由美国科学家完成的一项关键研究发现，参与催化反应的酶经过详细的构象变化，从而完成其生物学功能，该发现向传统药物合成途径的假想提出了挑战，并可能帮助未来的药物设计。传统认为，酶是主要以其生命存在来催化化学反应的生物学分子，酶催化作用传统模式将被这些发现重写，另外，该发现也对当前用于药品制造的抑制剂或工业应用的新颖酶催化剂的理性设计提出质疑。美国斯克利普斯研究院的科学家证明，酶动力学构象波动引导其完成自身的反应周期，蛋白质的热能运动被用来执行催化作用。
研究者使用核磁共振仪研究了大肠杆菌二氢叶酸还原酶(DHFR)高能激发态，结果表明在催化周期的各个阶段，前述酶以及下面提到的酶的激发态构象与基态构象类似。这样，基态和激发态之间的动力学波动使酶达到临近的中间状态构象，从而通过帮助配体与酶的结合或分开而更易于催化作用的进行。
美国斯克利普斯研究院分子生物学系（Scripps Research Department of Molecular Biology）的主席、美国斯克利普斯研究院Skaggs生物化学研究所（Skaggs Institute for Chemical Biology at Scripps Research）的成员Peter Wright说：“蛋白质固有的运动对它们生物学功能是必要的，目前对这一点的认知越来越多。这些新发现与传统的‘诱导模式’假说对照，假说的一种原则认为配体的结合导致酶构象的变化从而增加了配体与酶之间的偶联。”
在过去多年，制药业都按照该假说执行，认为大部分酶都是天生可以自由变形的，然而，对蛋白质与催化功能波动偶联的机理的了解却非常少。
新构象模型被期望能对酶的偶联作用有更深入的认识，并引导制药业向更高战略性途径发展。“我们的研究适用广阔的催化周期的各个环节，”Wright说，“结果意味着对DHFR酶循环的任一中间物来说，最低能量激发态都是机能最相关的构象”。
酶以一个首选的基态构象与配体适应性结合，但也采取其他相关高能构象，以保证它能快速前进到下一个催化步骤。当配体改变后，酶的易接近的能量状态也相应改变，因此，这种动态的能量势垒能有效地为酶提供一个特殊的动力学途径，在此途径中连续构象之间的能量垒的数量和高度都是最小的。
附：美国斯克利普斯研究院简介
美国斯克利普斯研究院是全球规模最大的非盈利性独立生物医学研究机构，它站在生物基础科学的最前沿，寻求了解最基础的生命过程。斯克利普斯研究院的研究在免疫学、分子和细胞生物学、化学、神经科学、自体免疫，心血管、传染病和人造疫苗等领域方面得到了国际认可。研究院仍然保持了1961年的机构配置，它雇用大约3,000位科学家、博士后、科技人员、博士学位研究生和行政与技术支持人员。总部设在加利福尼亚州拉乔拉(La Jolla)。斯克利普斯研究院佛罗里达部将研究重心集中于基本的生物医学、药物发现和技术开发。当前科研工作临时设在Jupiter，2009年将永久搬到校园。
部分英文原文：
Study Details Structural Changes of a Key Catalytic Enzyme
Scientists at The Scripps Research Institute have detailed a new hypothesis of how a key catalytic enzyme, dihydrofolate reductase (DHFR)—which is the target of several anticancer and antibiotic therapies—cycles through structural changes as it plays a critical role in promoting cell growth and proliferation.
The study was published in the September 15 (Volume 314, Issue 5793) edition of the journal Science.
Enzymes are complex proteins capable of catalyzing specific biochemical reactions in cells. While it has long been recognized that dynamic fluctuations in protein conformation or structure play a central role in enzyme catalysis, the new findings indicate that the "dynamic energy landscape" of the enzyme funnels it along a preferred pathway that actually minimizes the number and dimension of the energetic barriers to these catalytic changes.
"There is a growing awareness that the inherent motions of proteins are essential to their functions," said Peter Wright, who is chair of the Scripps Research Department of Molecular Biology and a member of the Skaggs Institute for Chemical Biology at Scripps Research. "The importance of this study is that it reveals how dynamic structural fluctuations channel an enzyme through its reaction cycle—the thermal motions of the protein are harnessed to perform its biological function, in this case, catalysis. Knowledge of the excited-state conformations of proteins may offer new opportunities for drug design."
The researchers used nuclear magnetic resonance (NMR) to detect and characterize higher energy structural sub-states (excited states) of E. coli dihydrofolate reductase, which has been used extensively as a model enzyme for investigating the relations between structure, dynamics, and function in proteins. The researchers found that, at each stage in the catalytic cycle, the excited-state conformations resembled the ground-state structures of both the preceding and the following intermediates. This means that the dynamic fluctuations between the ground state and the excited state were "priming" the enzyme to take up the conformation of the adjacent intermediate state, facilitating the progress of catalysis by aiding the movement of ligands (molecules that bind to one chemical entity to form a larger complex) on and off the enzyme.
"These findings contrast with the traditional 'induced fit' hypothesis," Wright said. "One of the tenets of that hypothesis is that the binding of ligands induces a structural change that increases the complementary relationship between the ligand and the enzyme."
更多原文链接：http://www.scripps.edu/news/press/091906.html
http://www.drugresearcher.com/news/ng.asp?n=70741-enzyme-dihydrofolate-reductase-catalyst
