Mechanism-Based Carbohydrate Chemistry and Biochemistry

这项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，其生存依赖于代谢(分解)各种饮食营养的能力。新陈代谢有两个不同的阶段：(1)产生能量的分解代谢过程，涉及碳水化合物、蛋白质和脂肪等复杂食物来源的降解，以产生更简单的分子；(2)合成代谢，这一阶段与自然过程有关，在这个过程中，简单的成分，如葡萄糖，被用来形成更复杂的分子，这是有机体生长和生存所必需的。这两种代谢途径使用的酶要么是降解型反应所特有的，要么是在导致复杂分子组装的反应中发挥作用的酶。 该项目的一个目标是为这两种糖加工酶设计抑制剂，因为这些酶中的许多都与各种疾病有关，包括结核病和法布里病。在这项研究过程中制造的抑制剂将有可能成为治疗剂。这项建议的第二个目标是将从碳水化合物反应研究中获得的基本信息应用于糖分解代谢酶(一种糖苷酶)的修饰，使其能够针对不同的糖。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 (breakdown) 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 natural 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 studies to the modification of sugar-catabolizing enzyme (a glycosidase) so that it can target different sugars. 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 slowly, but inexorably, improves enzyme efficiency.