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

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.

Noninvasive nasopharyngeal proteomics of COVID-19 patient identify abnormalities related to complement and coagulation cascade and mucosal immune system

“…A literature search of the relationship between these identified proteins and SARS-CoV-2 was conducted. Among the proteins, thimet oligopeptidase, an oligopeptidase that can convert angiotensin I into angiotensin 1-7, was only identified in SARS-CoV-2 positive samples, which is in consistent with the evidence that COVID patients have significantly increased circulating levels of angiotensin 1-7 and decreased angiotensin II [26]. Furthermore, inhibitors of Calpain-13, a calcium-activated neutral proteinase, and Kallikrein-14, a serine-type endopeptidase with a dual trypsin-like and chymotrypsin-like substrate specificity, have been investigated as a treatment for COVID-19 disease [27,28].…”

Proteomic analysis of pulmonary arteries and lung tissues from dogs affected with pulmonary hypertension secondary to degenerative mitral valve disease

“…LB1 is a nuclear component involved in regulating of nuclear functions and cell proliferation [46]. TOP1 is a metalloendopeptidase, it hydrolyzes neuroendocrine and cardiovascular peptides [47], and may affect angiotensin converting enzyme II (ACEII) expression in alveolar epithelial cells and vascular endothelial cells that is associated with alveolar fluid clearance [47]. ESRP2 is an RNA binding proteins that controls splicing events during epithelial-mesenchymal transition [48] and is required for maintenance of epithelial cell barriers [49] and lung cell homeostasis [50].…”

Extracellular vesicles and angiotensin-converting enzyme 2 in COVID-19 disease

“…Exosomes are formed by the exocytosis of endosomal multivesicular bodies into the extracellular milieu [1,2]. MVs are membrane vesicles derived from the cell plasma membrane surface [1,2,5]. Apoptotic bodies are large membrane vesicles released in the late stages of apoptosis and can carry nuclear fragments and mitochondria [1,2].…”

“…EVs are heterogeneous in size and composition [1,[4][5][6][7][8]. Like their parental cells of origin, EVs have double-layer lipid membranes and may contain cellular components from the nucleus, cytoplasm, or cell membrane [1,[4][5][6][7][8].…”

“…EVs are heterogeneous in size and composition [1,[4][5][6][7][8]. Like their parental cells of origin, EVs have double-layer lipid membranes and may contain cellular components from the nucleus, cytoplasm, or cell membrane [1,[4][5][6][7][8]. When EVs bud off of their parental cells, they harbor a vast array of bioactive molecules, including lipids, proteins, and nucleic acids (DNA, RNA, siRNA, microRNA, and lncRNA) [1,[4][5][6][7][8].…”