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1.
Versatile roles of cysteine persulfides in tumor biology.
Borbényi-Galambos, K, Czikora, Á, Erdélyi, K, Nagy, P
Current opinion in chemical biology. 2024;:102440
Abstract
Rewiring the transsulfuration pathway is recognized as a rapid adaptive metabolic response to environmental conditions in cancer cells to support their increased cysteine demand and to produce Reactive Sulfur Species (RSS) including hydrogen sulfide (H2S) and cysteine persulfide. This can directly (via RSS) or indirectly (by supplying Cys) trigger chemical or enzyme catalyzed persulfidation on critical protein cysteine residues to protect them from oxidative damage and to orchestrate protein functions, and thereby contribute to cancer cell plasticity. In this review key aspects of persulfide-mediated biological processes are highlighted and critically discussed in relation to cancer cell survival, bioenergetics, proliferation as well as in tumor angiogenesis, adaptation to hypoxia and oxidative stress, and regulation of epithelial to mesenchymal transition.
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2.
Shifting paradigms and novel players in Cys-based redox regulation and ROS signaling in plants - and where to go next.
Meyer, AJ, Dreyer, A, Ugalde, JM, Feitosa-Araujo, E, Dietz, KJ, Schwarzländer, M
Biological chemistry. 2021;(3):399-423
Abstract
Cys-based redox regulation was long regarded a major adjustment mechanism of photosynthesis and metabolism in plants, but in the recent years, its scope has broadened to most fundamental processes of plant life. Drivers of the recent surge in new insights into plant redox regulation have been the availability of the genome-scale information combined with technological advances such as quantitative redox proteomics and in vivo biosensing. Several unexpected findings have started to shift paradigms of redox regulation. Here, we elaborate on a selection of recent advancements, and pinpoint emerging areas and questions of redox biology in plants. We highlight the significance of (1) proactive H2O2 generation, (2) the chloroplast as a unique redox site, (3) specificity in thioredoxin complexity, (4) how to oxidize redox switches, (5) governance principles of the redox network, (6) glutathione peroxidase-like proteins, (7) ferroptosis, (8) oxidative protein folding in the ER for phytohormonal regulation, (9) the apoplast as an unchartered redox frontier, (10) redox regulation of respiration, (11) redox transitions in seed germination and (12) the mitochondria as potential new players in reductive stress safeguarding. Our emerging understanding in plants may serve as a blueprint to scrutinize principles of reactive oxygen and Cys-based redox regulation across organisms.
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3.
Redox chemistry of lens crystallins: A system of cysteines.
Serebryany, E, Thorn, DC, Quintanar, L
Experimental eye research. 2021;:108707
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Abstract
The nuclear region of the lens is metabolically quiescent, but it is far from inert chemically. Without cellular renewal and with decades of environmental exposures, the lens proteome, lipidome, and metabolome change. The lens crystallins have evolved exquisite mechanisms for resisting, slowing, adapting to, and perhaps even harnessing the effects of these cumulative chemical modifications to minimize the amount of light-scattering aggregation in the lens over a lifetime. Redox chemistry is a major factor in these damages and mitigating adaptations, and as such, it is likely to be a key component of any successful therapeutic strategy for preserving or rescuing lens transparency, and perhaps flexibility, during aging. Protein redox chemistry is typically mediated by Cys residues. This review will therefore focus primarily on the Cys-rich γ-crystallins of the human lens, taking care to extend these findings to the β- and α-crystallins where pertinent.
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4.
Role of Glutathionylation in Infection and Inflammation.
Checconi, P, Limongi, D, Baldelli, S, Ciriolo, MR, Nencioni, L, Palamara, AT
Nutrients. 2019;(8)
Abstract
Glutathionylation, that is, the formation of mixed disulfides between protein cysteines and glutathione (GSH) cysteines, is a reversible post-translational modification catalyzed by different cellular oxidoreductases, by which the redox state of the cell modulates protein function. So far, most studies on the identification of glutathionylated proteins have focused on cellular proteins, including proteins involved in host response to infection, but there is a growing number of reports showing that microbial proteins also undergo glutathionylation, with modification of their characteristics and functions. In the present review, we highlight the signaling role of GSH through glutathionylation, particularly focusing on microbial (viral and bacterial) glutathionylated proteins (GSSPs) and host GSSPs involved in the immune/inflammatory response to infection; moreover, we discuss the biological role of the process in microbial infections and related host responses.
