四硫钼酸铵通过形成金属簇来抑制铜转运蛋白。
Tetrathiomolybdate inhibits copper trafficking proteins through metal cluster formation.
机构信息
The Chemistry of Life Processes Institute, Northwestern University, Evanston, IL 60208, USA.
出版信息
Science. 2010 Jan 15;327(5963):331-4. doi: 10.1126/science.1179907. Epub 2009 Nov 26.
Abstract
Tetrathiomolybdate (TM) is an orally active agent for treatment of disorders of copper metabolism. Here we describe how TM inhibits proteins that regulate copper physiology. Crystallographic results reveal that the surprising stability of the drug complex with the metallochaperone Atx1 arises from formation of a sulfur-bridged copper-molybdenum cluster reminiscent of those found in molybdenum and iron sulfur proteins. Spectroscopic studies indicate that this cluster is stable in solution and corresponds to physiological clusters isolated from TM-treated Wilson's disease animal models. Finally, mechanistic studies show that the drug-metallochaperone inhibits metal transfer functions between copper-trafficking proteins. The results are consistent with a model wherein TM can directly and reversibly down-regulate copper delivery to secreted metalloenzymes and suggest that proteins involved in metal regulation might be fruitful drug targets.
摘要
四硫钼酸盐 (TM) 是一种可口服的用于治疗铜代谢紊乱的药物。在这里，我们描述了 TM 如何抑制调节铜生理的蛋白质。晶体学结果表明，令人惊讶的是，该药物与金属伴侣蛋白 Atx1 的复合物非常稳定，这是由于形成了一个硫桥连的铜钼簇，类似于钼和铁硫蛋白中发现的那些。光谱研究表明，该簇在溶液中稳定，与从 TM 处理的威尔逊病动物模型中分离的生理簇相对应。最后，机制研究表明，该药物-金属伴侣蛋白抑制了铜转运蛋白之间的金属转移功能。结果与 TM 可直接且可逆地下调分泌金属酶的铜输送的模型一致，并表明参与金属调节的蛋白质可能是有希望的药物靶点。
相似文献
1
Tetrathiomolybdate inhibits copper trafficking proteins through metal cluster formation.四硫钼酸铵通过形成金属簇来抑制铜转运蛋白。
Science. 2010 Jan 15;327(5963):331-4. doi: 10.1126/science.1179907. Epub 2009 Nov 26.
2
Tetrathiomolybdate inhibits the reaction of cisplatin with human copper chaperone Atox1.四硫钼酸铵抑制顺铂与人铜伴侣 Atox1 的反应。
Metallomics. 2018 May 23;10(5):745-750. doi: 10.1039/c8mt00084k.
3
Novel model peptide for Atx1-like metallochaperones.用于Atx1样金属伴侣蛋白的新型模型肽。
Chem Commun (Camb). 2004 Apr 7(7):770-1. doi: 10.1039/b315489k. Epub 2004 Feb 6.
4
Tetrathiomolybdate causes formation of hepatic copper-molybdenum clusters in an animal model of Wilson's disease.四硫代钼酸盐在威尔逊病动物模型中可导致肝脏铜钼簇的形成。
J Am Chem Soc. 2003 Feb 19;125(7):1704-5. doi: 10.1021/ja029054u.
5
Visualizing the metal-binding versatility of copper trafficking sites .可视化铜转运部位的金属结合多功能性。
Biochemistry. 2010 Sep 14;49(36):7798-810. doi: 10.1021/bi101064w.
6
The crystal structures of a copper-bound metallochaperone from Saccharomyces cerevisiae.铜结合金属伴侣蛋白的晶体结构来自酿酒酵母。
J Inorg Biochem. 2017 Dec;177:368-374. doi: 10.1016/j.jinorgbio.2017.08.009. Epub 2017 Aug 24.
