Human and mammalian enzymes containing reactive cysteine residues

Human and mammalian enzymes containing reactive cysteine residues represent a broad and diverse class of proteins where a specific cysteine thiol acts as a nucleophile, either as part of a catalytic triad/dyad or as a regulatory site. This group includes cysteine proteases (e.g., cathepsins and caspases), deubiquitinating enzymes (DUBs), and various kinases that possess a non-catalytic but accessible cysteine in their ATP-binding pocket. These enzymes are prominent therapeutic targets because their reactive thiols can be selectively modified by covalent inhibitors, such as those containing acrylamide or vinyl sulfone 'warheads.' Such drugs, including ibrutinib and osimertinib, offer high potency and a prolonged duration of action by forming a stable bond with the target. However, the widespread presence of reactive cysteines across the human proteome (the 'cysteineome') presents significant challenges for selectivity, potentially leading to off-target toxicity or immunogenic responses. Consequently, drug development in this space requires precise mapping of cysteine reactivity and accessibility to ensure therapeutic safety and efficacy.

Other names

Cysteine-dependent enzymesCysteineomeThiol-reactive enzymesCovalent drug targetsReactive cysteine proteome

Covalent inhibition via nucleophilic attack by a cysteine thiolate on an electrophilic moiety (warhead) of the drug, resulting in an irreversible or slowly reversible bond.