Deciphering the roles of cystathionine gamma-lyase/H2S system in Fe-S protein biogenesis and iron homeostasis

解读胱硫醚γ-裂解酶/H2S系统在Fe-S蛋白生物发生和铁稳态中的作用

• 批准号: RGPIN-2022-05369
• 负责人: Yang, Guangdong
• 金额: $ 2.91万
• 依托单位: Laurentian University of Sudbury
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=748506
• 关键词: Deciphering; roles; cystathionine; gamma; lyase

Hydrogen sulfide (H2S) is traditionally known as a toxic gas but recently recognized as a ubiquitous signal molecule, which regulates a variety of physiological processes in many different species (from microbes to animals to human). H2S can be endogenously produced from the amino acid cysteine by a vitamin B6-dependent enzyme cystathionine gamma-lyase (CSE). H2S is capable of post-translational modification of proteins by yielding a hydropersulfide (-SSH) in the active cysteine residues, termed as S-sulfhydration. Fe-S clusters are the most ancient redox centers for numerous proteins involved in energy production, oxygen transport, DNA replication and repair in all kingdoms of life. Another highly conserved vitamin B6-dependent enzyme cysteine desulfurase (NFS1) can decompose cysteine for the very first step of Fe-S cluster biosynthesis. Given the facts that CSE and NFS1 share many similar chemical features and H2S and iron are mutually dependent in the regulation of cellular functions, it is indispensable to investigate the interconnections among H2S signals, iron metabolism, and Fe-S cluster formation in mammalian cells.         My long-term goal is to elucidate the biological importance of H2S in order to improve our understanding of the regulation of a multitude of cellular functions, and to better train the next generation of researchers in this field. The short-term goal, through this research program, is to determine the interaction of H2S metabolism and Fe-S protein biogenesis in iron homeostasis and iron-dependent cell death (ferroptosis) under various stress conditions.         Two specific objectives are proposed in this program: 1) investigate the regulation of CSE/H2S system on NFS1 functions and Fe-S cluster biosynthesis and stability; 2) examine the role of CSE/H2S system in iron metabolism and ferroptosis sensitivity under stress conditions (low oxygen and iron overload/deprivation). In combination with genetic, biochemical, spectroscopic, and mechanistic studies in both skeletal muscle cells and heart cells, this program may lead to new paradigms in the understanding of H2S signals and Fe-S protein biogenesis in mammalian cells.

传统上，硫化氢（H2S）被称为有毒气体，但最近被公认为无处不在的信号分子，它调节许多不同物种（从微生物到动物再到人类）的各种物理过程。 H2s可以通过维生素B6依赖性酶胱胱氨酰胺γ-酯（CSE）从氨基酸半胱氨酸内源产生。 H2S能够通过在活性半胱氨酸残基中产生氢氟（-ssh）来对蛋白质进行翻译后修饰，称为S-硫化。 Fe-S簇是涉及能源生产，氧运输，DNA复制和维修的众多蛋白质的最古老的氧化还原中心。另一个高度组成的维生素B6依赖性酶半胱氨酸脱硫酶（NFS1）可以在Fe-S簇生物合成的第一步中分解半胱氨酸。鉴于CSE和NFS1具有许多相似的化学特征，H2S和铁在细胞功能的调节中相互依赖，因此研究H2S信号之间的互连，铁代谢和Fe-Spers形成是必不可少的。我的长期目标是阐明H2的生物学重要性，以提高我们对多种细胞功能的调节的理解，并更好地培训该领域的下一代研究人员。通过该研究计划，短期目标是确定在各种应力​​条件下铁稳态和铁依赖性细胞死亡（铁凋亡）中H2S代谢和Fe-S蛋白生物发生的相互作用。该程序中提出了两个具体的目标：1）研究在NFS1功能和Fe-S聚集生物合成和稳定性上的CSE/H2S系统的调节； 2）检查CSE/H2S系统在压力条件下（低氧和铁过载/剥夺）下的铁代谢和铁凋亡敏感性的作用。结合骨骼肌细胞和心脏细胞中的遗传，生化，光谱和机械研究，该程序在理解H2S信号和哺乳动物细胞中的Fe-S蛋白生物发生方面可能会导致新的范式。