人类线粒体谷转移酶:线粒体向组在基质中的动态参数和适应
Patrick A Cardwell1, Carlo Del Moro2, Michael P Murphy2
1School of Chemistry, Joseph Black Building, University Avenue, University of Glasgow, Glasgow G12 8QQ, UK.
Bioorganic & medicinal chemistry
|April 9, 2024
概括
研究人员鉴定了线粒体中的谷氨转移酶 (GST) 异型,这对细胞解毒至关重要. 他们修改了线粒体向基质,以选择性地破坏癌细胞的谷氨池,提供了潜在的癌症治疗点.
科学领域:
- 生物化学 生物化学
- 细胞生物学 细胞生物学
- 癌症研究 癌症研究
背景情况:
- 谷氨-S转移酶 (GSTs) 是细胞中异生菌和氧化应激产物的解毒的重要酶.
- GSTs催化了谷氨 (GSH) 与电友的结合,形成稳定的铁添加物.
- 特定的GST异型 (GSTK1-1,GSTA1-1,GSTA4-4) 存在于线粒体中,在癌细胞中分布变化,呈现出潜在的治疗点.
研究的目的:
- 为了确定人类GSTK1-1,GSTA1-1和GSTA4-4异型与GSH和1-chloro-2,4-dinitrobenzene (CDNB) 的动力参数 (kcat/Km).
- 研究 mitochondria-targeted CDNB (MitoCDNB) 基板的修改如何影响 GST 活动.
- 为了能够在表达特定GST异型的癌细胞中选择性地破坏线粒体GSH池.
主要方法:
- 进行了酶动力学测定,以测量GSH和CDNB类型的GST异型的kcat/Km值.
- 合成和测试了针对线粒体的CDNB基质,其中含有不同的取电子替代剂和三位.
- 分析了动力参数,以了解基质活动关系.
主要成果:
- 用GSH和CDNB对GSTK1-1,GSTA1-1和GSTA4-4的催化效率 (kcat/Km) 进行了量化.
- 对取电子替代剂的修改以及对线粒体向组在CDNB类似物上的位置改变了反应速率.
- 这项研究表明,它能够调整针对线粒体的GST基质的活性.
结论:
- 关键线粒体GST异型体的动态表征为向药物开发提供了基础.
- 针对线粒体向基质的定制修改可以选择性地调节GST活动.
- 这些发现为利用癌细胞中特定的GST异型表达开辟了道路,以破坏其线粒体GSH池以获得治疗益处.
更多相关视频
14:57Spectrophotometric Screening for Potential Inhibitors of Cytosolic Glutathione S-Transferases
Published on: October 10, 2020
14.4K
08:37Analyzing Supercomplexes of the Mitochondrial Electron Transport Chain with Native Electrophoresis, In-gel Assays, and Electroelution
Published on: June 1, 2017
14.1K
相关概念视频
Energy to Drive Translocation
2.1K
Mitochondrial protein import is powered by two distinct energy sources: ATP hydrolysis and electrochemical potential across the inner membrane. Newly synthesized precursors are bound by cytosolic chaperones of the Hsp70 family, which guide them to the import receptors on the mitochondrial surface. Utilizing the energy of ATP hydrolysis, Hsp70 chaperones transfer these precursors to the TOM receptors on the mitochondrial outer membrane.
Generally, polypeptides are unfolded by two distinct...
Generally, polypeptides are unfolded by two distinct...
2.1K
Translocation of Proteins into the Mitochondria
3.1K
Mitochondrial precursors are translocated to the internal subcompartments via independent mechanisms involving distinct protein machineries called translocases.
Sorting of outer membrane proteins:
Mitochondrial outer membrane proteins are of two types: the transmembrane, beta-barrel porins, and the membrane-anchored, alpha-helical proteins. Beta-barrel porin precursors are translocated by the TOM complex and inserted into the outer mitochondrial membrane by the SAM complex. In contrast,...
Sorting of outer membrane proteins:
Mitochondrial outer membrane proteins are of two types: the transmembrane, beta-barrel porins, and the membrane-anchored, alpha-helical proteins. Beta-barrel porin precursors are translocated by the TOM complex and inserted into the outer mitochondrial membrane by the SAM complex. In contrast,...
3.1K
The ADP/ATP Carrier Protein
3.2K
ADP/ATP carrier or AAC protein is the most abundant carrier protein in the inner mitochondrial membrane. It transports large quantities of ADP and ATP, equivalent to the average human body weight, every day. Among other transporters, ACC protein is one of the best-studied members of the mitochondrial carrier protein family. The ADP/ATP carrier protein comprises two transmembrane helices connected to a loop and a single alpha-helix on the matrix side. It switches between two conformational...
3.2K
Mitochondrial Protein Sorting
4.3K
Mitochondria are double-membrane organelles of the eukaryotes involved in cellular metabolism, signaling, ATP synthesis, and programmed cell death. Each of these processes requires specific proteins and enzymes that must be correctly sorted to the right mitochondrial subcompartment for the proper functioning of the organelle.
Most of these mitochondrial proteins are encoded by the nucleus and imported to the mitochondria as unfolded or loosely folded precursors. Mitochondrial precursors...
Most of these mitochondrial proteins are encoded by the nucleus and imported to the mitochondria as unfolded or loosely folded precursors. Mitochondrial precursors...
4.3K
ATP Synthase: Mechanism
14.6K
In animals, the mitochondrial F1F0 ATP synthase is the key protein that synthesizes ATP molecules through a complex catalytic mechanism. While the nuclear genome encodes the majority of ATP synthase subunits, the mitochondrial genome encodes some of the enzyme's most critical components. The formation of this multi-subunit enzyme is a complex multi-step process regulated at the level of transcription, translation, and assembly. Defects in one or more of these steps can result in decreased...
14.6K
Mitochondrial Precursor Proteins
2.6K
Mitochondrial precursors are partially unfolded or loosely folded polypeptide chains. Newly synthesized precursors are inhibited from spontaneously folding into their native conformation by the cytosolic chaperones, heat shock proteins 70 (Hsp70), and mitochondrial import stimulation factors (MSFs). Precursors bound to MSFs are guided to the TOM70-TOM37 receptors, while precursors bound to Hsp70 chaperones are targetted to TOM20-TOM22 receptor complexes.
Most of the mitochondrial...
Most of the mitochondrial...
2.6K
