Terazosin activates Pgk1 and Hsp90 to promote stress resistance.
Terazosin activates Pgk1 and Hsp90 to promote stress resistance.
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DOI：
10.1038/nchembio.1657
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发表时间：
2015-01
影响因子：
14.8
通讯作者：
Liu, Lei
中科院分区：
文献类型：
--
作者：
Chen, Xinping;Zhao, Chunyue;Li, Xiaolong;Wang, Tao;Li, Yizhou;Cao, Cheng;Ding, Yuehe;Dong, Mengqiu;Finci, Lorenzo;Wang, Jia-huai;Li, Xiaoyu;Liu, Lei
迫切需要能够防止器官损伤的药物，特别是对于败血症和脑中风等疾病。我们已经发现特拉唑嗪（TZ），一种广泛销售的α 1-肾上腺素能受体激动剂，在中风和败血症的啮齿动物模型中减轻器官损伤并提高存活率。通过酶学和X射线晶体学的结合研究，我们发现TZ结合到一个新的靶点，磷酸甘油酸激酶1（Pgk 1），并激活其酶活性，可能是通过1，3-二氨基-6，7-二甲氧基异喹啉的能力，促进ATP从Pgk 1释放。从机制上讲，从Pgk 1产生的ATP可以增强Hsp 90的伴侣活性，Hsp 90是一种已知与Pgk 1相关的ATP酶。激活后，Hsp 90促进多重胁迫抗性。我们的研究表明，TZ具有一个新的蛋白质靶点Pgk 1，并揭示了其相应的生物学效应。作为一种临床药物，TZ可以迅速转化为治疗包括中风和败血症在内的毁灭性疾病。
Drugs that can protect against organ damage are urgently needed, especially for diseases such as sepsis and brain stroke. We have discovered that terazosin (TZ), a widely marketed alpha1-adrenergic receptor agonist, alleviated organ damage and improved survival in rodent models of stroke and sepsis. Through combined studies of enzymology and X-ray crystallography, we have discovered that TZ binds to a novel target, phosphoglycerate kinase 1 (Pgk1) and activates its enzymatic activity, probably through 1,3-diamino-6,7-dimethoxyisoquinoline's ability to promote ATP release from Pgk1. Mechanistically, the ATP generated from Pgk1 may enhance the chaperone activity of Hsp90, an ATPase known to associate with Pgk1. Upon activation, Hsp90 promotes multi-stress resistance. Our studies have demonstrated that TZ has a novel protein target, Pgk1, and has revealed its corresponding biological effect. As a clinical drug, TZ may be quickly translated into treatment of devastating diseases including stroke and sepsis.
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DOI：
10.1164/rccm.200702-291oc
发表时间：
2007-10-01
影响因子：
24.7
作者：
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通讯作者：
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影响因子：
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DOI：
10.1152/ajplung.00350.2007
发表时间：
2008-04-01
影响因子：
4.9
作者：
Chatterjee, Anuran;Snead, Connie;Catravas, John D.
通讯作者：
Catravas, John D.
影响因子：
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作者：
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Zhou, Qin