Serine hydrolase (SH) (SH)

Serine hydrolases represent one of the largest and most diverse enzyme superfamilies in the human proteome, comprising approximately 1% of all predicted genes (Bachovchin & Cravatt, 2012). These enzymes are characterized by a conserved catalytic mechanism involving a nucleophilic serine residue, often part of a Ser-His-Asp catalytic triad, which facilitates the hydrolysis of ester, amide, and thioester bonds (Long & Cravatt, 2011). They play critical roles in a wide array of physiological processes, including digestion, blood coagulation, immune response, and neurotransmission (Simon & Cravatt, 2010). Dysregulation of serine hydrolase activity is linked to numerous pathologies, including cancer, diabetes, and neurodegenerative disorders (Bachovchin & Cravatt, 2012). Consequently, they are major targets for drug development, with many clinically approved drugs acting as inhibitors of specific family members like dipeptidyl peptidase 4 (DPP4) or acetylcholinesterase (AChE) (Long & Cravatt, 2011). Therapeutic strategies often involve the design of small molecules that mimic the enzyme's natural substrate to achieve high affinity and selectivity (Bachovchin & Cravatt, 2012). Advances in activity-based protein profiling (ABPP) have significantly enhanced the ability to characterize these enzymes in complex biological systems and identify selective inhibitors (Simon & Cravatt, 2010).

Other names

Serine-dependent hydrolaseSerine proteaseSerine esteraseSerine lipaseSerine thioesterase

Drugs targeting serine hydrolases primarily function as competitive or covalent inhibitors. Covalent inhibitors often utilize a reactive functional group (e.g., carbamate, phosphate, or fluorophosphonate) to form a stable bond with the nucleophilic active-site serine, thereby irreversibly or semi-irreversibly blocking enzymatic activity (Bachovchin & Cravatt, 2012). Competitive inhibitors bind non-covalently to the active site, preventing substrate access and effectively lowering the rate of reaction (Long & Cravatt, 2011).