蛋白质组学

新型人造酶可用于标记蛋白

使用一种不被自然利用的稀有金属,莱斯大学的化学家们发明了一种合成酶,有助于解开难以研究的数千种蛋白质的身份,其中包括许多在癌症和其他疾病发挥关键角色的蛋白质。这项研究最近在线发表在《美国化学学会杂志》上。

“我们已经将铑的化学性能和目前生物学已知能识别和选择的特定蛋白结合在一起,”共同研究作者Zachary Ball,莱斯大学化学助理教授说,“结果是一种工具,在许多方面,比任何单独使用生物或化学的方法更有效。”

Ball三年前开始研究双铑催化剂。他一开始没有试图用它们们来合成酶,但他对一个研究产生了兴趣,双铑催化剂可用于修饰色氨酸,后者是构成生命基本组成部分的21种氨基酸其中之一。

催化剂增加反应速率而促进化学反应,而自己不被消耗。在生物体内,称为酶的蛋白质发挥同样的功能。但不同于许多无机催化剂,酶是非常具有选择性的。在生物学家常常比作 “锁和钥匙”的过程中,酶只和分子形状与之精确配对的分子相作用,这可以避免整个细胞产生无关的反应。

Ball和博士后研究员Brian Popp想知道酶反应的选择性是否可以和铑基催化剂相结合。他们对设想进行了验证,通过将催化剂连接到到能与其他蛋白质结合在一起的蛋白质的部分区域,形如一条纤维束。这种“卷曲螺旋”包装模式在生物学中常见,尤其是在信号蛋白中。信号蛋白是那些能激活或失活诸如凋亡的关键过程的蛋白,“程序性死亡”在癌症中发挥关键作用。

“信号通路犹如多米诺骨牌,”Ball说, “数十种蛋白质参与其中,它们相互作用形成级联反应。在大多数情况下,相互作用短暂和微弱,很难用传统方法观察到,因此我们对于关键信号蛋白在健康和疾病发挥的作用还不清楚。”

Ball说,他和Popp合成酶的策略可能有助于解决这一问题。在他们的试验中,化学家能够开发出可以选择性地与蛋白质结合的合成酶,并进行标记,以便让生物学家能识别它们。

除色氨酸外,用同样的方法研究了苯丙氨酸和酪氨酸,它们是信号蛋白质中两个2个常见的氨基酸。最近尚未发表的研究表明,这个研究策略可能在更多氨基酸中起效。

巴尔说,这个过程必须加以完善,才能在大多数生物实验室中使用,但他和Popp已经为实现该战略广泛应用而努力。

该研究由韦尔奇基金会和莱斯大学资助。

Synthetic Enzymes Could Help ID Proteins
Using a rare metal that's not utilized by nature, Rice University chemists have created a synthetic enzyme that could help unlock the identities of thousands of difficult-to-study proteins, including many that play key roles in cancer and other diseases.

The research was recently published online in the Journal of the American Chemical Society.

"We have combined the chemical capabilities of rhodium with what biology already knows about recognizing and selecting specific proteins," said study co-author Zachary Ball, assistant professor of chemistry at Rice. "The result is a tool that, in many ways, is more powerful than any biological or chemical approach alone."

Ball began studying dirhodium catalysts more than three years ago. He did not start out trying to create enzymes with them, but he was intrigued by a study that showed dirhodium catalysts could be used to modify tryptophan, one of the 21 amino acids that are the basic building blocks of life.

Catalysts enhance chemical reactions by increasing the rate of reaction without being consumed themselves. In living things, proteins called enzymes serve the same purpose. But unlike many inorganic catalysts, enzymes are very selective. In a process that biologists often liken to a "lock and key," enzymes associate only with molecules that match their shape exactly. This prevents them from spurring extraneous reactions throughout the cell.

Ball and postdoctoral research associate Brian Popp wondered if they could marry the selectivity of enzymatic reactions with a rhodium-based catalyst. They tested the idea by attaching their catalyst to a short segment of protein that can wrap with other proteins, like strands of rope fiber. This "coiled coil" wrapping motif is common in biology, particularly in signaling proteins. Signaling proteins are those that activate or deactivate key processes like apoptosis, the "programmed death" response that's known to play a key role in cancer.

"Signaling pathways are like a trail of dominos," Ball said. "Dozens of proteins can be involved, and they interact one after the other in a cascade. In most cases, the interactions are both fleeting and weak. They are difficult to observe with traditional methods, and as a result we are still in the dark about the roles that key signaling proteins play in health and disease."

Ball said his and Popp's synthetic enzyme strategy might help solve that problem. In their tests, the chemists were able to develop synthetic enzymes that could selectively bind with proteins and attach tags that would allow biologists to identify them.

In addition to tryptophan, the method worked with phenylalanine and tyrosine, two amino acids commonly found in signaling proteins. And recent unpublished studies indicate the researchers' strategy might work for even more amino acids.

Ball said the process must be refined before it can be used in the majority of biology labs, but he and Popp are already working toward realizing broad applications of the strategy.

The research was funded by the Welch Foundation and Rice University.

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