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

碳水化合物化学和生物化学中的催化、反应性和探针开发

• 批准号: RGPIN-2017-04910
• 负责人: Bennet, Andrew
• 金额: $ 6.56万
• 依托单位: Simon Fraser University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=747774
• 关键词: Catalysis; Reactivity; Probe; Development; Carbohydrate

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.

在生命系统中，比如我们自己，糖类的添加和去除都受到严格的控制。也就是说，我们通过摄入碳水化合物所获得的大量能量来确保我们体内的分子具有正确的糖类。如果这个系统“失灵”，那么严重的疾病就会接踵而至。NSERC的这项发现拨款提案为我们的研究项目寻求资金，该项目集中在当前碳水化合物化学和生物学的三个感兴趣的领域。首先，我们将调查一系列关键酶(大自然用于执行反应的催化剂)如何通过化学键将它们连接在一起来向分子添加糖。这些酶被称为糖转移酶，它们很重要，因为它们中的一些与包括癌症在内的许多疾病有关。我们希望了解这些酶是如何工作的，以便我们能够设计分子来防止特定情况下的糖转移，例如在癌症中。第二，我们将继续努力制造反应性非糖分子，我们已经设计了这种分子来模仿碳水化合物。到目前为止，我们的分子已经显示出显著的能力来降低(或抑制)酶的活性，这些酶从碳水化合物链中移除糖，比如淀粉中的那些。我们的新抑制剂将在酶活性高于正常人正常水平的情况下进行测试。也就是说，如果我们能通过给予我们的分子来降低酶的活性，使之降到非疾病个体(正常水平)的水平，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。在这项工作中，我们使用了一种酶(称为唾液酸酶)的经验，这种酶调节着自我识别的几个关键过程，这一点很重要，因为我们不想让我们的免疫系统攻击我们。我们在唾液酸酶方面有十多年的经验，我们将利用这些经验来修改这种酶，以便它可以用来测试附着在各种细胞上的碳水化合物的异常。对于对细胞间交流感兴趣的研究人员来说，这种修饰的酶将是非常有用的工具，例如，一个细胞必须知道它的邻居是否也是人类细胞。我们改良的酶还可以用于检测各种类型的癌症，因为许多癌细胞的表面显示出异常的碳水化合物阵列。