X-prolyl aminopeptidase 3 (XPNPEP3)

X-prolyl aminopeptidase 3 (XPNPEP3) is a mitochondrial and cytosolic enzyme that removes the N-terminal amino acid from peptides where a proline resides in the penultimate position, and is critical for mitochondrial protein processing and stability. It functions as a metallopeptidase (M24B family), utilizing a metal cofactor for activity, and is essential for mitochondrial proteostasis. XPNPEP3 is also involved in ciliary function, and mutations in this gene cause nephronophthisis-like ciliopathy (a cystic kidney disease). Beyond its enzymatic role, one isoform (localized to mitochondria) acts as an adaptor in TNF-TNFR2 signaling, modulating cell death pathways independently of its enzymatic activity. Structural studies reveal distinct substrate specificity and a unique pocket accommodating proline in the P1’ position[1][2][3][4][5].

Other names

Xaa-Pro aminopeptidase 3X-Pro aminopeptidase 3APP3NPHPL1ICP55Aminopeptidase P3Intermediate Cleaving Peptidase 55

Inhibitors may act by binding to the active site and blocking catalytic removal of the N-terminal residue (as shown with apstatin in crystal structure analyses)[1].