Prolyl endopeptidase

Prolyl endopeptidase (PEP), also known as prolyl oligopeptidase or post-proline cleaving enzyme, is an enzyme that in humans is encoded by the PREP gene. PEP is a serine protease that is involved in the maturation and degradation of peptide hormones and neuropeptides. It plays a crucial role in various physiological processes, including memory and learning, by cleaving peptide bonds at the carboxyl side of proline residues within peptides shorter than 30-mer. Due to its unique substrate specificity and widespread presence in the central nervous system, prolyl endopeptidase has been implicated in several neurological disorders, making it a target of interest for therapeutic intervention.

Structure

Prolyl endopeptidase is a cytosolic enzyme that is approximately 710 amino acids in length, depending on the species. It has a distinctive structure consisting of a catalytic domain and a β-propeller domain. The catalytic domain contains the serine protease triad (Ser, His, Asp), which is essential for its enzymatic activity. The β-propeller domain is believed to play a role in substrate recognition and binding, although the exact mechanism remains under investigation.

Function

The primary function of prolyl endopeptidase is to cleave peptide bonds at the carboxyl side of proline residues. This specificity is unique among proteases and allows PEP to process a variety of substrates, including peptide hormones, neuropeptides, and growth factors. By modulating the activity of these peptides, PEP influences several physiological processes such as memory formation, learning, and behavior. Additionally, PEP has been shown to degrade amyloid beta peptides in vitro, suggesting a potential role in the pathogenesis of Alzheimer's disease.

Clinical Significance

Alterations in prolyl endopeptidase activity have been associated with several neurological and psychiatric disorders, including schizophrenia, bipolar disorder, and Alzheimer's disease. Reduced PEP activity has been observed in the brains of patients with these conditions, leading to speculation that enhancing PEP activity could have therapeutic benefits. Consequently, PEP inhibitors and activators are being explored as potential drugs for treating cognitive disorders and neurodegenerative diseases.

Research

Research on prolyl endopeptidase has focused on understanding its structure-function relationship, substrate specificity, and physiological roles. Additionally, there is significant interest in developing PEP inhibitors as therapeutic agents. These inhibitors could potentially treat a range of disorders by modulating the activity of peptide hormones and neuropeptides affected by PEP. However, the development of specific, potent, and safe PEP inhibitors remains a challenge in the field.

See Also

• Serine protease
• Peptide hormone
• Neuropeptide
• Alzheimer's disease
• Schizophrenia