?在研究引起非洲瞌睡病的寄生虫时,来自约翰.霍普金斯大学的科学家已经发现先前尚未人知的分泌脂肪酸的途径,它是脂肪和所有细胞外层的组份。该研究发现揭示了更多的这种难杀死的寄生虫的生物学机理,并可以引导设计新的药物来对付此疾病,这种疾病影响将近500,000人,每年有50,000人命丧于此。
??该研究发现发表在8月份25期《细胞》杂志上。来自霍普金斯基础医学院生物化学系攻读博士后的哲学博士Soo Hee Lee 认为:“这是一个全新对的合成脂肪酸的生化途径。这个过程中涉及的酶可能对于设计治疗这种瞌睡病的药物提供了更好的研究靶点”。
??引起非洲瞌睡病的细胞锥虫在人与动物之间通过吸血舌蝇进行传播,在它的生命周期中会经历几个不同的时期。其中一个时期是在昆虫体内度过,其他时期是在宿主的血液中完成。
??该寄生虫通过在的外膜替代10,000,000种蛋白来避免人类免疫系统的侦察,这些不同的蛋白不能被免疫细胞所识别。通过十四酸脂脂肪酸的部分参与锚定而使这些蛋白黏附在细胞膜上,然而传统地在其他微生物中,这种参与锚定的都是16或者18碳单位的脂肪酸。
??来自霍普金斯大学基础医学院的生物化学专业的教授,哲学博士Paul Englund认为:“过去很多年我们都认为寄生虫必须从人类宿主得到十四酸脂,因为我们从来都没有观察到寄生虫自身可以生成脂肪酸的证据。几年前,我们发现寄生虫本身确实可以产生十四酸脂以及其他脂肪酸,现在我们发现它能用于我们以前从未找到过的生化途径中”。
??他们通过寻找锥虫基因组DNA条带中已知涉及在其他物种(象在动物以及植物中存在的)中可以合成脂肪酸的区域认识了这个脂肪酸合成的途径。
研究人员佯细描述了敲除脂肪酸合成基因可以阻止寄生虫分泌十四酸脂及其他脂肪酸。
??但是该研究团队的成员Jennifer Stephens敲除了在锥虫中和其他物种中已知的合成脂肪酸途径中的单个基因时,寄生虫合成十四酸脂的能力没有改变。奇怪的是,这是研究人员更仔细地检查了锥虫的基因组,发现在其他物种中作为抑止能增加脂肪酸长度的分子(同步复制延伸酶,目的是合成更长的脂肪酸,但是从来没有发现它真正能合成脂肪酸分子)。
??Lee敲除了这些延伸酶基因来看看寄生虫是否遇到合成脂肪酸障碍。让研究人员感到惊讶的是缺延伸酶的寄生虫不能合成14单位的十四酸脂或者其他脂肪酸。
??Lee谈到:“延伸酶途径最新颖的特色是包含有四种不通的酶依次参与脂肪酸的延伸。这个分子途径允许寄生虫控制它自身合成脂肪酸的长度”。
??Englund认为:“这个结果证明锥虫使用完全独特的合成脂肪酸的机制。先前研究的没有其他物种使用延伸酶来合成脂肪酸。同时建议攻击合成脂肪断的这个生化途径可能是治疗瞌睡病的一种方法。依照研究人员的意图,研究团体完全可以将兴趣放在研发涉及细菌脂肪酸合成的靶酶的新药上。”其中一个叫异烟肼的例子,就是目前用于治疗结核的药物。
??Englund认为:“锥虫在非洲那样卫生条件恶劣的偏远地区引起了严重的公共卫生问题,那里急切需要新药来治愈这些疾病”。
英文原文:
??African parasite makes component of fat differently from all other organisms
Studying the parasite that causes African sleeping sickness, scientists at Johns Hopkins have discovered a previously unknown way of making fatty acids, a component of fat and the outer layer of all cells. The find unveils more about the biology of this hard-to-kill parasite and could lead to a target for designing new drugs to fight the illness that infects a half-million people and kills 50,000 a year worldwide.
Results of the study, in the Aug. 25 issue of Cell, "show that this is a completely new biochemical pathway for making fatty acids," says Soo Hee Lee, Ph.D., a postdoctoral fellow in the Department of Biological Chemistry at the Institute for Basic Biomedical Sciences at Hopkins. "It may be that the enzymes in the pathway could be good targets for designing drugs to treat sleeping sickness."
The single-celled trypanosome that causes African sleeping sickness, transmitted between humans and animals by bloodsucking tsetse flies, goes through several different stages in its life cycle. One such form is harbored by the insect and the other multiplies in a host's bloodstream.
There, the parasite avoids detection by the human immune system by replacing each of the 10 million proteins on its outer layer - known as the cell membrane - with different proteins that are not recognized by immune cells. These proteins are attached to the cell membrane by an anchor composed in part of a fatty acid only 14 units long - dubbed myristate -- whereas typically, in other organisms, these types of anchors contain longer fatty acids, generally 16 or 18 units long.
"For many years we thought the parasite had to get the myristate from its human host because we never could see any evidence that it could make the fatty acid itself," says Paul Englund, Ph.D., a professor of biological chemistry in the Institute of Basic Biomedical Sciences at Hopkins. "Several years ago we found that it does actually make myristate as well as other fatty acids, and now we found that it uses a biochemical pathway we never knew to look for."
They learned about this new fatty acid-making pathway by hunting the trypanosome genome for stretches of DNA known to be involved in fatty acid synthesis in other organisms, like animals and plants.
The researchers reasoned that knocking out the fatty acid-making genes would prevent the parasite from making myristate and other fatty acids.
But when one member of the research team, Jennifer Stephens, knocked out a single gene in the trypanosome known to make fatty acids in other organisms, there was no change in the parasite's ability to make myristate. Surprised, the researchers then examined the trypanosome genome more carefully and discovered enzymes that in other organisms are known to increase the size of a fatty acid molecule - dubbed elongases, for making fatty acids longer - but never have been shown to actually make a new fatty acid molecule.
Lee knocked out these elongases to see if the parasite might have difficulty making fatty acids. To the researchers' surprise, the parasites lacking elongases were unable to make the 14-unit myristate or other fatty acids.
"A novel feature of the elongase pathway is that it contains four different enzymes that take turns in elongating fatty acids," says Lee. "This modular pathway allows the parasite to control the size of the fatty acids it makes."
"It turns out that trypanosomes use an entirely unique mechanism of making fatty acids. No other organism ever studied uses elongases to make them," says Englund, suggesting that attacking biochemical pathways that make fatty acids could be a way to treat sleeping sickness. According to the researchers, the research community is extremely interested in developing drugs that target bacterial enzymes involved in fatty acid synthesis. An example of one is called isoniazid, which currently is used to treat tuberculosis.
"Trypanosomes cause significant health problems in remote areas of Africa with poor health care," says Englund. "There is tremendous need for new drugs to cure these diseases."