生物谷报道：一些生物化学过程被认为已经被研究得非常完整，因此科学家相信不会再取得任何这方面的发现。叶酸（Flolic acid）是一种广泛存在于绿色蔬菜中的B族维生素，由于它最早从植物叶子中提取而得，故命名为"叶酸"。此前，人们对叶酸生化过程有了较深入的了解，但是一种叶酸酶却始终是一个未能解开的谜团。但是最近Johns Hopkins大学的科学家的发现推翻了这个理论，他们确认了一种30年来一直是个谜的酶。该结果发表在《结构》（Structure）上。
霍普金斯的生物物理和生物物理化学教授L. Mario Amzel、文章的作者之一解释说，当他们意识到发现的是细菌制造维生素B叶酸的酶时，感到非常惊讶和意外，因为从1974年开始科学家就推测存在这种酶，但30年来却一直未能证实它的存在。
Amzel和同事Maurice Bessman当时正在系统地分析细菌中一个相关酶家族如何识别特定分子。他们纯化了这个家族中的每个酶，并将其结晶，然后利用X射线分析技术确定出酶的三维结构。
有了三维结构，小组就可以利用计算机模型分析这种酶如何结合并作用于另外一个分子。
文章作者Sandra Gabelli解释说，在Maurice开始搜寻旧资料前他们并未觉得这有何特别的。但是查阅资料的结果发现，Suzuki等人在1974年发表文章称大肠杆菌中存在一种和这种酶类似的酶，它能启动叶酸的生物合成。”
因此，研究人员想要知道敲除了orf17基因的细菌是否能制造叶酸。当研究人员敲除细菌的这种基因后发现，其结果和预想的一样，细菌制造的叶酸比正常情况少减少了10倍。
细菌制造叶酸的机制对于希望设计更有效的抗生素药物的研究人员来说尤其具有重要意义。人类之所以无法合成叶酸，是因为没有相同的分子机器。因此，有可能设计出能够靶向细菌叶酸机器的药物，从而减少抗生素药物对人体的副作用。
叶酸的化学名为"蝶酰谷氨酸"，系由喋啶酸、对氨基苯甲酸与氨酸结合而成。叶酸对人体的重要营养作用早在1948年即已得到证实，人类（或其他动物）如缺乏叶酸可引起巨红细胞性贫血以及白细胞减少症。此外，研究还发现，叶酸对孕妇尤其重要。如在怀孕头3个月内缺乏叶酸，可导致胎儿神经管发育缺陷，从而增加裂脑儿，无脑儿的发生率。其次，孕妇经常补充叶酸，可防止新生儿体重过轻、早产以及婴儿腭裂（兔唇）等先天性畸形。
近几年来，国内外学者陆续发现了叶酸有不少令人感举的新用途，其中包括：抗肿瘤作用；对婴幼儿的神经细胞与脑细胞发育有促进作用等。
此外，国内外研究人员还发现叶酸可作为精神分裂症病人的辅助治疗剂，它对此病有显著的缓解作用。它还可用于治疗慢性萎缩性胃炎、抑制支气管鳞状转化以及防治因高同型半胱氨酸血症引起的冠状动脉硬化症、心肌损伤与心肌梗塞等。
原文报道：
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