7
The Atx1-Ccc2 complex is a metal-mediated protein-protein interaction.Atx1-Ccc2复合物是一种金属介导的蛋白质-蛋白质相互作用。
Nat Chem Biol. 2006 Jul;2(7):367-8. doi: 10.1038/nchembio797. Epub 2006 May 28.
8
Energetics of copper trafficking between the Atx1 metallochaperone and the intracellular copper transporter, Ccc2.Atx1金属伴侣蛋白与细胞内铜转运蛋白Ccc2之间铜转运的能量学
J Biol Chem. 2000 Jun 23;275(25):18611-4. doi: 10.1074/jbc.C000172200.
9
A docking approach to the study of copper trafficking proteins; interaction between metallochaperones and soluble domains of copper ATPases.一种用于研究铜转运蛋白的对接方法；金属伴侣蛋白与铜ATP酶可溶性结构域之间的相互作用。
Structure. 2004 Apr;12(4):669-76. doi: 10.1016/j.str.2004.03.006.
10
Atx1-like chaperones and their cognate P-type ATPases: copper-binding and transfer.Atx1样伴侣蛋白及其同源P型ATP酶：铜结合与转运
Biometals. 2007 Jun;20(3-4):275-89. doi: 10.1007/s10534-006-9068-1. Epub 2007 Jan 16.
引用本文的文献
1
Dynamic assessment of the allocation of copper to cytochrome c oxidase using size-exclusion chromatography (SEC) combined with inductively coupled plasma mass spectrometry (ICP-MS).使用尺寸排阻色谱法（SEC）结合电感耦合等离子体质谱法（ICP-MS）对铜向细胞色素c氧化酶的分配进行动态评估。
bioRxiv. 2025 Jun 16:2025.06.11.659066. doi: 10.1101/2025.06.11.659066.
2
Augment proteasome inhibitor efficacy activates CD8 T cell-mediated antitumor immunity in breast cancer.增强蛋白酶体抑制剂疗效可激活乳腺癌中CD8 T细胞介导的抗肿瘤免疫。
Cell Rep Med. 2025 Jul 15;6(7):102211. doi: 10.1016/j.xcrm.2025.102211. Epub 2025 Jul 2.
3
Metal coordination polymer nanoparticles for cancer therapy.用于癌症治疗的金属配位聚合物纳米颗粒。
Essays Biochem. 2025 Apr 10;69(2):EBC20253012. doi: 10.1042/EBC20253012.
4
Blocking copper transporter protein-dependent drug efflux with albumin-encapsulated Pt(IV) for synergistically enhanced chemo-immunotherapy.用白蛋白包裹的铂（IV）阻断铜转运蛋白依赖性药物外排以协同增强化学免疫疗法。
J Nanobiotechnology. 2025 Mar 18;23(1):217. doi: 10.1186/s12951-025-03310-4.
5
Iron-mediated post-transcriptional regulation in Toxoplasma gondii.弓形虫中铁介导的转录后调控
PLoS Pathog. 2025 Feb 3;21(2):e1012857. doi: 10.1371/journal.ppat.1012857. eCollection 2025 Feb.
6
Role of copper homeostasis and cuproptosis in heart failure pathogenesis: implications for therapeutic strategies.铜稳态和铜死亡在心力衰竭发病机制中的作用：对治疗策略的启示。
Front Pharmacol. 2025 Jan 9;15:1527901. doi: 10.3389/fphar.2024.1527901. eCollection 2024.
7
Copper ions: The invisible killer of cardiovascular disease (Review).铜离子：心血管疾病的隐形杀手（综述）。
Mol Med Rep. 2024 Nov;30(5). doi: 10.3892/mmr.2024.13334. Epub 2024 Sep 20.
8
Superoxide is an Intrinsic Signaling Molecule Triggering Muscle Hypertrophy.超氧化物是触发肌肉肥大的一种内在信号分子。
Antioxid Redox Signal. 2025 Jan;42(1-3):1-15. doi: 10.1089/ars.2024.0595. Epub 2024 Jul 12.
