Marine organisms : a source of biomedically relevant metallo M1, M2 and M17 exopeptidase inhibitors
Isel Pascual AlonsoLaura Rivera MéndezFabiola Almeida GarcíaMario E. Valdés‐TresancoYarini Arrebola SánchezAida Hernández-ZanuyLuis Álvarez-LajonchèreDagmara DíazBelinda Sánchez PérezIsabelle FlorentMarjorie SchmittMiguel CisnerosJean Louis Charli
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Proteolytic enzymes, known as peptidases or proteases, are critical in all living organisms. They can act as exo- and/or endo-peptidases. Peptidases are segregated in classes that strongly depend on the chemical nature of the groups involved in catalysis. Peptidases control the activation, synthesis, and turnover of proteins and regulate most biochemical and physiological processes. They are consequently major regulators of homeostasis, ageing, diseases, and death. Proteases are also essential for propagation of infectious agents, being major contributors of pathogenesis in several infectious diseases, including the current coronavirus emergent pandemic COVID-19. Exopeptidases catalyze the cleavage of the N-terminal or C-terminal amino acids of proteins or peptide substrates. They are distributed in many phylla and play critical roles in physiology and pathophysiology. Most of them are metallo peptidases belonging to the M1, M2, and M17 families, among others. Some, such as M1 aminopeptidases N, A and thyrotropin-releasing hormone degrading ectoenzyme, M2 angiotensin converting enzyme and M17 leucyl aminopeptidase are targets for the development of therapeutic agents for human diseases including cancer, hypertension, central nervous system disorders, inflammation, immune system disorders, skin pathologies and infectious diseases, like malaria and coronavirus-induced syndromes. The relevance of exopeptidases has driven the search and identification of potent and selective inhibitors, as major tools to control proteolysis with impact in biochemistry, biotechnology, and biomedicine. The present contribution focuses on marine biodiversity as an important and promising source of inhibitors of metallo exopeptidases from different families, with biomedical applications in human diseases.Keywords:
Exopeptidase
Proteolysis
Deubiquitinating enzyme
Proteolytic enzymes (or proteases, peptidases, or proteinases) hydrolyze the peptide bond in proteins and peptides. The nomenclature is imprecise, but there is a broad acceptance that endopeptidases break bonds that are "internal" in the primary sequences, whereas exopeptidases trim one, two, or perhaps three amino acids from the amino or carboxy terminus of the substrate. Every cell and subcellular compartment has its own complement of proteolytic enzymes, and in normal circumstances, the activities of the proteolytic enzymes are well regulated. When a tissue is disrupted, however, this control is lost, and the proteinases may then attack proteins at a rate that leads to a loss of those proteins within the time scale of the study. Adventitious proteolysis is a technical problem that may require modification to methodology to minimize the assault on the protein of interest (1–4).
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In mammals the M1 aminopeptidase family consists of nine different proteins, five of which are integral membrane proteins. The aminopeptidases are defined by two motifs in the catalytic domain; a zinc binding motif HEXXH-(X18)-E and an exopeptidase motif GXMEN. Aminopeptidases of this family are able to cleave a broad range of peptides down to only to a single peptide. This ability to either generate or degrade active peptide hormones is the focus of this review. In addition to their capacity to degrade a range of peptides a number of these aminopeptidases have novel functions that impact on cell signalling and will be discussed. Keywords: aminopeptidase, apa, apn, trh-de, eraap, angiotensin iv, irap
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A protease can be defined as an enzyme that hydrolyses peptide bonds. Proteases can be divided into endopeptidases, which cleave internal peptide bonds in substrates, and exopeptidases, which cleave the terminal peptide bonds. Exopeptidases can be further subdivided into aminopeptidases and carboxypeptidases. The Schechter and Berger nomenclature provides a model for describing the interactions between the peptide substrate and the active site of a protease. Proteases can also be classified as aspartic proteases, cysteine proteases, metalloproteases, serine proteases and threonine proteases, depending on the nature of the active site. Different inhibitors can be used experimentally to distinguish between these classes of protease. The MEROPs database groups proteases into families on the basis of similarities in sequence and structure. Protease activity can be regulated in vivo by endogenous inhibitors, by the activation of zymogens and by altering the rate of their synthesis and degradation.
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Proteolytic enzymes (or proteases, peptidases, or proteinases) hydrolyze the peptide bond in proteins and peptides. The nomenclature is imprecise, but there is a broad acceptance that endopeptidases break bonds that are "internal" in the primary sequences, whereas exopeptidases trim one, two, or perhaps three amino acids from the amino or carboxy terminus of the substrate. Every cell and subcellular compartment has its own complement of proteolytic enzymes, and in normal circumstances, the activities of the proteolytic enzymes are well regulated. When a tissue is disrupted, however, this control is lost, and the proteinases may then attack proteins at a rate that leads to a loss of those proteins within the time scale of the study (). Adventitious proteolysis is a technical problem that may require modification to methodology to minimize the assault on the protein of interest (, , , ).
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Exopeptidase
Proteolytic enzymes
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Leucyl aminopeptidase
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