Understanding the structure and function of an important human metabolic enzyme.

了解重要的人类代谢酶的结构和功能。

• 批准号: 2589476
• 金额: --
• 依托单位: University of St Andrews
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2589476
• 关键词: Understanding; structure; function; important; human

Various types of carbohydrates, or sugars, are ubiquitous throughout nature and perform a number of important functions in our cells. Carbohydrates can exist in long chains, composed of one or more types of monosaccharides, which is how energy is stored in cells from the food we ingest, why wood is strong, and is responsible for the molecular glue that sticks our cells together. At the other end of the scale, single or small groups of specialized monosaccharides can be appended to other biomolecules such as proteins and lipids, where they work to coordinate cell processes such as inter- and intra-cellular signalling, and defence against pathogens. The structure and sequence of carbohydrates are complex and highly variable, but unlike DNA there is no genetic code that can be read to determine how it should exist. Instead, carbohydrate structure and sequence are defined only by the enzymes that synthesize, degrade and modify the carbohydrate molecules.Human carbohydrate processing enzymes are therefore vitally important, but they are less well studied and the enzymes are poorly characterised. For those that are well understood, the malfunction or mis-regulation of such enzymes is strongly associated with diseases such as cancer and metabolic and inflammatory disorders. One such human metabolic enzyme that is poorly understood is N-acetylglucosamine-6-phosphate deacetylase, or NagA. NagA catalyses the deacetylation of N-acetylglucosamine-6-phosphate to produce glucosamine-6-phosphate. The structure of human NagA has been solved and it was found to have a promiscuous substrate scope. Although the human NagA is poorly understood, there are bacterial homologues which are more well characterised. Interestingly, bacterial NagA does not show the same substrate promiscuity, suggesting that human NagA has evolved this function for a particular reason.Little work has been done to characterise the enzyme, and its physiological role is not understood. At the moment we hypothesize this enzyme acts as a gate-keeper to ensure no erroneous groups can make their way into metabolic pathways, which could have fundamental consequences in a number of downstream processes. Human carbohydrate processing enzymes perform important biological functions and when they fail to work properly are implicated in diseases including cancer, and metabolic and inflammatory disorders. Understanding this human metabolic enzyme at the molecular level, by firstly deducing how it works, and then understanding its biological function, could have an important impact on the health and disease in the future.

各种类型的碳水化合物或糖在自然界中普遍存在，并在我们的细胞中发挥着许多重要的功能。碳水化合物可以以长链形式存在，由一种或多种单糖组成，这就是我们摄入的食物中能量储存在细胞中的方式，也是木材坚固的原因，也是将我们的细胞粘在一起的分子胶的原因。另一方面，单个或一小群特殊的单糖可以附加到其他生物分子（例如蛋白质和脂质）上，它们可以协调细胞过程，例如细胞间和细胞内信号传导以及对病原体的防御。碳水化合物的结构和序列非常复杂且高度可变，但与 DNA 不同的是，没有可以读取的遗传密码来确定它应该如何存在。相反，碳水化合物的结构和序列仅由合成、降解和修饰碳水化合物分子的酶来定义。因此，人类碳水化合物加工酶至关重要，但对它们的研究较少，而且酶的特征也很差。众所周知，这些酶的故障或失调与癌症、代谢和炎症性疾病等疾病密切相关。 N-乙酰氨基葡萄糖-6-磷酸脱乙酰酶（NagA）是一种人们知之甚少的人类代谢酶。 NagA 催化 N-乙酰氨基葡萄糖-6-磷酸脱乙酰化生成氨基葡萄糖-6-磷酸。人类NagA的结构已被解析，并发现其具有混杂的底物范围。尽管对人类 NagA 知之甚少，但细菌同源物的特征更为明确。有趣的是，细菌 NagA 并没有表现出相同的底物混杂性，这表明人类 NagA 出于特定原因进化出了这种功能。很少有工作来表征该酶，其生理作用尚不清楚。目前，我们假设这种酶充当看门人的角色，以确保没有错误的基团能够进入代谢途径，这可能会对许多下游过程产生根本性的影响。人类碳水化合物加工酶具有重要的生物学功能，当它们不能正常工作时，就会导致包括癌症、代谢和炎症性疾病在内的疾病。在分子水平上了解这种人体代谢酶，首先推导它的工作原理，然后了解其生物学功能，可能会对未来的健康和疾病产生重要影响。