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Proteomics has matured into a discipline capable of quantifying nearly every protein encoded by the genome, yet it remains largely blind to the true operational units of physiology: proteoforms. Each proteoform—defined by a specific sequence and post-translationally modified state—represents a unique molecular identity with distinct chemical, functional, and structural properties. This review proposes the proteoform functor: a mathematical map between the abstract proteoform state space and the realised physiological space of biological function—and ultimately complex phenotypes. Show less

Hydrogen sulfide (H2S) played a pivotal role in the early evolution of life on Earth before the predominance of atmospheric oxygen. The legacy of a persistent role for H2S in life's processes recently emerged through its discovery in modern biochemistry as an endogenous cellular signalling modulator involved in numerous biological processes. One major mechanism through which H2S signals is protein cysteine persulfidation, an oxidative post-translational modification. In recent years, chemoproteomic technologies have been developed to allow the global scanning of protein persulfidation targets in mammalian cells and tissues, providing a powerful tool to elucidate the broader impact of altered H2S in organismal physiological health and human disease states. While hundreds of proteins were confirmed to be persulfidated by global persulfidome methodologies, the targeting of specific proteins of interest and the investigation of further mechanistic studies are still underdeveloped due to a lack of stringent specificity of the methods and the inherent instability of persulfides. This review provides an overview of the processes of endogenous H2S production, oxidation, and signalling and highlights the application and limitations of current persulfidation labelling approaches for investigation of this important evolutionarily conserved biological switch for protein function. Show less

SLC7A11/xCT is an antiporter that mediates the uptake of extracellular cystine in exchange for glutamate. Cystine is reduced to cysteine, which is a rate-limiting precursor in glutathione synthesis; a process that protects cells from oxidative stress and is, therefore, critical to cell growth, proliferation, and metabolism. SLC7A11 is expressed in different tissues and plays diverse functional roles in the pathophysiology of various diseases, including cancer, by regulating the processes of redox homeostasis, metabolic flexibility/nutrient dependency, immune system function, and ferroptosis. SLC7A11 expression is associated with poor prognosis and drug resistance in cancer and, therefore, represents an important therapeutic target. In this review, we discuss the molecular functions of SLC7A11 in normal versus diseased tissues, with a special focus on how it regulates gastrointestinal cancers. Further, we summarize current therapeutic strategies targeting SLC7A11 as well as novel avenues for treatment. Show less

Iron-sulfur (FeS) proteins are ancient and fundamental to life, being involved in electron transfer and CO₂ fixation. FeS clusters have structures similar to the unit-cell of FeS minerals such as greigite, found in hydrothermal systems linked with the origin of life. However, the prebiotic pathway from mineral surfaces to biological clusters is unknown. Here we show that FeS clusters form spontaneously through interactions of inorganic Fe²⁺/Fe³⁺ and S^2- with micromolar concentrations of the amino acid cysteine in water at alkaline pH. Bicarbonate ions stabilize the clusters and even promote cluster formation alone at concentrations >10 mM, probably through salting-out effects. We demonstrate robust, concentration-dependent formation of [4Fe4S], [2Fe2S] and mononuclear iron clusters using UV-Vis spectroscopy, ⁵⁷Fe-Mössbauer spectroscopy and ¹H-NMR. Cyclic voltammetry shows that the clusters are redox-active. Our findings reveal that the structures responsible for biological electron transfer and CO₂ reduction could have formed spontaneously from monomers at the origin of life. Show less

Significance: Oxidative stress is thought to account for aberrant redox homeostasis and contribute to aging and disease. However, more often than not, administration of antioxidants is ineffective, suggesting that our current understanding of the underlying regulatory processes is incomplete. Recent Advances: Similar to reactive oxygen species and reactive nitrogen species, reactive sulfur species are now emerging as important signaling molecules, targeting regulatory cysteine redox switches in proteins, affecting gene regulation, ion transport, intermediary metabolism, and mitochondrial function. To rationalize the Show less

Oxaliplatin undergoes extensive non-enzymatic chemical transformation in the body. Complexes with sulphur-containing compounds have previously been found in plasma from patients treated with oxaliplatin. We have studied the kinetics for the reactions between oxaliplatin and cysteine, methionine, and glutathione, by determination of the degradation of oxaliplatin using liquid chromatography with UV-detection. We also studied the degradation of oxaliplatin in plasma ultrafiltrate (PUF). For the degradation of oxaliplatin in the presence of glutathione, methionine, and cysteine, the second-order rate constants were 4.7M(-1)min(-1) (95% confidence interval [C.I.], 4.4-5.0M(-1)min(-1)), 5.5M(-1)min(-1) (95% C.I., 5.2-5.7M(-1)min(-1)), and 15M(-1)min(-1) (95% C.I., 14-17M(-1)min(-1)), respectively. The reaction rate was much faster than previously reported kinetics for cisplatin. The degradation rate of oxaliplatin in PUF was biphasic. The rate constant for the first phase varied from 9.5x10(-3) to 0.13min(-1) and for the second phase from (1.7 to 1.8)x10(-3)min(-1) in PUF from five healthy volunteers. The first hours of the degradation of oxaliplatin in PUF are accounted for by the degradation of oxaliplatin in a cocktail of sodium chloride and sulphur-containing compounds at physiological plasma concentrations. In conclusion, the rate of the reaction of oxaliplatin with three sulphur-containing compounds was faster for oxaliplatin than what is previously known for cisplatin. This may be important with respect to differences in the cellular effects of cisplatin and oxaliplatin treatment. Show less