Structural and Functional Studies on Glutamate Decarboxylase.

谷氨酸脱羧酶的结构和功能研究。

• 批准号: nhmrc : 436740
• 负责人: A/Pr Merrill Rowley
• 金额: $ 33.37万
• 依托单位: Monash University
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2007
• 资助国家: 澳大利亚
• 起止时间: 2007-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/structural-functional-studies-glutamate-decarboxylase/97920
• 关键词: Structural; Functional; Studies; Glutamate; Decarboxylase.

This proposal aims to determine the molecular structure of the two known isoforms of Glutamate Decarboxylase (GAD65 and GAD67). GAD in an essential human enzyme that is responsible for synthesising the primary inhibitory neurotransmitter gamma-aminobutyric acid (GABA). GABA functions in the human Central Nervous System (CNS) to dampen down excitatory signals. Proper control of GABA synthesis is important and perturbations in GABA levels lies behind human diseases such as intractable epilepsy, depression and schizophrenia. As a result of this role, numerous common therapeutics (for example benzodiazepines) target proteins involved in the GABA neurotransmitter system. The goal of this proposal is to use the molecular structures of GAD to understand how to achieve fine control of GABA production. In addition to its role in the CNS, GAD is an important human autoantigen. Antibodies to one isoform of GAD, GAD65, are found in most patients with type I diabetes as well as certain patients with the movement disorder stiff person syndrome and related diseases of the CNS. It is suggested that the development of auto-antibodies may play a key role in the pathophysiology of these conditions. Despite sharing >80% sequence similarity with GAD65, autoantibodies to the other isoform of GAD, GAD67, are rarely found in patients with disease. The aim of this grant is to characterise the region of GAD that is targetted by autoantibodes. These data will allow us to understand why certain autoantibodes are able to inhibit GAD enzyme activity and why GAD65, but not GAD67 is recognised by autoantibodes.

该提案旨在确定谷氨酸脱羧酶的两种已知亚型（GAD65 和 GAD67）的分子结构。 GAD 是一种人体必需酶，负责合成主要抑制性神经递质 γ-氨基丁酸 (GABA)。 GABA 在人类中枢神经系统 (CNS) 中发挥作用，抑制兴奋信号。正确控制 GABA 合成非常重要，GABA 水平的扰动是顽固性癫痫、抑郁症和精神分裂症等人类疾病的根源。由于这种作用，许多常见的治疗药物（例如苯二氮卓类药物）都以参与 GABA 神经递质系统的蛋白质为目标。该提案的目标是利用GAD的分子结构来了解如何实现GABA生产的精细控制。除了在中枢神经系统中发挥作用外，GAD 也是一种重要的人类自身抗原。大多数 I 型糖尿病患者以及某些患有运动障碍、僵人综合征和中枢神经系统相关疾病的患者体内都发现了针对 GAD 一种异构体 GAD65 的抗体。这表明自身抗体的产生可能在这些病症的病理生理学中发挥关键作用。尽管与 GAD65 具有 >80% 的序列相似性，但在疾病患者中很少发现 GAD 的另一种亚型 GAD67 的自身抗体。这笔资助的目的是确定自身抗体针对的 GAD 区域的特征。这些数据将使我们能够理解为什么某些自身抗体能够抑制 GAD 酶活性，以及​​为什么自身抗体能够识别 GAD65 而不能识别 GAD67。