Reactive oxygen species (ROS) are produced as undesirable by-products of metabolism in various cellular compartments, especially in response to unfavorable environmental conditions, throughout the life cycle of plants. Stress-induced ROS production disrupts normal cellular function and leads to oxidative damage. To cope with excessive ROS, plants are equipped with a sophisticated antioxidative defense system consisting of enzymatic and non-enzymatic components that scavenge ROS or inhibit their harmful effects on biomolecules. Nonetheless, when maintained at relatively low levels, ROS act as signaling molecules that regulate plant growth, development, and adaptation to adverse conditions. Here, we provide an overview of current approaches for detecting ROS. We also discuss recent advances in understanding ROS signaling, ROS metabolism, and the roles of ROS in plant growth and responses to various abiotic stresses. This article is protected by copyright. All rights reserved.

Reactive Oxygen Species: Multidimensional Regulators of Plant Adaptation to Abiotic Stress and Development.

Fundamentals of redox regulation in biology.

Fuels for ROS signaling in plant immunity.

Reactive oxygen species (ROS) have been described to induce a broad range of redox-dependent signaling reactions in physiological conditions. Nevertheless, an excessive accumulation of ROS leads to oxidative stress, which was traditionally considered as detrimental for cells and organisms, due to the oxidative damage they cause to biomolecules. During ageing, elevated ROS levels result in the accumulation of damaged proteins, which may exhibit altered enzymatic function or physical properties (e.g., aggregation propensity). Emerging evidence also highlights the relationship between oxidative stress and age-related pathologies, such as protein misfolding-based neurodegenerative diseases (e.g., Parkinson’s (PD), Alzheimer’s (AD) and Huntington’s (HD) diseases). In this review we aim to introduce the role of oxidative stress in physiology and pathology and then focus on the state-of-the-art techniques available to detect and quantify ROS and oxidized proteins in live cells and in vivo, providing a guide to those aiming to characterize the role of oxidative stress in ageing and neurodegenerative diseases. Lastly, we discuss recently published data on the role of oxidative stress in neurological disorders.

/pdf/oxidative-stress-in-age-related-neurodegenerative-diseases-1b3wx702.pdf

Oxidative Stress in Age-Related Neurodegenerative Diseases: An Overview of Recent Tools and Findings

Covalent inhibitors and other types of covalent modalities have seen a revival in the past two decades, with a variety of new targeted covalent drugs having been approved in recent years. A key feature of such molecules is an intrinsically reactive group, typically a weak electrophile, which enables the irreversible or reversible formation of a covalent bond with a specific amino acid of the target protein. This reactive group, often called the "warhead", is a critical determinant of the ligand's activity, selectivity, and general biological properties. In 2019, we summarized emerging and re-emerging warhead chemistries to target cysteine and other amino acids (Gehringer, M.; Laufer, S. A. J. Med. Chem. 2019, 62, 5673-5724; DOI: 10.1021/acs.jmedchem.8b01153). Since then, the field has rapidly evolved. Here we discuss the progress on covalent warheads made since our last Perspective and their application in medicinal chemistry and chemical biology.

Emerging and Re-emerging Warheads for Targeted Covalent Inhibitors: An Update.

The cytosolic thiol peroxidase PRXIIB is an intracellular sensor for H2O2 that regulates plant immunity through a redox relay

Abstract ‘Turn-on’ fluorescence probes for detecting H 2 O 2 in cells are established, but equivalent tools to monitor the products of its reaction with protein cysteines have not been reported. Here we describe fluorogenic probes for detecting sulfenic acid, a redox modification inextricably linked to H 2 O 2 signaling and oxidative stress. The reagents exhibit excellent cell permeability, rapid reactivity, and high selectivity with minimal cytotoxicity. We develop a high-throughput assay for measuring S -sulfenation in cells and use it to screen a curated kinase inhibitor library. We reveal a positive association between S -sulfenation and inhibition of TK, AGC, and CMGC kinase group members including GSK3, a promising target for neurological disorders. Proteomic mapping of GSK3 inhibitor-treated cells shows that S -sulfenation sites localize to the regulatory cysteines of antioxidant enzymes. Our studies highlight the ability of kinase inhibitors to modulate the cysteine sulfenome and should find broad application in the rapidly growing field of redox medicine. 

