Biochemistry, physiology and implications in human diseases of mammalian aminopeptidase N: A review

Aminopeptidases are proteases that selectively hydrolyze an amino acid residue from the amino terminus of proteins and peptides, leading to their activation or inactivation. These enzymes are predominantly metallopeptidases. One of them, membrane alanyl aminopeptidase, also known as aminopeptidase N (APN, EC 3.4.11.2), a M1 family metallo-aminopeptidase, plays essential roles in mammals. APN regulates pain sensitivity, central nervous system control of blood pressure, the final steps of protein degradation, cell motility and adhesion, and coronavirus entry. Furthermore, upregulated expression of APN has been implicated in the pathogenesis of various human disorders, including cancers, inflammation, and pressure dysregulation. APN is a multifunctional protein, and its ligation or inhibition of enzymatic activity may have therapeutic applications. Here, we focus on human and porcine enzymes as models to review the most important structural and functional features of mammalian APN, its roles in mammalian physiology, and the pathophysiological aspects in humans, with particular emphasis on cancer. We illustrate how APN is a tool for diagnosing and monitoring cancer and other pathologies, and discuss the obstacles to the therapeutic use of its inhibitors.