Quantum Mechanics/Molecular Mechanics Simulations Distinguish Insulin-Regulated Aminopeptidase Substrate (Oxytocin) and Inhibitor (Angiotensin IV) and Reveal Determinants of Activity and Inhibition.

ABSTRACT: Insulin-regulated aminopeptidase (IRAP) is a zinc-dependent metalloenzyme identified as a novel target for combating diabetes-induced diseases due to its crucial role in glucose metabolism and insulin sensitivity regulation. IRAP's catalytic domain catalyzes the N-terminal peptide bond hydrolysis of natural substrate oxytocin, a neuroactive peptide linked to improved cognition and other elemental brain functions. Angiotensin IV and similar peptides are recognized as cognitive enhancers due to their ability to competitively inhibit IRAP's proteolytic activity, thereby mitigating natural neuropeptide degradation. Despite a very similar binding complex between the substrate and the inhibitor with IRAP, particularly around the scissile bond, it is unclear why the enzyme metabolizes oxytocin bu

SUBMITTER: Hanzevacki M 

PROVIDER: S-EPMC12199304 | biostudies-literature | 2025 Jun

REPOSITORIES: biostudies-literature