Actin and other accessible protein thiols

Actin and other accessible protein thiols represent a heterogeneous group of molecular targets defined by the presence of reactive cysteine sulfhydryl (-SH) groups. Actin is a primary component of this group because its Cys374 residue is highly nucleophilic and solvent-accessible, making it a frequent site for covalent modification by electrophilic compounds (Biochemistry, 1990). These thiol groups are essential for maintaining protein structure, regulating enzymatic activity, and facilitating redox-sensitive signaling pathways (Nature Reviews Molecular Cell Biology). Drugs such as the loop diuretic ethacrynic acid interact with these targets by acting as electrophilic Michael acceptors, forming stable covalent adducts with the sulfhydryl groups (DrugBank). This interaction leads to the disruption of the actin cytoskeleton and the inhibition of various thiol-dependent enzymes, such as glutathione S-transferase, which can result in cellular morphological changes like blebbing (Journal of Pharmacology and Experimental Therapeutics). While this mechanism is utilized for therapeutic effects in managing edema and exploring cancer sensitization, the inherent lack of specificity for a single protein poses significant safety concerns, including ototoxicity and systemic oxidative stress (StatPearls).

Other names

Protein sulfhydrylsReactive protein thiolsCysteine sulfhydryl groupsProtein-bound thiolsReactive cysteine residues

Covalent modification of sulfhydryl (-SH) groups on cysteine residues via Michael addition or oxidation, leading to protein dysfunction, enzymatic inhibition, and cytoskeletal disruption.