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.

在我们自己的生活系统中，糖的添加和去除（也称为碳水化合物）受到严格调节。 也就是说，我们通过食用碳水化合物来利用很多能量来确保体内的分子在其上具有正确的糖。 如果该系统“陷入困境”，那么可能会发生严重的疾病。 这项NSERC Discovery Grant提案为我们的研究计划寻求资金，该计划集中在当前对碳水化合物化学和生物学感兴趣的领域。首先，我们将研究如何通过与化学键一起加入一系列重要的酶（自然的催化剂（自然的催化剂），以执行反应的催化剂）。 这些酶称为糖转移酶，很重要，因为其中一些酶与包括癌症在内的许多疾病状态有关。 我们希望了解这些酶如何起作用，以便我们可以设计分子以防止在特定情况下（例如在癌症）中转移糖分。第二，我们将继续努力制造反应性的非糖分子，我们旨在模仿碳水化合物。 迄今为止，我们的分子已经显示出降低（或抑制）酶的活性的巨大能力，这些酶从碳水化合物链中除去糖（例如淀粉中发现的糖）的活性。 我们的新抑制剂将在情况下进行测试，因为酶活性比正常个体的活性大。 也就是说，如果我们可以通过降低酶活性，通过将我们的分子施用到非养殖个体（正常水平）的分子，那么这些化合物是潜在的治疗剂。我们将使用现代分子生物学中的最新技术来开发新的酶催化剂。 在这项工作中，我们利用我们的经验来调节几个关键的自我识别过程，这很重要，因为我们不希望免疫系统攻击我们。 我们在唾液酸酶酶方面拥有超过十年的经验，并将利用这种经验来修饰酶，以便可以用于测试附着在各种细胞上的碳水化合物中的异常。 对于对细胞通信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，细胞必须知道其邻居是否也是人类细胞。 我们的改良酶也可以用于测试各种类型的癌症，因为许多癌细胞在其表面上显示出异常的碳水化合物。