Unique Cellular and Biochemical Features of Human Mitochondrial Peroxiredoxin 3 Establish the Molecular Basis for Its Specific Reaction with Thiostrepton.
Unique Cellular and Biochemical Features of Human Mitochondrial Peroxiredoxin 3 Establish the Molecular Basis for Its Specific Reaction with Thiostrepton.
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DOI：
10.3390/antiox10020150
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发表时间：
2021-01-20
期刊：
影响因子：
--
通讯作者：
Cunniff B
中科院分区：
文献类型：
--
作者：
Nelson KJ;Messier T;Milczarek S;Saaman A;Beuschel S;Gandhi U;Heintz N;Smalley TL;Lowther WT;Cunniff B
肿瘤发生的中心标志是增加线粒体活性氧（mROS）的代谢改变。作为回应，癌细胞上调其抗氧化能力和氧化还原反应信号通路。一种有前途的化疗方法是将ROS增加到与肿瘤细胞存活不相容的水平。线粒体过氧化物酶3（PRX 3）在过氧化氢（H2 O2）的解毒中起着重要作用。PRX 3是硫链丝菌素（TS）的分子靶标，TS是一种天然产物和FDA批准的抗生素。TS通过共价加合PRX 3的两个催化半胱氨酸残基并交联同二聚体来灭活PRX 3。使用恶性间皮瘤的细胞模型，我们在这里表明，PRX 3表达和细胞中的mROS水平与TS的敏感性相关，TS选择性地与PRX 3相对于其他PRX亚型反应。使用重组PRXs 1-5，我们表明，TS优先与还原硫醇在PRX 3二聚体在线粒体pH值。我们还表明，部分氧化PRX 3完全解离二聚体，而部分氧化PRX 1和PRX 2主要保持十聚体。TS在线粒体pH下与PRX 1和PRX 2的工程化二聚体反应的能力，但在细胞质pH下与野生型十聚体蛋白反应效率低下，这支持了一种新的作用机制，并解释了TS对PRX 3的特异性。因此，PRX 3形成二聚体的独特结构和倾向有助于其对TS介导的失活的敏感性增加，使PRX 3成为促氧化剂癌症治疗的有希望的靶点。
A central hallmark of tumorigenesis is metabolic alterations that increase mitochondrial reactive oxygen species (mROS). In response, cancer cells upregulate their antioxidant capacity and redox-responsive signaling pathways. A promising chemotherapeutic approach is to increase ROS to levels incompatible with tumor cell survival. Mitochondrial peroxiredoxin 3 (PRX3) plays a significant role in detoxifying hydrogen peroxide (H2O2). PRX3 is a molecular target of thiostrepton (TS), a natural product and FDA-approved antibiotic. TS inactivates PRX3 by covalently adducting its two catalytic cysteine residues and crosslinking the homodimer. Using cellular models of malignant mesothelioma, we show here that PRX3 expression and mROS levels in cells correlate with sensitivity to TS and that TS reacts selectively with PRX3 relative to other PRX isoforms. Using recombinant PRXs 1–5, we demonstrate that TS preferentially reacts with a reduced thiolate in the PRX3 dimer at mitochondrial pH. We also show that partially oxidized PRX3 fully dissociates to dimers, while partially oxidized PRX1 and PRX2 remain largely decameric. The ability of TS to react with engineered dimers of PRX1 and PRX2 at mitochondrial pH, but inefficiently with wild-type decameric protein at cytoplasmic pH, supports a novel mechanism of action and explains the specificity of TS for PRX3. Thus, the unique structure and propensity of PRX3 to form dimers contribute to its increased sensitivity to TS-mediated inactivation, making PRX3 a promising target for prooxidant cancer therapy.
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影响因子：
5.6
作者：
Cunniff, Brian;Benson, Kira;Stumpff, Jason;Newick, Kheng;Held, Paul;Taatjes, Douglas;Joseph, Joy;Kalyanaraman, Balaraman;Heintz, Nicholas H.
通讯作者：
Heintz, Nicholas H.
影响因子：
2.9
作者：
Nelson, Kimberly J.;Parsonage, Derek;Poole, Leslie B.
通讯作者：
Poole, Leslie B.
影响因子：
22.7
作者：
Corsello, Steven M.;Nagari, Rohith T.;Golub, Todd R.
通讯作者：
Golub, Todd R.
影响因子：
3.7
作者：
Newick K;Cunniff B;Preston K;Held P;Arbiser J;Pass H;Mossman B;Shukla A;Heintz N
通讯作者：
Heintz N
影响因子：
4.3
作者：
Murphy, Michael P.
通讯作者：
Murphy, Michael P.