/pdf/reaction-based-fluorogenic-probes-for-detecting-protein-tglgidwo.pdf

Reaction-based fluorogenic probes for detecting protein cysteine oxidation in living cells

Over 50 billion cells undergo apoptosis each day in an adult human to maintain immune homeostasis. Hydrogen sulfide (H2S) is also required to safeguard the function of immune response. However, it is unknown whether apoptosis regulates H2S production. Here, we show that apoptosis-deficient MRL/lpr (B6.MRL-Faslpr/J) and Bim-/- (B6.129S1-Bcl2l11tm1.1Ast/J) mice exhibit significantly reduced H2S levels along with aberrant differentiation of Th17 cells, which can be rescued by the additional H2S. Moreover, apoptotic cells and vesicles (apoVs) express key H2S-generating enzymes and generate a significant amount of H2S, indicating that apoptotic metabolism is an important source of H2S. Mechanistically, H2S sulfhydrates selenoprotein F (Sep15) to promote signal transducer and activator of transcription 1 (STAT1) phosphorylation and suppress STAT3 phosphorylation, leading to the inhibition of Th17 cell differentiation. Taken together, this study reveals a previously unknown role of apoptosis in maintaining H2S homeostasis and the unique role of H2S in regulating Th17 cell differentiation via sulfhydration of Sep15C38. 

Apoptosis releases hydrogen sulfide to inhibit Th17 cell differentiation.

With an eye toward expanding chemistries used for covalent ligand discovery, we elaborated an umpolung strategy that exploits the 'polarity reversal' of sulfur when cysteine is oxidized to sulfenic acid, a widespread post-translational modification, for selective bioconjugation with C-nucleophiles. Here we present a global map of a human sulfenome that is susceptible to covalent modification by members of a nucleophilic fragment library. More than 500 liganded sulfenic acids were identified on proteins across diverse functional classes, and, of these, more than 80% were not targeted by electrophilic fragment analogs. We further show that members of our nucleophilic fragment library can impair functional protein-protein interactions involved in nuclear oncoprotein transport and DNA damage repair. Our findings reveal a vast expanse of ligandable sulfenic acids in the human proteome and highlight the utility of nucleophilic small molecules in the fragment-based covalent ligand discovery pipeline, presaging further opportunities using non-traditional chemistries for targeting proteins. 

/pdf/nucleophilic-covalent-ligand-discovery-for-the-cysteine-2d9za45p.pdf

Nucleophilic covalent ligand discovery for the cysteine redoxome.

Covalent drug discovery has experienced a revival since the 2013 approval of the first cysteine-targeting kinase inhibitors. Many drugs that were discovered by serendipity also possess the ability to react with cysteine residues, leading to interactions with multiple proteins. This widespread interaction, known as promiscuity, necessitates a comprehensive study of how these drugs engage with cysteines throughout the proteome. Here we report a large-scale analysis to meet this need by defining proteome-wide cysteine ligandability maps of 70 drugs in native biological systems. We examined over 24,000 cysteines in the human proteome, pinpointing 279 proteins as potential drug targets across diverse functional categories. We further validated several cysteine engagement events, uncovering previously unknown cysteine sites on both established drug targets and proteins that are generally difficult to address with small molecules. Additionally, our findings highlighted an opportunity to harness a drug-cysteine interaction for targeted protein degradation. Together, our analysis provides an invaluable resource for advancing the development of covalent drugs. Many drugs discovered by serendipity possess the ability to react with cysteine residues on target proteins. Here the authors report a large-scale chemoproteomic analysis to define proteome-wide ligandability maps of 70 drugs with diverse cysteine-reactive chemotypes in native biological systems.

Proteome-wide ligandability maps of drugs with diverse cysteine-reactive chemotypes

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