Catalysis and reactivity in carnohydrate chemistry and biochemistry

本提案中概述的研究涉及碳水化合物（糖）化学的两个主要领域。 我们计划研究碳水化合物的生物反应的基本方面，以及它们如何偏离水中的相应反应。 生物体是复杂的实体，其存在依赖于代谢各种膳食营养素的能力。 代谢存在两个不同的阶段：（1）产生能量的分解代谢过程，涉及复杂的食物来源，如碳水化合物，蛋白质和脂肪的降解，以产生更简单的分子;和（2）生长，与生物合成过程有关的阶段，其中简单的成分，如葡萄糖，用于形成生物体生长和生存所需的更复杂的分子。 这两种类型的代谢途径使用对降解型反应具有特异性的酶，或者在导致复杂分子组装的反应中起作用的酶。该项目的一个目标是为这两种类型的糖加工酶设计抑制剂，因为这些酶中的许多与包括结核病和法布里病在内的各种疾病有关。 在这个研究计划的过程中产生的抑制剂将有可能成为治疗剂。 该提案的第二个目标是将从碳水化合物反应机制研究中获得的基本信息应用于糖分解代谢酶（糖苷酶）的修饰，使得其可以使用新的作用机制降解糖。 以这种方式修饰糖苷酶有什么好处？ 从这项研究中收集的信息将使研究人员更好地了解生物进化以及自然如何缓慢但无情地提高酶的效率。

The research outlined in this proposal involves two main areas of carbohydrate (sugar) chemistry.  We plan to investigate the fundamental aspects of the biological reactions of carbohydrates and how they deviate from the corresponding reactions in water.  Organisms are complex entities whose very existence depends on the ability to metabolize various dietary nutrients.  Two distinct phases of metabolism exist: (1) energy-yielding catabolic processes that involve the degradation of complex food sources such as carbohydrates, proteins, and fats to produce simpler molecules; and (2) anabolism, that phase that is concerned with biosynthetic processes in which simple components, such as glucose are used to form more complex molecules that are required for the growth and survival of an organism.  These two types of metabolic pathways employ enzymes that are either specific for degradation-type reactions, or that function in reactions which lead to the assembly of complex molecules. A goal of this project is to design inhibitors for both types of sugar processing enzymes because many of these enzymes are implicated in various ailments including tuberculosis and Fabry's disease.  The inhibitors made during the course of this program of research will have the potential to become therapeutic agents.  A second goal of this proposal is to apply the fundamental information gained from the carbohydrate reaction mechanism studies to the modification of sugar-catabolizing enzyme (a glycosidase) so that it can degrade sugars using a novel mechanism of action.  What would be the advantage of modifying a glycosidase in this way?  Information gleaned from this study will allow researchers to get a better understanding of biological evolution and how nature slower, but inexorably, improves enzyme efficiency.