Catalysis, Reactivity and Probe Development in Carbohydrate-Based Chemistry and Biochemistry

在生命系统中，比如我们自己，糖的添加和去除，也被称为碳水化合物，受到严格的调控。 也就是说，我们使用大量的能量，我们通过吃碳水化合物，以确保我们体内的分子有正确的糖连接到他们。 如果这个系统“不正常”，那么严重的疾病就会接踵而至。 NSERC的发现资助计划旨在为我们的研究项目寻求资金，该项目主要集中在碳水化合物化学和生物学的三个当前感兴趣的领域。首先，我们将研究一系列关键酶（自然界进行反应的催化剂）如何通过化学键将糖分子连接在一起。 这些酶被称为糖转移酶，它们很重要，因为其中一些与许多疾病状态有关，包括癌症。 我们希望了解这些酶是如何工作的，以便我们可以设计分子来防止在特定情况下，如癌症中的糖转移。其次，我们将继续努力制造活性非糖分子，我们已经设计了模仿碳水化合物。 到目前为止，我们的分子已经显示出显著的能力，以减少（或抑制）酶的活性，从碳水化合物链中去除糖，如淀粉中发现的那些。 我们的新抑制剂将在酶活性高于正常个体的情况下进行测试。 也就是说，如果我们可以通过给药我们的分子来降低酶的活性，使其达到非患病个体的活性（正常水平），那么这些化合物就是潜在的治疗剂。最后，我们将利用现代分子生物学的最新技术来开发新的酶催化剂。 在这项努力中，我们正在利用我们对一种酶（称为唾液酸酶）的经验，这种酶调节自我识别的几个关键过程，这很重要，因为我们不希望我们的免疫系统攻击我们。 我们有超过十年的唾液酸酶经验，并将利用这些经验来修改酶，使其可用于测试附着在各种细胞上的碳水化合物的异常。 这种修饰的酶将是对细胞间通讯感兴趣的研究人员非常有用的工具，例如，一个细胞必须知道它的邻居是否也是人类细胞。 我们的修饰酶也可用于检测各种类型的癌症，因为许多癌细胞在其表面显示出异常的碳水化合物阵列。

In living systems, such as ourselves, the addition and removal of sugars, which are also known as carbohydrates, is tightly regulated. That is, we use a lot of the energy that we get by eating carbohydrates to ensure that molecules within our bodies have the correct sugars attached to them. If this systems gets "out of whack" then serious diseases can ensue. This NSERC Discovery Grant proposal seeks funds for our research program that is concentrated on three areas of current interest in carbohydrate chemistry and biology.Firstly, we will investigate how a series of crucial enzymes (Nature's catalysts for performing reactions) add sugars to molecules by joining them together with a chemical bond. These enzymes are called sugar transferases and are important because some of them are implicated in many disease states including cancer. We wish to understand how these enzyme work in order that we can design molecules to prevent the transfer of sugars in specific cases, such as in cancer.Secondly, we will continue our efforts in making reactive non-sugar molecules, which we have designed to imitate carbohydrates. To date, our molecules have shown a dramatic ability to decrease (or inhibit) the activity of enzymes that remove sugars from carbohydrate chains such as those found in starch. Our new inhibitors will be tested in situations were enzyme activity is greater than it should be in normal individuals. That is, if we can lower the enzyme activity, by administering our molecules, to that of a non-diseased individual (normal level) then these compounds are potential therapeutic agents.Lastly, we will use the latest techniques in modern molecular biology to develop new enzyme catalysts. In this endeavour we are using our experience with an enzyme (called a sialidase) that regulates several critical processes of self-recognition, which is important since we don't want our immune system to attack us. We have over ten years of experience with sialidase enzymes and will use this experience to modify the enzyme so that it can be used to test for abnormalities in the carbohydrates that are attached to various cells. Such modified enzymes will be very useful tools for researchers who are interested in cell to cell communication, for example, a cell has to know whether its neighbor is also a Human cell. Our modified enzymes can also be used to test for various types of cancer as many cancer cells show an abnormal array of carbohydrates on their surfaces.