Bioorganic Reactivity: Patterns, Principles and Applications

生物有机反应：模式、原理和应用

• 批准号: RGPIN-2020-04113
• 负责人: Kluger, Ronald
• 金额: $ 3.5万
• 依托单位: University of Toronto
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2021
• 资助国家: 加拿大
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=739671
• 关键词: Bioorganic; Reactivity; Patterns; Principles; Applications

I propose that my students and I will do interesting and significant research that is at the intersection of chemistry and biology. We have three principal areas of interest. In one, we learn how biological systems are able to produce CO2 with compounds that are otherwise stable. We will study compounds with characteristics that relate to those in enzymes. This allows us to compare the rates and products. The parallels and differences reveal the critical parts of the enzyme. We focus on  enzymes that form intermediates derived from combining the reacting compound with a derivative of  vitamin B1. The enzymes change the reactivity of the compound that will lose CO2. We can follow the exact components without an enzyme that lead to a slower path and different products. This contrast allows us to focus on the detailed steps that account for the difference. We will examine the consequences of those differences. The first thing we will learn is how the enzyme, with the aid of a protein, speeds up the process. Then from that lesson, we will develop improved reactions that work without the protein. We want to find how CO2 is released very rapidly as a result of metabolism, a common occurrence in living systems, while the same compounds without an enzyme are persistent. We will test ideas by which we may achieve a similar outcome in a solution reaction as occurs on the enzyme. Through these efforts, the students will gain insights that would not have otherwise accessible. Our approach involves adding a trapping component (an auxiliary acid) to the nonenzymic reaction system that could block the return of CO2, as it would occur on the enzyme. This should enhance the rate of the overall process without the enzyme and therefore produce more rapid reactions without the enzyme. This gives students diverse knowledge, challenges that develop reasoning, and valuable technical skils.  We also work in other areas where chemistry interacts biology.  We are developing new chemical  methods that will allow the addition  of unnatural amino acids in place of amino acids in proteins. This will create  proteins in ribosomes with unnatural amino acid components. This would make new  proteins with useful properties and many applications. We will do this by developing new chemical reactions that add the unnatural amino acids onto transfer RNA, which carries them into the ribosome where then are added to form a protein. We also will use the same method to modify carbohydrates for use as materials that are altered at specific sites. Finally, we are developing ways to allow the natural oxygen carrier,  hemoglobin, to survive outside red blood cells in solutions, as in circulation in place of red blood cells. Such a product would have many applications, from red cells replacements, to oxygen carriers for perfusion. Our approach takes hemoglobin from red cells that are not used for transfusions and convert them.

我建议我的学生和我将在化学和生物学的交叉点上做有趣而有意义的研究。我们有三个主要关注领域。在一个，我们学习如何生物系统能够产生二氧化碳的化合物，否则是稳定的。我们将研究具有与酶相关特性的化合物。这使我们能够比较价格和产品。这些相似之处和差异揭示了酶的关键部分。我们专注于酶，形成来自反应化合物与维生素B1衍生物结合的中间体。这些酶改变了化合物的反应性，使其失去二氧化碳。我们可以在没有酶的情况下跟踪精确的组分，从而导致更慢的路径和不同的产品。这种对比使我们能够专注于解释差异的详细步骤。我们将研究这些差异的后果。我们首先要了解的是酶如何在蛋白质的帮助下加速这一过程。然后从这个教训，我们将开发改进的反应，没有蛋白质的工作。我们想知道二氧化碳是如何在新陈代谢的过程中迅速释放的，这在生命系统中很常见，而没有酶的相同化合物是持久的。我们将测试一些想法，通过这些想法，我们可以在溶液反应中获得与酶反应类似的结果。通过这些努力，学生们将获得否则无法获得的见解。我们的方法包括在非酶反应系统中加入一种捕获成分（一种辅助酸），可以阻止CO2的返回，因为它会发生在酶上。这将提高没有酶的整个过程的速率，因此在没有酶的情况下产生更快的反应。这为学生提供了多样化的知识，发展推理的挑战和宝贵的技术技能。 我们也在化学与生物学相互作用的其他领域工作。我们正在开发新的化学方法，允许添加非天然氨基酸代替蛋白质中的氨基酸。这将在核糖体中产生含有非天然氨基酸成分的蛋白质。这将使新的蛋白质具有有用的特性和许多应用。我们将通过开发新的化学反应来实现这一点，将非天然氨基酸添加到转移RNA上，转移RNA将它们携带到核糖体中，然后添加形成蛋白质。我们也将使用相同的方法来修饰碳水化合物，以用作在特定位点改变的材料。最后，我们正在研究让天然氧载体血红蛋白在红细胞外的溶液中存活的方法，就像在循环中代替红细胞一样。这样的产品将有许多应用，从红细胞替代品到用于灌注的氧载体。我们的方法从不用于输血的红细胞中提取血红蛋白并将其转化。