Regulation of Peptidase Activity beyond the Active Site in Human Health and Disease

Abstract

This comprehensive review addresses the intricate and multifaceted regulation of peptidase activity in human health and disease, providing a comprehensive investigation that extends well beyond the boundaries of the active site. Our review focuses on multiple mechanisms and highlights the important role of exosites, allosteric sites, and processes involved in zymogen activation. These mechanisms play a central role in shaping the complex world of peptidase function and are promising potential targets for the development of innovative drugs and therapeutic interventions. The review also briefly discusses the influence of glycosaminoglycans and non-inhibitory binding proteins on enzyme activities. Understanding their role may be a crucial factor in the development of therapeutic strategies. By elucidating the intricate web of regulatory mechanisms that control peptidase activity, this review deepens our understanding in this field and provides a roadmap for various strategies to influence and modulate peptidase activity.

Transcriptome Analysis of Juvenile Black Rockfish Sebastes schlegelii under Air Exposure Stress

“…This immediate stress triggers a rapid response from the body to meet the energy demands for survival. Peptidases, as enzymes that break down peptides into amino acids, play a critical role in this process by accelerating protein catabolism to quickly release energy [30,31]. As previously reported, dipeptidyl peptidase 3 (DPP3), a zinc-dependent aminopeptidase, moonlights as a regulator of the cellular oxidative stress response pathway, e.g., the Keap1-Nrf2 mediated antioxidative response [32].…”

Bait and Cleave: Exosite-Binding Peptides on Quantum Dots Selectively Accelerate Protease Activity for Sensing with Enhanced Sensitivity

“…Perhaps more interesting is the possibility of in vitro selection of an exosite binder for any particular protease of interest via peptide libraries (e.g., combinatorial, phage display) and nucleic acid aptamers, where a mix of negative and positive selection may enable a high level of specificity for a given protease and not require knowledge of a naturally occurring binding motif. Small-molecule binders of protease exosites, appended to suitable linkers or ligands on the QD, may also be useful for exploring targeted acceleration of protease activity with the potential to draw from known exosite-binding drugs. , There is also the question of whether active site-targeting drugs might be useful as bait on a QD, and if an acceleratory effect from protease localization to the QD would exceed an inhibitory effect from competition with substrate for the active site.…”

“…Small-molecule binders of protease exosites, appended to suitable linkers or ligands on the QD, may also be useful for exploring targeted acceleration of protease activity with the potential to draw from known exosite-binding drugs. 81,82 There is also the question of whether active site-targeting drugs might be useful as bait on a QD, and if an acceleratory effect from protease localization to the QD would exceed an inhibitory effect from competition with substrate for the active site. Expansion to nonprotease classes of enzymes with known exosite-binding motifs (e.g., kinases, 83,84 nucleases, 85 and others 86−88 ) is also something to explore in the future.…”