUS, M
通讯作者：
KALOUS, M
影响因子：
5.8
作者：
COONEY, GJ;DAWSON, AG
通讯作者：
DAWSON, AG
影响因子：
56.9
作者：
Eto, K;Tsubamoto, Y;Kadowaki, T
通讯作者：
Kadowaki, T