PREP

PREP Full Name

prolyl endopeptidase

PREP Introduction

Introduction
The PREP (prolyl endopeptidase) gene, also widely known as prolyl oligopeptidase (POP), encodes a unique serine protease that specifically cleaves peptide bonds on the carboxyl side of proline residues within short peptides. As a member of the S9 family of serine proteases, PREP stands apart from typical proteases due to its inability to degrade large proteins, instead targeting peptides up to approximately 30 amino acids in length. This enzyme is broadly distributed throughout the human body with particularly high expression in the brain, testis, and liver, reflecting its diverse physiological roles. Beyond its classical enzymatic function, PREP has emerged as a multifaceted protein involved in protein-protein interactions, transcriptional regulation, and the pathogenesis of neurodegenerative diseases, cancer, and fibrotic disorders, positioning it as an attractive therapeutic target.

Figure 1. Strcuture of prolyl endopeptidase.

Catalytic Mechanism and Enzymatic Activity
PREP functions as a serine endopeptidase that specifically hydrolyzes peptide bonds following proline residues. The catalytic mechanism follows the classical serine protease pathway: the nucleophilic Ser554 attacks the carbonyl carbon of the scissile bond, forming a tetrahedral intermediate stabilized by the oxyanion hole. This intermediate then collapses to release the amine product and form an acyl-enzyme intermediate, which is subsequently hydrolyzed by water to release the carboxyl product and regenerate the free enzyme.The enzyme exhibits strict substrate size selectivity, efficiently cleaving peptides ranging from 3 to 30 amino acids while showing no activity against larger proteins. This selectivity arises from the physical constraints imposed by the β-propeller domain, which physically excludes folded protein substrates from accessing the buried active site. PREP cleaves a variety of bioactive peptides including neurotensin, substance P, bradykinin, thyrotropin-releasing hormone (TRH), and arginine-vasopressin, implicating the enzyme in neuropeptide metabolism and hormonal regulation.

Traditional Functions in Peptide Metabolism
Classically, PREP has been recognized as a key enzyme in the maturation and degradation of peptide hormones and neuropeptides. By cleaving after proline residues, PREP regulates the bioavailability and activity of numerous signaling peptides involved in neuroendocrine function, cognition, and behavior. The enzyme degrades thyrotropin-releasing hormone (TRH), influencing thyroid hormone regulation, and metabolizes substance P and neurotensin, peptides involved in pain transmission and neuroinflammation. In the gastrointestinal system, PREP selectively degrades gluten peptides in vitro, offering a potential therapeutic strategy for celiac disease. Proline-rich gluten peptides resist complete digestion by gastric proteases, and PREP-mediated cleavage can reduce their immunogenicity. In metabolic dysfunction-associated fatty liver disease (MAFLD), PREP works synergistically with matrix metalloproteinases (MMP8/9) to hydrolyze collagen degradation products, generating prolyl-glycyl-proline (PGP)—a potent neutrophil chemoattractant that promotes inflammatory disease progression.

Alternate Names for PREP

PREP; prolyl endopeptidase; prolyl oligopeptidase; post-proline cleaving enzyme; dJ355L5.1 (prolyl endopeptidase); PE; PEP; MGC16060;