生物谷報(bào)道：一些生物化學(xué)過(guò)程被認(rèn)為已經(jīng)被研究得非常完整,，因此科學(xué)家相信不會(huì)再取得任何這方面的發(fā)現(xiàn),。葉酸（Flolic acid）是一種廣泛存在于綠色蔬菜中的B族維生素，由于它最早從植物葉子中提取而得,，故命名為"葉酸",。此前，人們對(duì)葉酸生化過(guò)程有了較深入的了解,，但是一種葉酸酶卻始終是一個(gè)未能解開(kāi)的謎團(tuán),。但是最近Johns Hopkins大學(xué)的科學(xué)家的發(fā)現(xiàn)推翻了這個(gè)理論，他們確認(rèn)了一種30年來(lái)一直是個(gè)謎的酶,。該結(jié)果發(fā)表在《結(jié)構(gòu)》（Structure）上,。
霍普金斯的生物物理和生物物理化學(xué)教授L. Mario Amzel、文章的作者之一解釋說(shuō),，當(dāng)他們意識(shí)到發(fā)現(xiàn)的是細(xì)菌制造維生素B葉酸的酶時(shí)，感到非常驚訝和意外,，因?yàn)閺?974年開(kāi)始科學(xué)家就推測(cè)存在這種酶,，但30年來(lái)卻一直未能證實(shí)它的存在。
Amzel和同事Maurice Bessman當(dāng)時(shí)正在系統(tǒng)地分析細(xì)菌中一個(gè)相關(guān)酶家族如何識(shí)別特定分子,。他們純化了這個(gè)家族中的每個(gè)酶,，并將其結(jié)晶，然后利用X射線分析技術(shù)確定出酶的三維結(jié)構(gòu),。
有了三維結(jié)構(gòu),，小組就可以利用計(jì)算機(jī)模型分析這種酶如何結(jié)合并作用于另外一個(gè)分子。
文章作者Sandra Gabelli解釋說(shuō),，在Maurice開(kāi)始搜尋舊資料前他們并未覺(jué)得這有何特別的,。但是查閱資料的結(jié)果發(fā)現(xiàn)，Suzuki等人在1974年發(fā)表文章稱(chēng)大腸桿菌中存在一種和這種酶類(lèi)似的酶，它能啟動(dòng)葉酸的生物合成,。”
因此,，研究人員想要知道敲除了orf17基因的細(xì)菌是否能制造葉酸。當(dāng)研究人員敲除細(xì)菌的這種基因后發(fā)現(xiàn),，其結(jié)果和預(yù)想的一樣,，細(xì)菌制造的葉酸比正常情況少減少了10倍。
細(xì)菌制造葉酸的機(jī)制對(duì)于希望設(shè)計(jì)更有效的抗生素藥物的研究人員來(lái)說(shuō)尤其具有重要意義,。人類(lèi)之所以無(wú)法合成葉酸,，是因?yàn)闆](méi)有相同的分子機(jī)器。因此,，有可能設(shè)計(jì)出能夠靶向細(xì)菌葉酸機(jī)器的藥物,，從而減少抗生素藥物對(duì)人體的副作用。
葉酸的化學(xué)名為"蝶酰谷氨酸",，系由喋啶酸,、對(duì)氨基苯甲酸與氨酸結(jié)合而成。葉酸對(duì)人體的重要營(yíng)養(yǎng)作用早在1948年即已得到證實(shí),，人類(lèi)（或其他動(dòng)物）如缺乏葉酸可引起巨紅細(xì)胞性貧血以及白細(xì)胞減少癥,。此外，研究還發(fā)現(xiàn),，葉酸對(duì)孕婦尤其重要,。如在懷孕頭3個(gè)月內(nèi)缺乏葉酸，可導(dǎo)致胎兒神經(jīng)管發(fā)育缺陷,，從而增加裂腦兒,，無(wú)腦兒的發(fā)生率。其次,，孕婦經(jīng)常補(bǔ)充葉酸,，可防止新生兒體重過(guò)輕、早產(chǎn)以及嬰兒腭裂（兔唇）等先天性畸形,。
近幾年來(lái),，國(guó)內(nèi)外學(xué)者陸續(xù)發(fā)現(xiàn)了葉酸有不少令人感舉的新用途，其中包括：抗腫瘤作用,；對(duì)嬰幼兒的神經(jīng)細(xì)胞與腦細(xì)胞發(fā)育有促進(jìn)作用等,。
此外，國(guó)內(nèi)外研究人員還發(fā)現(xiàn)葉酸可作為精神分裂癥病人的輔助治療劑,，它對(duì)此病有顯著的緩解作用,。它還可用于治療慢性萎縮性胃炎、抑制支氣管鱗狀轉(zhuǎn)化以及防治因高同型半胱氨酸血癥引起的冠狀動(dòng)脈硬化癥,、心肌損傷與心肌梗塞等,。
原文報(bào)道：
Folate mystery finally solved
The accompanying image illustrates the stages of enzyme activity of the first step of folate biosynthesis: free enzyme (orange), enzyme with substrate bound (salmon), and enzyme with pyrophosphate bound (gold), superimposed on a drawing of E. coli and the folate biosynthetic pathway. The free floating substrate is shown in blue, with the phosphates in red. Credit: The rendition was contributed by Devon Nikasa an alumna of the Art as Applied to Medicine Program at Hopkins.
Some biochemical processes, especially those in bacteria, have been so well studied it’s assumed that no discoveries are left to be made. Not so, it turns out, for Johns Hopkins researchers who have stumbled on the identity of an enzyme that had been a mystery for more than 30 years. The report appears in the May 15 issue of Structure.
“It was really quite a surprise when we realized we had discovered the unknown player in how bacteria make the B vitamin folate, a player that we’ve known of since 1974,” says study author L. Mario Amzel, Ph.D., professor and director of biophysics and biophysical chemistry at Hopkins. “Basic research can be so serendipitous at times.”
Amzel and colleague Maurice Bessman and their labs were in the middle of systematically characterizing how members of a family of related enzymes in bacteria can recognize specific molecules. With each family member, they isolated purified enzyme, grew crystals of pure enzyme, and figured out the enzyme’s 3-D structure by using techniques that use X-rays.
Armed with the 3-D structure, they then used computer modeling to analyze how the enzyme binds to and acts on another molecule, its substrate.
“We still didn’t know that it was anything special until Maurice started searching old publications,” says study author Sandra Gabelli, Ph.D. “As it turns out, Suzuki and coworkers in 1974 had published evidence of an enzyme in the bacteria E. coli with similar characteristics to ours that could initiate folate biosynthesis.”
“So we had to ask, Can the bacteria make folate if we remove the orf17 gene"” says Amzel. Bessman and colleagues then “knocked-out” the gene and, predictably, the bacteria made 10 times less folate than usual.
“It was such a sweet discovery,” says Gabelli. “It’s scientific discovery the old-fashioned way, finding something we weren’t looking for.”
The mechanics behind how bacteria make folate are of particular interest to scientists who want to design more powerful antibacterial drugs. Humans cannot make folate because they do not have any of the same molecular machinery. Therefore, it’s possible to design drugs that target the bacterial folate machinery that would not lead to side effects in humans.
Their discovery, says Amzel, identifies yet another potential antibacterial target. “We are not in that business of drug design—we’re focused on the basics, figuring out how things work,” he says. “We do hope that others can use what we find to make new drugs.”
Source: Johns Hopkins Medical Institutions
