Zinc-dependent aminopeptidases: new perspectives on structure, function, and biomedical applications

Zinc-dependent aminopeptidases are a subclass of exopeptidases implicated in the hydrolysis of N-terminal residues from peptides through a Zn(II) co-factor dependent hydrolytic mechanism. In humans, the prominent members of this class of enzymes (ERAP1/2, IRAP, APN/CD13, APA) catalyse peptide trimming in antigen presentation, peptide hormone regulation, and peptide homeostasis. Since the catalytic activity of these enzymes relies on a tightly coordinated Zn(II) ion in their conserved H-E-X-X-H…E motif, they constitute attractive yet challenging therapeutic targets. In this review, I provide an updated survey of their structural and mechanistic principles, evaluate their physiological and pathological roles, and outline emerging strategies for selective modulation and biotechnological usage. I also discuss current obstacles and future directions in deploying zinc-targeted aminopeptidase chemistry in translational settings.