SIRT5 Deacylation Specificity: From Structural Insights and Pathophysiological Functions to Modulator Development

Abstract

SIRT5 is a key deacylase that specifically catalyzes desuccinylation, demalonylation, and deglutarylation, participating in glycolysis, mitochondrial energy metabolism, and oxidative stress, and represents a promising target for disease intervention.The “acidic acyl-binding groove (AABG)” formed by Tyr102 and Arg105 in the catalytic pocket of SIRT5 acts as the core structure for specific recognition of acidically acylated substrates. Modulators binding to this groove through hydrogen bonds and/or electrostatic interactions and a salt bridge generally exhibit superior activity and selectivity. Focusing on the AABG, this paper systematically reviews the latest advances in SIRT5 concerning its protein structure, specific deacidicacylation mechanism, pathophysiological functions and modulator development. It mainly illustrates the strategies and binding modes of modulators designed based on the anchoring effect of the groove, aiming to provide comprehensive theoretical references for exploring the molecular functions of SIRT5 and advancing the research of targeted therapeutic drugs. This perspective systematically elaborates SIRT5’s unique acidic acyl-binding pocket mechanism, sorts modulators by Tyr102/Arg105 anchoring mode, clarifies its bidirectional disease roles, and proposes novel selective modulator design strategies to advance SIRT5-targeted precision drug development.