在基质和明显的非竞争性抑制剂之间,细胞染色体P450的合作抑制
Yu Hirano1, Sachiyo Yoneda2, Kaori Yasuda2
1Institute for Quantum Life Science, National Institutes for Quantum Science and Technology, Chiba, Japan; Quantum Life Science Course, Graduate School of Science and Engineering, Chiba University, Chiba, Japan.
The Journal of biological chemistry
|April 17, 2025
概括
研究人员对细胞P450酶的酶基质抑制剂复合物进行了结构性验证. 这项研究揭示了一种新的合作性抑制机制,该机制涉及Lanoconazole和Diclofenac在CYP105A1.1.中.
科学领域:
- 生物化学 生物化学
- 结构生物学 结构生物学
- 酶动力学 酶动力学
背景情况:
- 细胞染色体P450 (CYP) 酶对于新陈代谢至关重要,它们利用血红组进行催化.
- 抑制剂与CYPs的结合通常通过生物化学和结构方法进行研究,非竞争性抑制剂通常被认为与全结合.
- 在CYP中缺乏酶基质抑制剂 (ESI) 复合物的实验结构证据.
研究的目的:
- 研究含伊米达化合物对CYP105A1.1.的抑制机制.
- 为CYP酶提供ESI复合体的第一个实验性结构验证.
- 阐明绑定相互作用,并提出一种合作性抑制机制.
主要方法:
- 生物化学酶抑制测定使用基托可纳,兰可纳和米可纳.
- 用X射线结晶学测定CYP105A1与抑制剂 (EI) 以及基质和抑制剂 (ESI) 的结构.
- 量子力学计算分析ESI综合体内的分子间相互作用.
主要成果:
- 基托可纳和米可纳被确定为竞争性抑制剂,而拉诺可纳则作为CYP105A1.1.的非竞争性抑制剂.
- X射线结构揭示了兰诺可纳对血红铁的多种结合方向.
- 确定的ESI复合体结构显示,兰可纳与海姆铁结合,二甲与兰可纳相互作用,但与海姆铁相距较远.
结论:
- 兰诺可纳是一种明显的非竞争性抑制剂,可以与CYP105A1.1.一起形成ESI复合物.
- 狄克洛菲纳克和兰诺可纳之间的相互作用,以及狄克洛菲纳克和阿尔金因残留物,稳定ESI复合体.
- 提出了合作性抑制机制,挑战了非竞争性抑制剂结合部位的传统观点.
相关概念视频
02:34Enzymes
80.2K
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...
80.2K
01:30Enzyme Inhibition
77.6K
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.
77.6K
00:46Feedback Inhibition
53.4K
Biochemical reactions are occurring constantly in cells, converting starting substances to different products, usually with the help of enzymes that speed the reactions. Without enzymes, it would take far too long for most reactions to occur to be useful to the cell!
53.4K
01:58Cooperative Allosteric Transitions
7.8K
Cooperative allosteric transitions can occur in multimeric proteins, where each subunit of the protein has its own ligand-binding site. When a ligand binds to any of these subunits, it triggers a conformational change that affects the binding sites in the other subunits; this can change the affinity of the other sites for their respective ligands. The ability of the protein to change the shape of its binding site is attributed to the presence of a mix of flexible and stable segments in the...
7.8K
01:18Indirect-Acting Cholinergic Agonists: Mechanism of Action
1.5K
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,...
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,...
1.5K
01:08Allosteric Regulation
57.3K
Allosteric regulation of enzymes occurs when the binding of an effector molecule to a site that is different from the active site causes a change in the enzymatic activity. This alternate site is called an allosteric site, and an enzyme can contain more than one of these sites. Allosteric regulation can either be positive or negative, resulting in an increase or decrease in enzyme activity. Most enzymes that display allosteric regulation are metabolic enzymes involved in the degradation or...
57.3K