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5.
Effects of the Usage of l-Cysteine (l-Cys) on Human Health.
Clemente Plaza, N, Reig García-Galbis, M, Martínez-Espinosa, RM
Molecules (Basel, Switzerland). 2018;(3)
Abstract
This review summarizes recent knowledge about the use of the amino acid l-Cysteine (l-Cys) through diet, nutritional supplements or drugs with the aim to improve human health or treat certain diseases. Three databases (PubMed, Scopus, and Web of Science) and different keywords have been used to create a database of documents published between 1950 and 2017 in scientific journals in English or Spanish. A total of 60,885 primary publications were ultimately selected to compile accurate information about the use of l-Cys in medicine and nutritional therapies and to identify the reported benefits of l-Cys on human health. The number of publications about the use of l-Cys for these purposes has increased significantly during the last two decades. This increase seems to be closely related to the rise of nutraceutical industries and personalized medicine. The main evidence reporting benefits of l-Cys usage is summarized. However, the lack of accurate information and studies based on clinical trials hampers consensus among authors. Thus, the debate about the role and effectiveness of supplements/drugs containing l-Cys is still open.
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6.
Peptide Lipidation - A Synthetic Strategy to Afford Peptide Based Therapeutics.
Kowalczyk, R, Harris, PWR, Williams, GM, Yang, SH, Brimble, MA
Advances in experimental medicine and biology. 2017;:185-227
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Abstract
Peptide and protein aberrant lipidation patterns are often involved in many diseases including cancer and neurological disorders. Peptide lipidation is also a promising strategy to improve pharmacokinetic and pharmacodynamic profiles of peptide-based drugs. Self-adjuvanting peptide-based vaccines commonly utilise the powerful TLR2 agonist PamnCys lipid to stimulate adjuvant activity. The chemical synthesis of lipidated peptides can be challenging hence efficient, flexible and straightforward synthetic routes to access homogeneous lipid-tagged peptides are in high demand. A new technique coined Cysteine Lipidation on a Peptide or Amino acid (CLipPA) uses a 'thiol-ene' reaction between a cysteine and a vinyl ester and offers great promise due to its simplicity, functional group compatibility and selectivity. Herein a brief review of various synthetic strategies to access lipidated peptides, focusing on synthetic methods to incorporate a PamnCys motif into peptides, is provided.
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7.
Protein oxidation: an overview of metabolism of sulphur containing amino acid, cysteine.
Ahmad, S, Khan, H, Shahab, U, Rehman, S, Rafi, Z, Khan, MY, Ansari, A, Siddiqui, Z, Ashraf, JM, Abdullah, SM, et al
Frontiers in bioscience (Scholar edition). 2017;(1):71-87
Abstract
The available data suggest that among cellular constituents, proteins are the major target for oxidation primarily because of their quantity and high rate of interactions with ROS. Proteins are susceptible to ROS modifications of amino acid side chains which alter protein structure. Among the amino acids, Cysteine (Cys) is more prone to oxidation by ROS because of its high nucleophilic property. The reactivity of Cys with ROS is due to the presence of thiol group. In the oxidised form, Cys forms disulfide bond, which are primary covalent cross-link found in proteins, and which stabilize the native conformation of a protein. Indirect evidence suggests that thiol modifications by ROS may be involved in neurodegenerative disorders, but the significance and precise extent of the contributions are poorly understood. Here, we review the role of oxidized Cys in different pathological consequences and its biochemistry may increase the research in the discovery of new therapies. The purpose of this review is to re-examine the role and biochemistry of oxidised Cys residues.
