生物谷报道:纽约大学和Scripps研究所的研究人员发现了一种称为GAPDH的酶,能够调节胰岛素通路――这个发现为治疗糖尿病提供了新方向。这一研究在最新一期自然.化学生物学杂志上有所报道。
以前并不知道GAPDH这种酶是人产生糖尿病的因素之一,现在,该研究还发现,抑制GAPDH的活性能减轻动物模型的糖尿病症状。
该研究队伍来自纽约大学生物学与化学系和Scripps细胞生物学部,他们用秀丽隐杆线虫(C.elegans)来分离鉴定治疗糖尿病的新的靶点蛋白。秀丽隐杆线虫是第一个被发现存在RNA干扰(RNAi)的动物,也是研究化学遗传学的很好的模式生物。在该研究中,研究人员用糖尿病突变株作为糖尿病模型,从秀丽隐杆线虫身上上百种化合物中筛选一种能够让糖尿病秀丽隐杆线虫存活的化合物。于是,他们找到了目标蛋白――GAPDH酶。科学家很早就知道GAPDH是一种重要的糖酵解酶,而且它的功能是受胰岛素影响的。然而,这是首次发现GAPDH能积极的调节胰岛素通路。
虽然市场上已经有很多治疗糖尿病的药物,但是已知的产生糖尿病的蛋白靶点的数目是不多的。因为糖尿病是多因素产生的,针对几个不同的蛋白进行治疗是最有希望的治疗方法。GAPDH的发现为该疾病的联合治疗添加了又一靶点。
英文原文:
NYU, Scripps Finding Offers New Path for Treatment of Diabetes
11/27/06 -- Researchers at New York University and the Scripps Research Institute have discovered a new enzyme, GAPDH, which regulates insulin pathways--a finding that offers a new direction for the treatment of diabetes. The research is reported in the most recent issue of the journal Nature Chemical Biology.
The enzyme GAPDH was previously unknown to be a factor in the development of diabetes in humans. It has also been discovered that the inhibition of GAPDH attenuates the diabetic disease symptom in model animals.
The research team, which included NYU?s Departments of Biology and Chemistry and Scripps? Department of Cell Biology, used the worm Caenorhabditis elegans (C. elegans) to identify a new therapeutic target protein for diabetic treatment. C. elegans is the first animal species where RNA interference (RNAi) is discovered and thus, an excellent model organism for chemical genetic research. In this study, the researchers screened hundreds of chemical compounds to find one hit compound, which rescues the mutant C. elegans (diabetics model) from diabetes. Then, they identified the target protein, which was found to be the enzyme GAPDH. GAPDH has long been known as one of the important glycolytic enzymes, and its function is affected by insulin. However, this is the first discovery that GAPDH actively regulates the insulin pathway.
The research team constructed all the molecules by incorporating the fishing tag (linker) from the beginning, and facilitated the target fishing. The hit compound was named GAPDS (GAPDH segregator) as GAPDS disassemble the multi-part structure of GAPDH into monomers. The segregation of GAPDH releases the suppressor of insulin signaling from the cell membrane, and thus activates the insulin signaling to eventually help to treat diabetes.
While the C-elegans is a recommended model for chemical genetic study, treating them with chemical compounds presented difficulties for the researchers because they grow on the surface of agar. To overcome these challenges, the researchers devised a soaking method in which the worms were placed in a compound solution for 24 hours. By this method, the worms were exposed to equitable concentration of the compounds. The mutant C-elegans are in a growth arrested status. By addition of compounds, a re-growing of the worms into normal size was observed by GAPDS, which is analogous to treating diabetes patients with a drug.
While there are many drugs on the market to treat diabetes, the number of known disease-producing protein targets is small. Because diabetes has many causes, targeting several different proteins offers the most promising method for treatment. The discovery of GAPDH adds another target that can be addressed in combating the disease.
Source: New York University
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