Bacterial proteins with reactive cysteine residues

Bacterial proteins with reactive cysteine residues represent a diverse functional group of proteins that utilize the nucleophilic properties of the cysteine thiol group for catalysis, regulation, and structural integrity. These proteins are critical for bacterial survival and pathogenesis, participating in essential processes such as peptidoglycan cell wall synthesis (e.g., MurA), protein folding and disulfide bond formation (e.g., DsbA), and the maintenance of redox homeostasis (e.g., Thioredoxin and OxyR) [Backus et al., 2016, Nature Chemical Biology]. The high nucleophilicity of specific "hotspot" cysteines makes these proteins susceptible to covalent modification by electrophilic small molecules, which can irreversibly inhibit their function [Kwon et al., 2020, JAC]. A prominent clinical example is the antibiotic fosfomycin, which targets the reactive Cys115 of MurA to block the first step of peptidoglycan biosynthesis [Skarzynski et al., 1996, Structure]. Beyond MurA, other targets include cysteine proteases like sortases in Gram-positive bacteria and various virulence factors [Mazmanian et al., 1999, Science]. However, the therapeutic challenge lies in achieving high selectivity for bacterial cysteines over the vast human "cysteineome" to minimize off-target toxicity and adverse effects [Vinogradova et al., 2020, Cell].

Other names

Bacterial cysteine-dependent enzymesBacterial thiol-proteomeCysteine-reactive bacterial targetsBacterial thiol-based redox proteins

Covalent inhibition of essential bacterial enzymes through the alkylation or modification of reactive cysteine thiol groups, leading to irreversible loss of protein function [Skarzynski et al., 1996; Backus et al., 2016].