Cysteine reactivity across the subcellular universe

Abstract

Cysteine residues are concentrated at key functional sites within proteins, performing diverse roles in metal binding, catalysis, and redox chemistry. Chemoproteomic platforms to interrogate the reactive cysteinome have developed significantly over the past 10 years, resulting in a greater understanding of cysteine functionality, modification, and druggability. Recently, chemoproteomic methods to examine reactive cysteine residues from specific subcellular organelles have provided significantly improved proteome coverage and highlights the unique functionalities of cysteine residues mediated by cellular localization. Here, the diverse physicochemical properties of the mammalian subcellular organelles are explored in the context of their effects on cysteine reactivity. The unique functions of cysteine residues found in the mitochondria and endoplasmic reticulum are highlighted, together with an overview into chemoproteomic platforms employed to investigate cysteine reactivity in subcellular organelles.

Cysteine and homocysteine as biomarker of various diseases

“…It catalyses many important metabolic reactions (Sameem et al., 2019). It takes part in lipid biosynthesis (Sameem et al., 2019), iron–sulfur biosynthesis (Bak, Bechtel, Falco, & Weerapana, 2019), which is an important constituent of skeletal muscles (Papet et al., 2019), keratin (Wang, Yang, McKittrick, & Meyers, 2016), and is also a source of taurine, glutathione, and coenzyme A (Bin et al., 2017; Papet et al., 2019).…”

“…Cysteine residues are important for many mitochondria‐associated unique functions like iron–sulfur biosynthesis and help in the electron transport chain by providing redox cofactors. Cysteine residues support many processes in ER; especially synthesis, trafficking and folding of proteins, and also lipid biosynthesis, detoxification, and steroid metabolism carried out in ER (Bak et al., 2019).…”

The crosstalk of NAD, ROS and autophagy in cellular health and ageing

“…Cys is one of the least represented, and yet often highly conserved amino acids that participates in protein structural integrity by formation of covalent disulphide-bridges between two cysteine residues, or protein enzymatic activity, i.e. by thioester bond formation or co-factor stabilisation (Bak et al 2019;Marino and Gladyshev 2010).…”

Tumor Microenvironment: A Metabolic Player that Shapes the Immune Response

“…Cysteine amino acid is widely used throughout the cell for diverse roles including catalysis, protein folding, trafficking, and mediating the major antioxidant defense [99,100]. Although protein synthesis accounts for the majority of cellular cysteine usage, another essential use of cysteine is the production of the tripeptide glutathione (GSH) for antioxidant defense and maintenance of thiol status [99,101].…”

“…Cysteine amino acid is widely used throughout the cell for diverse roles including catalysis, protein folding, trafficking, and mediating the major antioxidant defense [99,100]. Although protein synthesis accounts for the majority of cellular cysteine usage, another essential use of cysteine is the production of the tripeptide glutathione (GSH) for antioxidant defense and maintenance of thiol status [99,101]. Cysteine can be easily oxidized to form a dimer containing disulfide bridge between two cysteines called cystine, and both are transported over the plasma membrane by ASCT1, ASCT2 (although controversial), and by xCT (which together with CD98/Slc3a2 form system x c − cystine/glutamate antiporter), respectively [102,103].…”