Serine–lysine catalytic dyad (Ser–Lys dyad) (Ser–Lys dyad)

Serine–lysine (Ser–Lys) catalytic dyads are specialized active-site configurations found in a distinct group of enzymes, including bacterial Type I signal peptidases (SPase I), Lon proteases, and certain beta-lactamases (Paetzel, M., et al., 2002, Chemical Reviews). Unlike the classical Ser–His–Asp catalytic triad, these enzymes utilize a lysine residue as a general base to activate the nucleophilic serine for peptide bond hydrolysis or acyl-enzyme formation (Botos, I., et al., 2004, Nature). In bacteria, SPase I is essential for removing signal peptides from secreted proteins, making the Ser–Lys dyad a critical target for novel antibiotics such as arylomycins, which bypass traditional resistance mechanisms (Smith, P. A., et al., 2018, Nature). In eukaryotes, the Lon protease employs this dyad within the mitochondria to degrade misfolded proteins and regulate metabolic enzymes, and its overexpression is often linked to cancer cell survival and stress resistance (Cheng, C., et al., 2019, Cell Reports). Other enzymes utilizing this mechanism include the LexA repressor and penicillin-binding proteins (PBPs), where the lysine facilitates the nucleophilic attack on the peptide bond or beta-lactam ring (Slilaty, S. N., & Little, J. W., 1987, PNAS). The unique nature of the Ser–Lys mechanism compared to human cytosolic proteases provides a window for therapeutic selectivity, although potential cross-reactivity with mitochondrial enzymes remains a safety consideration.

Other names

Ser–Lys dyadSerine–lysine protease motifLysine-dependent serine proteaseType I signal peptidase active siteLon protease active site

Drugs targeting Ser–Lys catalytic dyads typically function as covalent inhibitors that react with the nucleophilic serine residue. For example, arylomycins bind to the SPase I active site and mimic the signal peptide, effectively blocking the dyad's ability to process essential secreted proteins (Smith, P. A., et al., 2018, Nature). In the case of penicillin-binding proteins (PBPs) and beta-lactamases, beta-lactam antibiotics act as suicide substrates that form a stable acyl-enzyme intermediate with the serine, assisted by the lysine general base, thereby inhibiting cell wall synthesis or antibiotic degradation (Drawz, S. M., & Bonomo, R. A., 2010, Clinical Microbiology Reviews).