Microbial enzymes containing reactive cysteine residues

Microbial enzymes containing reactive cysteine residues represent a diverse group of proteins essential for the survival, replication, and virulence of various pathogens, including bacteria, viruses, and parasites (Sali et al., 1993). These enzymes utilize the high nucleophilicity of the cysteine thiol group to perform critical catalytic functions, such as peptide bond hydrolysis, redox reactions, and post-translational modifications. In many pathogens, these enzymes are responsible for critical processes such as the processing of viral polyproteins, as seen with the SARS-CoV-2 main protease, or the assembly of bacterial cell walls via enzymes like Sortase A (Jin et al., 2020). Because the reactive cysteine is often indispensable for enzymatic activity, it serves as an attractive site for covalent drug design. Many antimicrobial and antiviral agents, such as Nirmatrelvir, function by forming a stable bond with this residue, thereby inactivating the enzyme (Owen et al., 2021). However, a significant challenge in targeting these enzymes is achieving selectivity to avoid cross-reactivity with human cysteine-containing proteins like cathepsins or caspases. Such off-target interactions could lead to adverse side effects or systemic toxicity (McKerrow et al., 2009). Despite these challenges, this class of enzymes remains a cornerstone of drug discovery efforts for treating infectious diseases.

Other names

Cysteine-dependent microbial enzymesThiol-based microbial enzymesMicrobial cysteine proteasesCysteine-centered catalytic proteins

Covalent inhibition of the active-site cysteine thiol group, leading to irreversible or reversible inactivation of the enzyme.