人类G6PC1的诱导适应和催化机制
Qihao Chen1,2, Yuhang Wang1,2, Renjie Li1,2
1Key Laboratory of Biomacromolecules (CAS), National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
Cell discovery
|July 15, 2025
概括
人类葡萄糖-6-酸酶催化子单元1 (hG6PC1) 对于葡萄糖代谢和能量恒温至关重要. 这项研究揭示了它的结构,提供了对引起疾病的突变和脂素潜在调节的见解.
科学领域:
- 生物化学 生物化学
- 结构生物学 结构生物学
- 代谢障碍 代谢障碍 代谢障碍
背景情况:
- 人类葡萄糖-6-酸酶催化子单元1 (hG6PC1) 对于葡萄糖代谢至关重要,调节葡萄糖生成和糖原分解.
- 功能障碍的hG6PC1会导致1a型的葡萄糖储存疾病,导致低血糖和血糖升高.
- hG6PC1是葡萄糖代谢障碍的一个关键治疗点.
研究的目的:
- 为了确定hG6PC1.6的冷电子显微镜 (cryo-EM) 结构.
- 为了阐明酶的水解和诱导适合的机制.
- 为了解致病突变和新型监管机制提供结构基础.
主要方法:
- 电子显微镜 (cryo-EM) 结构的确定.
- 对hG6PC1.1的apo和基质/产品结合状态的分析.
- 不同形状状态的结构比较.
主要成果:
- 在部分开放和完全开放状态下确定hG6PC1的冷EM结构.
- 捕获的结构在阿波形式和复杂的葡萄糖-6-酸盐 (G6P),果糖-6-酸盐 (F6P) 和酸盐.
- 提供了有关水解机制和诱导适应过程的见解.
结论:
- 确定的结构为诊断与疾病相关的G6PC1突变提供了基础.
- 提出了一种对hG6PC1活性的脂胺调节的潜在机制.
- 这项工作为hG6PC1功能及其对代谢调节的影响提供了新的视角.
相关概念视频
Induced-fit Model
Most chemical reactions in cells require enzymes—biological catalysts that speed up the reaction without being consumed or permanently changed. They reduce the activation energy needed to convert the reactants into products. Enzymes are proteins, that usually work by binding to a substrate—a reactant molecule that they act upon.
Enzymes exhibit substrate specificity, meaning that they can only bind to certain substrates. This is mainly determined by the shape and chemical characteristics of...
Enzymes exhibit substrate specificity, meaning that they can only bind to certain substrates. This is mainly determined by the shape and chemical characteristics of...
Enzymes
Inside living organisms, enzymes act as catalysts for many biochemical reactions involved in cellular metabolism. The role of enzymes is to reduce the activation energies of biochemical reactions by forming complexes with its substrates. The lowering of activation energies favor an increase in the rates of biochemical reactions.
Enzyme deficiencies can often translate into life-threatening diseases. For example, a genetic abnormality resulting in the deficiency of the enzyme G6PD...
Enzyme deficiencies can often translate into life-threatening diseases. For example, a genetic abnormality resulting in the deficiency of the enzyme G6PD...
GTPases and their Regulation
Guanine nucleotide-binding proteins (G-proteins), also known as GTPases, are a superfamily of proteins that regulate many cellular processes, such as cell signaling, vesicular transport, and the regulation of cell shape and motility. Mutation or dysfunction of these proteins can lead to disease. There are around 40,000 known G-proteins that can broadly be classified into two groups ‒ small G-proteins consisting of a single domain and large multi-domain G-proteins.
Large G-proteins, also known...
Large G-proteins, also known...
Activation and Inactivation of G Proteins
Heterotrimeric G proteins are guanine nucleotide-binding proteins. As the name suggests, heterotrimeric G proteins are composed of three subunits: alpha, beta, and gamma. They remain GDP-bound or GTP-bound inside the cells and switch between inactive/active states. The Gα subunit possesses the nucleotide-binding pocket that binds guanine nucleotides and switches between GDP or GTP-bound states. In contrast, the Gꞵ and Gγ subunits are always bound together with high affinity and are together...
GPCRs Regulate Adenylyl Cylase Activity
Some GPCRs transmit signals through adenylyl cyclase (AC), a transmembrane enzyme. AC helps synthesize second messenger cyclic adenosine monophosphate (cAMP). AC catalyzes cyclization reaction and converts ATP to cAMP by releasing a pyrophosphate. The pyrophosphate is further hydrolyzed to phosphate by the enzyme pyrophosphatase, which drives cAMP synthesis to completion. However, cAMP is rapidly degraded to 5′ AMP by the enzymes phosphodiesterase (PDE), preventing overstimulation of cells.
Two...
Two...
cAMP-dependent Protein Kinase Pathways
Cyclic Adenosine Monophosphate (cAMP) is an essential second messenger that activates protein kinase A (PKA) and regulates various biological processes. A single epinephrine molecule binds to GPCR and activates several heterotrimeric G proteins, each stimulating multiple adenylyl cyclase, amplifying the signal, and synthesizing large numbers of cAMP molecules. Small changes in cAMP concentration affect PKA activity. The binding of four cAMP molecules induces a conformational change in PKA,...


