通过α-GlcNAc硫硫酸盐对O-GlcNAc病例异型的特异性抑制
Eun J Kim1, Benjamin Amorelli, Mohannad Abdo
1Laboratory of Cell Biochemistry and Biology, NIDDK, National Institute of Health, Bethesda, Maryland 20892, USA.
Journal of the American Chemical Society
|November 13, 2007
概括
短O-GlcNAcase (OGA) 对常见的抑制剂具有抗性,与长OGA不同. 一种新的抑制剂,α-GlcNAc thiolsulfonate (2),可以选择性地准短期OGA,并不可逆转地抑制长期OGA.
科学领域:
- 生物化学 生物化学
- 酶学 是一种酶学.
- 细胞生物学 细胞生物学
背景情况:
- O-GlcNAcase (OGA) 调节O-GlcNAc代谢,这对细胞过程至关重要.
- 人类OGA存在两种拼接变体:长OGA (具有HAT域) 和短OGA (缺乏HAT域).
- 短OGA的功能和HAT域在OGA催化中的作用在很大程度上是未知的.
研究的目的:
- 为了研究短 OGA 的酶特性.
- 为了确定选择性抑制剂的短 OGA.
- 阐明OGA变体的差异性抑制机制.
主要方法:
- 使用已知的OGA抑制剂 (PUGNAc,NAG-thiazoline) 的酶抑制测定.
- 测试alpha-GlcNAc thiolsulfonate (2) 作为两种OGA变体的潜在抑制剂.
- 对抑制剂与OGA变体相互作用的分析,包括共价修饰研究.
主要成果:
- 短OGA显示对PUGNAc和NAG-thiazoline的耐药性,与长OGA不同.
- 阿尔法-GlcNAc硫硫酸盐 (2) 是一个强大的短OGA (Ki = 10微M) 抑制剂,具有选择性超过长OGA和六胺酶.
- 抑制剂2通过对HAT域的共价连接不可逆转地修改长OGA,改变其活性和caspase-3裂变.
结论:
- HAT域影响OGA抑制剂的敏感性.
- 阿尔法-GlcNAc硫硫酸盐 (2) 提供了一个选择性的抑制方法,用于短时间的OGA.
- 不同的抑制机制突出了OGA拼接变体的不同功能角色和监管可能性.
相关概念视频
01:19Allosteric Proteins-ATCase
Binding sites linkages can regulate a protein's function. For example, enzyme activity is often regulated through a feedback mechanism where the end product of the biochemical process serves as an inhibitor.
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis pathway,...
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis pathway,...
01:30Enzyme Inhibition
Inhibitors are molecules that reduce enzyme activity by binding to the enzyme. In a normally functioning cell, enzymes are regulated by a variety of inhibitors. Drugs and other toxins can also inhibit enzymes. Some inhibitors bind to the enzyme’s active site, while others inhibit enzymatic activity by binding to other sites on the protein structure.
01:18Indirect-Acting Cholinergic Agonists: Mechanism of Action
Indirect-acting cholinergic agonists work by interacting with an enzyme called acetylcholinesterase (AChE) in the synaptic cleft. They can be reversible or irreversible inhibitors and have different effects on the enzyme.
Reversible inhibitors like edrophonium bind to a specific part of the enzyme called the anionic catalytic site. They form noncovalent bonds, which means they are not strongly attached to the enzyme. This creates a temporary and less stable enzyme–inhibitor complex, leading to...
Reversible inhibitors like edrophonium bind to a specific part of the enzyme called the anionic catalytic site. They form noncovalent bonds, which means they are not strongly attached to the enzyme. This creates a temporary and less stable enzyme–inhibitor complex, leading to...
01:24Acetals and Thioacetals as Protecting Groups for Aldehydes and Ketones
Acetals are formed by reacting two equivalents of alcohol with carbonyl compounds like aldehydes or ketones. Acetals are unaffected by bases, nucleophiles, oxidizing agents, and reducing agents. They serve as protecting groups for aldehydes and ketones. Acetals can be easily formed and also easily removed via mild acid hydrolysis.
In the presence of multiple functional groups, when selective reduction of one group over the other is desired, groups like aldehydes and ketones that form acetals...
In the presence of multiple functional groups, when selective reduction of one group over the other is desired, groups like aldehydes and ketones that form acetals...
01:29Indirect-Acting Cholinergic Agonists: Chemistry and Structure-Activity Relationship
Indirect-acting cholinergic agonists are agents that interact with the acetylcholinesterase enzyme in the synaptic cleft, preventing the breakdown of acetylcholine into choline and acetate. Consequently, the concentration of acetylcholine in the synaptic cleft increases. These agonists can be classified into reversible and irreversible inhibitors based on their duration of action.
Reversible inhibitors display short to medium durations of action. Short-acting agents include simple alcohols with...
Reversible inhibitors display short to medium durations of action. Short-acting agents include simple alcohols with...
01:30Ligand-Gated Ion Channel Receptor: Gating Mechanism
Ligand-gated ion channels are transmembrane proteins that play a vital role in intercellular communication and functions of the nervous system. They allow the influx of ions across the membrane once the neurotransmitter binds, allowing the subsequent transmission of electrical excitation across the neurons. Other ligand-gated ion channels, like the γ-aminobutyric acid (GABA) receptor, permit anions like chloride into the cells on the binding of the GABA molecule. Their entry into the cell...