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To eat, or NOt to eat: S-nitrosylation signaling in autophagy.
Montagna, C, Rizza, S, Maiani, E, Piredda, L, Filomeni, G, Cecconi, F
The FEBS journal. 2016;(21):3857-3869
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Abstract
Autophagy is the main catabolic cellular process through which cells adapt their needs (e.g., growth and proliferation) to environmental availability of nutrients (e.g., amino acid and glucose) and growth factors. The rapid activation of the autophagy response essentially depends on protein post-translational modifications (PTMs), which act as molecular switches triggering signaling cascades. Deregulation of autophagy contributes to pathological conditions, such as cancer and neurodegeneration. Therefore, understanding how PTMs affect the occurrence of autophagy is of the highest importance for clinical applications. Besides phosphorylation and ubiquitylation, which represent the best known examples of PTMs, redox-based modifications are also emerging as contributing to the regulation of intracellular signaling. Of note, S-nitrosylation of cysteine residues is a redox PTM and is the principal mechanism of nitric oxide-based signaling. Results emerging in recent years suggest that NO has a role in modulating autophagy. However, the function of S-nitrosylation in autophagy regulation remains still unveiled. By this review, we describe the upstream events regulating autophagy activation focusing on recently published evidence implying a S-nitrosylation-dependent regulation.
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Terminal bacteroid differentiation in the legume-rhizobium symbiosis: nodule-specific cysteine-rich peptides and beyond.
Alunni, B, Gourion, B
The New phytologist. 2016;(2):411-7
Abstract
Contents 411 I. 411 II. 412 III. 412 IV. 413 V. 414 VI. 414 VII. 415 VIII. 415 416 References 416 SUMMARY Terminal bacteroid differentiation (TBD) is a remarkable case of bacterial cell differentiation that occurs after rhizobia are released intracellularly within plant cells of symbiotic legume organs called nodules. The hallmarks of TBD are cell enlargement, genome amplification and membrane permeabilization. This plant-driven process is governed by a large family of bacteroid-targeted nodule-specific cysteine-rich (NCR) peptides that were until recently thought to be restricted to a specific lineage of the legume family, including the model plant Medicago truncatula. Recently, new plant and bacterial factors involved in TBD have been identified, challenging our view of this phenomenon at mechanistic and evolutionary levels. Here, we review the recent literature and discuss emerging questions about the mechanisms and the role(s) of TBD.
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10.
Signaling in the plant cytosol: cysteine or sulfide?
Gotor, C, Laureano-Marín, AM, Moreno, I, Aroca, Á, García, I, Romero, LC
Amino acids. 2015;(10):2155-64
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Abstract
Cysteine (Cys) is the first organic compound containing reduced sulfur that is synthesized in the last stage of plant photosynthetic assimilation of sulfate. It is a very important metabolite not only because it is crucial for the structure, function and regulation of proteins but also because it is the precursor molecule of an enormous number of sulfur-containing metabolites essential for plant health and development. The biosynthesis of Cys is accomplished by the sequential reaction of serine acetyltransferase (SAT) and O-acetylserine(thiol)synthase (OASTL). In Arabidopsis thaliana, the analysis of specific mutants of members of the SAT and OASTL families has demonstrated that the cytosol is the compartment where the bulk of Cys synthesis takes place and that the cytosolic OASTL enzyme OAS-A1 is the responsible enzyme. Another member of the OASTL family is DES1, a novel L-cysteine desulfhydrase that catalyzes the desulfuration of Cys to produce sulfide, thus acting in a manner opposite to that of OAS-A1. Detailed studies of the oas-a1 and des1 null mutants have revealed the involvement of the DES1 and OAS-A1 proteins in coordinate regulation of Cys homeostasis and the generation of sulfide in the cytosol for signaling purposes. Thus, the levels of Cys in the cytosol strongly affect plant responses to both abiotic and biotic stress conditions, while sulfide specifically generated from the degradation of Cys negatively regulates autophagy induced in different situations. In conclusion, modulation of the levels of Cys and sulfide is likely critical for plant performance.