EasySep™小鼠TIL（CD45）正选试剂盒
产品号 #72922_C
AMPK活化剂
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总览
A769662是amp活化蛋白激酶（AMPK）的细胞渗透性直接活化剂，EC₅₀为116 nM （Goransson等人）。通过变构机制观察到4.1倍的AMPK刺激，这可能抑制Thr172上的去磷酸化(Goransson等人；Sanders等人)。A769662特异性激活含有AMPK的β1亚基异源三聚体，其作用不依赖于AMPK上游的激酶。激活AMPK可以抑制mTORC1信号通路（Huang 等人）。A769662也是Na(+)-K(+)- ATP酶的抑制剂（Benziane等人）。
重编程
·抑制小鼠成纤维细胞重编程为诱导多能干细胞（Vazquez-Martin等人）。
维护
·抑制间充质干细胞增殖（de Meester等人）。
癌症研究
·延迟pten缺陷小鼠的肿瘤发作（Huang等人）。
代谢
·抑制原代大鼠肝细胞脂肪酸合成，降低Sprague Dawley大鼠血糖（Cool等人）。
细胞类型
癌细胞及细胞系，间充质干/祖细胞，多能干细胞
种属
人，小鼠，非人灵长类，其他物种，大鼠
研究领域
癌症，上皮细胞研究，代谢，干细胞生物学
CAS 编号
844499-71-4
化学式
C₂₀H₁₂N₂O₃S
纯度
≥98%
通路
AMPK
靶点
AMPK
产品说明书及文档
请在《产品说明书》中查找相关支持信息和使用说明，或浏览下方更多实验方案。
相关材料与文献
技术资料 (2)
文献 (7)
Identification and characterization of a small molecule AMPK activator that treats key components of type 2 diabetes and the metabolic syndrome.
Cell metabolism 2006
Abstract
AMP-activated protein kinase (AMPK) is a key sensor and regulator of intracellular and whole-body energy metabolism. We have identified a thienopyridone family of AMPK activators. A-769662 directly stimulated partially purified rat liver AMPK (EC50 = 0.8 microM) and inhibited fatty acid synthesis in primary rat hepatocytes (IC50 = 3.2 microM). Short-term treatment of normal Sprague Dawley rats with A-769662 decreased liver malonyl CoA levels and the respiratory exchange ratio,VCO2/VO2,indicating an increased rate of whole-body fatty acid oxidation. Treatment of ob/ob mice with 30 mg/kg b.i.d. A-769662 decreased hepatic expression of PEPCK,G6Pase,and FAS,lowered plasma glucose by 40%,reduced body weight gain and significantly decreased both plasma and liver triglyceride levels. These results demonstrate that small molecule-mediated activation of AMPK in vivo is feasible and represents a promising approach for the treatment of type 2 diabetes and the metabolic syndrome.
Defining the mechanism of activation of AMP-activated protein kinase by the small molecule A-769662, a member of the thienopyridone family.
The Journal of biological chemistry 2007
Abstract
AMP-activated protein kinase (AMPK) plays a key role in maintaining energy homeostasis. Activation of AMPK in peripheral tissues has been shown to alleviate the symptoms of metabolic diseases,such as type 2 diabetes,and consequently AMPK is a target for treatment of these diseases. Recently,a small molecule activator (A-769662) of AMPK was identified that had beneficial effects on metabolism in ob/ob mice. Here we show that A-769662 activates AMPK both allosterically and by inhibiting dephosphorylation of AMPK on Thr-172,similar to the effects of AMP. A-769662 activates AMPK harboring a mutation in the gamma subunit that abolishes activation by AMP. An AMPK complex lacking the glycogen binding domain of the beta subunit abolishes the allosteric effect of A-769662 but not the allosteric activation by AMP. Moreover,mutation of serine 108 to alanine,an autophosphorylation site within the glycogen binding domain of the beta1 subunit,almost completely abolishes activation of AMPK by A-769662 in cells and in vitro,while only partially reducing activation by AMP. Based on our results we propose a model for activation of AMPK by A-769662. Importantly,this model may provide clues for understanding the mechanism by which AMP leads to activation of AMPK,which in turn may help in the identification of other AMPK activators.
Mechanism of Action of A-769662, a Valuable Tool for Activation of AMP-activated Protein Kinase
Journal of Biological Chemistry 2007
Abstract
We have studied the mechanism of A-769662,a new activator of AMP-activated protein kinase (AMPK). Unlike other pharmacological activators,it directly activates native rat AMPK by mimicking both effects of AMP,i.e. allosteric activation and inhibition of dephosphorylation. We found that it has no effect on the isolated alpha subunit kinase domain,with or without the associated autoinhibitory domain,or on interaction of glycogen with the beta subunit glycogen-binding domain. Although it mimics actions of AMP,it has no effect on binding of AMP to the isolated Bateman domains of the gamma subunit. The addition of A-769662 to mouse embryonic fibroblasts or primary mouse hepatocytes stimulates phosphorylation of acetyl-CoA carboxylase (ACC),effects that are completely abolished in AMPK-alpha1(-/-)alpha2(-/-) cells but not in TAK1(-/-) mouse embryonic fibroblasts. Phosphorylation of AMPK and ACC in response to A-769662 is also abolished in isolated mouse skeletal muscle lacking LKB1,a major upstream kinase for AMPK in this tissue. However,in HeLa cells,which lack LKB1 but express the alternate upstream kinase calmodulin-dependent protein kinase kinase-beta,phosphorylation of AMPK and ACC in response to A-769662 still occurs. These results show that in intact cells,the effects of A-769662 are independent of the upstream kinase utilized. We propose that this direct and specific AMPK activator will be a valuable experimental tool to understand the physiological roles of AMPK.
更多信息
| 物种 | 人, 其它物种, 大鼠, 小鼠, 非人灵长类 |
|---|---|
| Cas Number | 844499-71-4 |
| Chemical Formula | C₂₀H₁₂N₂O₃S |
| 纯度 | ≥ 98% |
| Target | AMPK |
| Pathway | AMPK |
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