9
Copper in Gynecological Diseases.铜与妇科疾病。
Int J Mol Sci. 2023 Dec 17;24(24):17578. doi: 10.3390/ijms242417578.
10
Top Five Stories of the Cellular Landscape and Therapies of Atherosclerosis: Current Knowledge and Future Perspectives.细胞景观与动脉粥样硬化治疗的五大研究热点：现状与展望。
Curr Med Sci. 2024 Feb;44(1):1-27. doi: 10.1007/s11596-023-2818-2. Epub 2023 Dec 7.
本文引用的文献
1
Tracing copper-thiomolybdate complexes in a prospective treatment for Wilson's disease.追踪硫代钼酸铜配合物在威尔逊病前瞻性治疗中的应用。
Biochemistry. 2009 Feb 10;48(5):891-7. doi: 10.1021/bi801926e.
2
Superoxide dismutase 1 (SOD1) is essential for H2O2-mediated oxidation and inactivation of phosphatases in growth factor signaling.超氧化物歧化酶1（SOD1）对于生长因子信号传导中H2O2介导的磷酸酶氧化和失活至关重要。
Proc Natl Acad Sci U S A. 2008 May 20;105(20):7147-52. doi: 10.1073/pnas.0709451105. Epub 2008 May 14.
3
Novel role of antioxidant-1 (Atox1) as a copper-dependent transcription factor involved in cell proliferation.抗氧化剂-1（Atox1）作为一种参与细胞增殖的铜依赖性转录因子的新作用。
J Biol Chem. 2008 Apr 4;283(14):9157-67. doi: 10.1074/jbc.M709463200. Epub 2008 Feb 2.
4
Reversible precipitation of bovine serum albumin by metal ions and synthesis, structure and reactivity of new tetrathiometallate chelating agents.金属离子引起的牛血清白蛋白可逆沉淀以及新型四硫代金属酸盐螯合剂的合成、结构与反应活性
J Inorg Biochem. 2007 Nov;101(11-12):1707-18. doi: 10.1016/j.jinorgbio.2007.07.015. Epub 2007 Jul 21.
5
How many metals does it take to fix N2? A mechanistic overview of biological nitrogen fixation.固定氮气需要多少种金属？生物固氮的机制概述。
Proc Natl Acad Sci U S A. 2006 Nov 14;103(46):17088-93. doi: 10.1073/pnas.0603978103. Epub 2006 Nov 6.
6
Copper binding by tetrathiomolybdate attenuates angiogenesis and tumor cell proliferation through the inhibition of superoxide dismutase 1.四硫代钼酸盐与铜的结合通过抑制超氧化物歧化酶1来减弱血管生成和肿瘤细胞增殖。
Clin Cancer Res. 2006 Aug 15;12(16):4974-82. doi: 10.1158/1078-0432.CCR-06-0171.
7
Cobalt, copper and molybdenum in the nutrition of animals and plants.动植物营养中的钴、铜和钼。
Physiol Rev. 1952 Jan;32(1):66-121. doi: 10.1152/physrev.1952.32.1.66.
8
Demyelination in lambs born of ewes maintained on high intakes of sulphate and molybdate.母羊摄入大量硫酸盐和钼酸盐后所产羔羊的脱髓鞘病变
Nature. 1960 Jan 2;185:20-2. doi: 10.1038/185020a0.
9
Copper chelation represses the vascular response to injury.铜螯合作用可抑制血管对损伤的反应。
Proc Natl Acad Sci U S A. 2003 May 27;100(11):6700-5. doi: 10.1073/pnas.1231994100. Epub 2003 May 16.
10
Transition metal speciation in the cell: insights from the chemistry of metal ion receptors.细胞中的过渡金属形态：来自金属离子受体化学的见解
Science. 2003 May 9;300(5621):931-6. doi: 10.1126/science.1085049.
Zotero 插件