Activation, interaction and intimation of Nrf2 pathway and their mutational studies causing Nrf2 associated cancer

IF 4.2 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Mridul Sahu, Utkarsh Jain
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引用次数: 0

Abstract

Responses against infection trigger several signaling pathways that lead to the production of cytokines, these cytokines release ROS and RNS, damaging DNA and proteins turn into various diseases including cancer. To combat these harmful cytokines, the Nrf2 pathway is activated. The gene NFE2L2 encodes Nrf2, which is divided into seven conserved domains (Neh1–7). The DLG and ETGE motifs, conserved sequences of amino acid in the Neh2 domain of Nrf2, bind to the BTB domain of Keap1. BTB domain promotes Keap1's homodimerization resulting in Cul3 recruitment providing scaffold formation to E2 ubiquitin ligase to form ubiquitin complex. Under normal conditions, this complex regularly degrades Nrf2. However, once the cell is exposed to oxidative stress by ROS interaction with Keap1 resulting in conformational changes that stabilize the Nrf2. Nrf2 further concentrates on the nucleus where it binds with the transcriptional factor to perform the desired genes transcription for synthesizing SOD, GSH, CAT, and various other proteins which reduce the ROS levels preventing certain diseases. To prevent cells from oxidative stress, molecular hydrogen activates the Nrf2 pathway. To activate the Nrf2 pathway, molecular hydrogen oxidizes the iron porphyrin which acts as an electrophile and interacts with Keap1's cysteine residue.

Abstract Image

这些细胞因子会释放 ROS 和 RNS,破坏 DNA 和蛋白质,导致包括癌症在内的各种疾病。为了对抗这些有害的细胞因子,Nrf2 通路被激活。NFE2L2 基因编码 Nrf2,它分为七个保守结构域(Neh1-7)。Nrf2 的 Neh2 结构域中的 DLG 和 ETGE 氨基酸保守序列与 Keap1 的 BTB 结构域结合。BTB 结构域可促进 Keap1 的同源二聚化,从而招募 Cul3,为 E2 泛素连接酶提供支架,形成泛素复合物。在正常情况下,该复合物会定期降解 Nrf2。然而,一旦细胞受到氧化压力,ROS 与 Keap1 相互作用,导致构象变化,从而稳定了 Nrf2。Nrf2 会进一步集中在细胞核中,与转录因子结合,执行所需的基因转录,合成 SOD、GSH、CAT 和其他各种蛋白质,从而降低 ROS 水平,预防某些疾病。为防止细胞受到氧化压力,分子氢可激活 Nrf2 通路。为了激活 Nrf2 通路,分子氢会氧化卟啉铁,卟啉铁作为亲电子体与 Keap1 的半胱氨酸残基相互作用。
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来源期刊
CiteScore
12.30
自引率
0.00%
发文量
218
审稿时长
32 days
期刊介绍: BBA Molecular Basis of Disease addresses the biochemistry and molecular genetics of disease processes and models of human disease. This journal covers aspects of aging, cancer, metabolic-, neurological-, and immunological-based disease. Manuscripts focused on using animal models to elucidate biochemical and mechanistic insight in each of these conditions, are particularly encouraged. Manuscripts should emphasize the underlying mechanisms of disease pathways and provide novel contributions to the understanding and/or treatment of these disorders. Highly descriptive and method development submissions may be declined without full review. The submission of uninvited reviews to BBA - Molecular Basis of Disease is strongly discouraged, and any such uninvited review should be accompanied by a coverletter outlining the compelling reasons why the review should be considered.
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