Thimet Oligopeptidase—A Classical Enzyme with New Function and New Form

Yu Liu,Lisa Bruce,Jeffrey Sigman,Adele Wolfson

doi:10.3390/immuno1040022

Abstract

Peptidases generate bioactive peptides that can regulate cell signaling and mediate intercellular communication. While the processing of peptide precursors is initiated intracellularly, some modifications by peptidases may be conducted extracellularly. Thimet oligopeptidase (TOP) is a peptidase that processes neuroendocrine peptides with roles in mood, metabolism, and immune responses, among other functions. TOP also hydrolyzes angiotensin I to angiotensin 1–7, which may be involved in the pathophysiology of COVID-19 infection. Although TOP is primarily cytosolic, it can also be associated with the cell plasma membrane or secreted to the extracellular space. Recent work indicates that membrane-associated TOP can be released with extracellular vesicles (EVs) to the extracellular space. Here we briefly summarize the enzyme’s classical function in extracellular processing of neuroendocrine peptides, as well as its more recently understood role in intracellular processing of various peptides that impact human diseases. Finally, we discuss new findings of EV-associated TOP in the extracellular space.

Highlights

Thimet Oligopeptidase—Classical Function, Regulation, and StructureThimet oligopeptidase (TOP), called endopeptidase 24.15 (E.C. 3.4.24.15), is a zinc metalloendopeptidase of molecular weight 77 kD [1,2]
Given the enzyme activity of TOP and its ability to degrade several bioactive peptides, Orlowski et al proposed a potential function of the metalloendopeptidase in neuropeptide metabolism [6]
TOP is expressed in a wide range of mammalian tissues and cell types, with the highest levels of TOP found in the brain, pituitary gland and testis, in keeping with its neuroendocrine function, while lower levels of TOP can be detected in liver, kidney, lung and spleen [2,4,41,42,43,44,45,46,47,48]

Summary

Introduction

Thimet oligopeptidase (TOP), called endopeptidase 24.15 (E.C. 3.4.24.15), is a zinc metalloendopeptidase of molecular weight 77 kD [1,2]. Site-directed mutagenesis esis of rat theenzyme rat enzyme established that His473, Glu474, and His477 the HEXXH of the established that His473, Glu474, and His477 make make up theup motif, motif, with Glu502 as the third zinc[25] Based on this active site architecwith Glu502 servingserving as the third zinc ligand. While TOP has yet to be crystallized in a closed conformation, several lines of evidence, including those from our laboratory, point to the role of an induced fit as a means for substrate selectivity controlled by repositioning of conserved, catalytic Tyr residues: Tyr residues 605 and 612 in domain II and opposite the enzyme active site have been shown to be critical for efficient catalysis [32,38]. The largest structural change occurring in the loop 600–612 contained conserved Tyr residues

TOP Plays Dual Roles as an Intracellular and Extracellular Peptidase

TOP-positive

Conclusions

Findings

Summary