Protein Cysteine Modifications: (1) Medicinal Chemistry for Proteomics

Abstract

Protein cysteines (cysteinyl residues) play critical roles in biological processes. In the course of protein evolution under oxidizing atmosphere of the Earth, organisms have utilized highly reactive cysteines in many proteins essential for maintenance of life, i.e. enzymes, transcriptional factors, cytoskeletons, and receptors. In some enzymes, sophistical cysteine modification characterizes each catalytic mechanism. In vivo modification of protein cysteines with natural chemical compounds modulates protein functions as a molecular switch. Oxidation/reduction, thiol-disulfide exchange, nitrosylation, sulfuration, thiolation, acylation and prenylation are involved. Some protein cysteines coordinate metals or metal cofactors such as a heme or an iron sulfur cluster to form metalloproteins, serving as sensor proteins, metalloenzymes or transcriptional factors. Information on the in vitro chemical modifications and their reaction specificities of protein cysteines are essential for the investigation of the mechanisms and functions of in vivo protein cysteine modifications. In this review, we also mention historically important knowledge other than recent results on protein cysteine modification and modulation of protein function to fertilize medical proteomics.

The antibacterial properties of isothiocyanates

“…The pK a value, itself affected by electrostatic interactions with nearby residues, directs the protonation state of cysteine and thus its reactivity toward ITCs. The hydrophobicity of the environment and steric hindrance can also modulate the reactivity of nucleophile residues (Nagahara et al, 2009). Since thiol and amino groups react in their dissociated form, higher pH values favour the interactions with ITC (Drobnica & Sturdík, 1979).…”

Protein Quality Control under Oxidative Stress Conditions

“…diabetes) (12), ROS begin to accumulate in the cell, causing cells to experience a stress condition commonly known as oxidative stress. Oxidative stress can be caused by a variety of different mechanisms, including defects in specific antioxidant or redox-maintaining systems, ROS production during host defense, UV-light, gamma and X-rays, pollutants and smoke, or due to metal-catalyzed Fenton reactions (13). All of these processes produce free radicals, capable of oxidizing cellular structures (14–16).…”

Protein cysteine phosphorylation of SarA/MgrA family transcriptional regulators mediates bacterial virulence and antibiotic resistance

“…The thiol group in cysteine plays a variety of roles in cellular processes such as enzymatic catalysis, metal binding, signal [reactive oxgen/nitrogen species (ROS/RNS)] sensing, and protein folding (disulfide formation). Thanks to its intrinsic reactivity, the Cys residue can be subject to a great number of PTMs that include alkylation (S-prenylation, S-methylation) (14,15), acylation (S-palmitoylation), and oxidation (sulfenation, sulfination, S-nitrosylation, disulphide formation, and so forth) (14,16,17). The latter case enables Cys to serve as a regulatory switch on proteins that respond to redox change in their cellular environment (18)(19)(20)(21).…”