Thiol- and metal-dependent enzymes

Thiol- and metal-dependent enzymes are a broad class of proteins that utilize specific chemical groups or inorganic ions to catalyze biochemical reactions (Source: Andreini et al., 2008, Journal of Proteome Research). Thiol-dependent enzymes typically feature a reactive cysteine residue in their active site, which acts as a nucleophile or a redox sensor (Source: Reddie & Carroll, 2008, Current Opinion in Chemical Biology). Metal-dependent enzymes, or metalloenzymes, incorporate metal ions like zinc, iron, or magnesium to stabilize substrates or facilitate electron transfer (Source: Holm et al., 1996, Chemical Reviews). These enzymes play fundamental roles in physiological processes such as extracellular matrix remodeling, signal transduction, and metabolic regulation (Source: Rawlings et al., 2018, Nucleic Acids Research). Dysregulation of these enzymes is linked to numerous pathologies, including cancer metastasis, chronic inflammation, and viral infections (Source: Bond & Butler, 1987, Annual Review of Biochemistry). Therapeutic strategies often involve small-molecule inhibitors that either covalently bind to the active-site thiol or coordinate with the essential metal ion (Source: Copeland, 2005, Evaluation of Enzyme Inhibitors in Drug Discovery). While highly effective, targeting these enzymes is challenging due to the high conservation of active-site architectures, which can lead to poor selectivity and adverse side effects (Source: Farina et al., 1999, Expert Opinion on Therapeutic Patents). Notable examples of drugs targeting this class include ACE inhibitors for hypertension and various protease inhibitors for infectious diseases (Source: PubChem; StatPearls).

Other names

Thiol enzymesMetalloenzymesSulfhydryl-dependent enzymesMetal-activated enzymesCysteine-dependent enzymes

Drugs targeting these enzymes typically function by either forming a covalent bond with a catalytic cysteine thiol (thiol-dependent) or by providing a ligand (such as a hydroxamate or carboxylate group) that coordinates to the active-site metal ion, thereby blocking substrate access and catalytic turnover (Source: Copeland, 2005; Gupta et al., 2020).