?在研究引起非洲瞌睡病的寄生蟲時，來自約翰.霍普金斯大學(xué)的科學(xué)家已經(jīng)發(fā)現(xiàn)先前尚未人知的分泌脂肪酸的途徑,，它是脂肪和所有細胞外層的組份。該研究發(fā)現(xiàn)揭示了更多的這種難殺死的寄生蟲的生物學(xué)機理，并可以引導(dǎo)設(shè)計新的藥物來對付此疾病，這種疾病影響將近500,000人,，每年有50,000人命喪于此。
??該研究發(fā)現(xiàn)發(fā)表在8月份25期《細胞》雜志上,。來自霍普金斯基礎(chǔ)醫(yī)學(xué)院生物化學(xué)系攻讀博士后的哲學(xué)博士Soo Hee Lee 認為：“這是一個全新對的合成脂肪酸的生化途徑,。這個過程中涉及的酶可能對于設(shè)計治療這種瞌睡病的藥物提供了更好的研究靶點”。
??引起非洲瞌睡病的細胞錐蟲在人與動物之間通過吸血舌蠅進行傳播,，在它的生命周期中會經(jīng)歷幾個不同的時期,。其中一個時期是在昆蟲體內(nèi)度過，其他時期是在宿主的血液中完成,。
??該寄生蟲通過在的外膜替代10,000,000種蛋白來避免人類免疫系統(tǒng)的偵察,，這些不同的蛋白不能被免疫細胞所識別。通過十四酸脂脂肪酸的部分參與錨定而使這些蛋白黏附在細胞膜上,，然而傳統(tǒng)地在其他微生物中,，這種參與錨定的都是16或者18碳單位的脂肪酸。
??來自霍普金斯大學(xué)基礎(chǔ)醫(yī)學(xué)院的生物化學(xué)專業(yè)的教授,，哲學(xué)博士Paul Englund認為：“過去很多年我們都認為寄生蟲必須從人類宿主得到十四酸脂,，因為我們從來都沒有觀察到寄生蟲自身可以生成脂肪酸的證據(jù)。幾年前,，我們發(fā)現(xiàn)寄生蟲本身確實可以產(chǎn)生十四酸脂以及其他脂肪酸,，現(xiàn)在我們發(fā)現(xiàn)它能用于我們以前從未找到過的生化途徑中”,。
??他們通過尋找錐蟲基因組DNA條帶中已知涉及在其他物種（象在動物以及植物中存在的）中可以合成脂肪酸的區(qū)域認識了這個脂肪酸合成的途徑,。
研究人員佯細描述了敲除脂肪酸合成基因可以阻止寄生蟲分泌十四酸脂及其他脂肪酸。
??但是該研究團隊的成員Jennifer Stephens敲除了在錐蟲中和其他物種中已知的合成脂肪酸途徑中的單個基因時,，寄生蟲合成十四酸脂的能力沒有改變,。奇怪的是，這是研究人員更仔細地檢查了錐蟲的基因組,，發(fā)現(xiàn)在其他物種中作為抑止能增加脂肪酸長度的分子（同步復(fù)制延伸酶,，目的是合成更長的脂肪酸，但是從來沒有發(fā)現(xiàn)它真正能合成脂肪酸分子）,。
??Lee敲除了這些延伸酶基因來看看寄生蟲是否遇到合成脂肪酸障礙,。讓研究人員感到驚訝的是缺延伸酶的寄生蟲不能合成14單位的十四酸脂或者其他脂肪酸。
??Lee談到：“延伸酶途徑最新穎的特色是包含有四種不通的酶依次參與脂肪酸的延伸,。這個分子途徑允許寄生蟲控制它自身合成脂肪酸的長度”,。
??Englund認為：“這個結(jié)果證明錐蟲使用完全獨特的合成脂肪酸的機制。先前研究的沒有其他物種使用延伸酶來合成脂肪酸。同時建議攻擊合成脂肪斷的這個生化途徑可能是治療瞌睡病的一種方法,。依照研究人員的意圖,，研究團體完全可以將興趣放在研發(fā)涉及細菌脂肪酸合成的靶酶的新藥上。”其中一個叫異煙肼的例子,，就是目前用于治療結(jié)核的藥物,。
??Englund認為：“錐蟲在非洲那樣衛(wèi)生條件惡劣的偏遠地區(qū)引起了嚴重的公共衛(wèi)生問題，那里急切需要新藥來治愈這些疾病”,。
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."
