阴阳性氨酸是可逆的蛋白酶体抑制剂
Anna Maria Santoro1, Maria Cristina Lo Giudice, Alessandro D'Urso
1IBB-CNR, Istituto di Biostrutture e Bioimmagini, UOS di Catania c/o Dipartimento di Scienze Chimiche Viale A. Doria 6 - 95125 Catania.
Journal of the American Chemical Society
|May 31, 2012
概括
阴阳性氨酸有效抑制蛋白酶活性,显示作为抗癌剂的承诺. 这些水溶性化合物为开发多目标疗法提供了新的支架,通过阻断蛋白质酶体催化部位来开发多目标疗法.
科学领域:
- 生物化学 生物化学
- 药用化学 医学化学
- 分子生物学分子生物学
背景情况:
- 蛋白酶体是一个关键的细胞机器,参与蛋白质降解.
- 蛋白酶活性失调与包括癌症在内的各种疾病有关.
- 氨酸因其光动力学和抗癌性质而闻名.
研究的目的:
- 研究水溶性氨酸作为蛋白酶体抑制剂的潜力.
- 阐明控制氨酸-蛋白酶体相互作用的结构-活性关系.
- 探索氨酸作为新型多目标抗癌药物设计的支架.
主要方法:
- 在体外抑制试验测量蛋白质酶酶活性.
- 使用紫外线对紫外线的光谱来监测氨酸-蛋白酶结合的光谱学表征.
- 分子对接模拟以可视化蛋白质酶活性部位内的氨酸相互作用.
主要成果:
- 与阴离子衍生物相比,阴离子氨酸氨酸表现出明显更高的蛋白质酶抑制活性.
- 抑制效率与氨酸宏循环的电荷和结构相关.
- 裸露的基氨酸氨酸是微分子范围中最强大的可逆抑制剂.
- 紫外线光谱学证实了抑制作用和光谱变化之间的直接相关性.
- 分子建模显示,基氨酸氨酸有效地阻断了蛋白质酶体的催化口袋.
结论:
- 溶于水的基氨酸氨酸是有效的可逆蛋白酶体抑制剂.
- 静电相互作用在氨酸-蛋白酶体结合中起着关键作用.
- 氨酸是开发具有双重作用机制的新型抗癌药物的有希望的支架.
相关概念视频
The Proteasome
Eukaryotic cells can degrade proteins through several pathways. One of the most important among these is the ubiquitin-proteasome pathway. It helps the cell eliminate the misfolded, damaged, or unwarranted cytoplasmic proteins in a highly specific manner.
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. This involves participation of a series of enzymes including— E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3 (ubiquitin...
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. This involves participation of a series of enzymes including— E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3 (ubiquitin...
The Proteasome
Eukaryotic cells can degrade proteins through several pathways. One of the most important amongst these is the ubiquitin-proteasome pathway. It helps the cell eliminate the misfolded, damaged, or unwarranted cytoplasmic proteins in a highly specific manner.
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. A series of enzymes carry out the ubiquitination of the target proteins - E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3...
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. A series of enzymes carry out the ubiquitination of the target proteins - E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3...
The Proteasome Structure
The ubiquitin-proteasome pathway is a well-known mechanism utilized by eukaryotic cells to remove cytoplasmic proteins that are misfolded, damaged, or no longer needed. In this pathway, the protein that needs to be eliminated undergoes a process called ubiquitination, where a chain of ubiquitin molecules is attached to the 48th lysine residue of the target protein. This ubiquitin modification helps the proteasome distinguish between a target protein and a healthy protein.
The proteasome is an...
The proteasome is an...
The Electron Transport Chain
The electron transport chain or oxidative phosphorylation is an exothermic process in which free energy released during electron transfer reactions is coupled to ATP synthesis. This process is a significant source of energy in aerobic cells, and therefore inhibitors of the electron transport chain can be detrimental to the cell's metabolic processes.
Inhibitors of the electron transport chain
Rotenone, a widely used pesticide, prevents electron transfer from Fe-S cluster to ubiquinone or Q in...
Inhibitors of the electron transport chain
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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,...
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Phase II biotransformations are detoxification mechanisms that conjugate xenobiotics with endogenous substances, neutralizing their toxicity.
A key example involves the conjugation of cyanide ions, which impair cellular respiration and alter hemoglobin into non-oxygen-carrying cyanmethemoglobin. To neutralize this threat, a sulfur atom from thiosulphate is transferred to the cyanide ion, catalyzed by the enzyme rhodanese, resulting in an inactive compound called thiocyanate. The production of...
A key example involves the conjugation of cyanide ions, which impair cellular respiration and alter hemoglobin into non-oxygen-carrying cyanmethemoglobin. To neutralize this threat, a sulfur atom from thiosulphate is transferred to the cyanide ion, catalyzed by the enzyme rhodanese, resulting in an inactive compound called thiocyanate. The production of...

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