Abstract
Endothelin-1 (ET-1), a 21-residue vasoactive peptide, is produced in vascular endothelial cells from the 38-residue inactive intermediate big endothelin-1 via a specific cleavage at Trp-21-Val-22. The protease that catalyzes the conversion, endothelin-converting enzyme (ECE), constitutes a potential regulatory site for the production of the active peptide. We report the identification of ECE-1, a novel membrane-bound neutral metalloprotease that is expressed abundantly in endothelial cells in vivo and is structurally related to neutral endopeptidase 24.11 and Kell blood group protein. When transfected into cultured cells that normally secrete only big ET-1, the ECE-1 cDNA conferred the ability to secrete mature ET-1. In transfected cells, ECE-1 processes endogenously synthesized big ET-1 as well as exogenously supplied big ET-1, which interacts with ECE-1 on the cell surface. ECE-1 may provide a target for pharmacological intervention to alter ET-1 production.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Animals
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Aspartic Acid Endopeptidases / antagonists & inhibitors
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Aspartic Acid Endopeptidases / genetics
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Aspartic Acid Endopeptidases / isolation & purification
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Aspartic Acid Endopeptidases / metabolism*
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Base Sequence
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Biological Assay
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Cattle
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Cloning, Molecular
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Coronary Vessels / enzymology
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Endothelin-1
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Endothelin-Converting Enzymes
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Endothelins / biosynthesis
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Endothelins / metabolism*
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Membrane Proteins / genetics
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Membrane Proteins / isolation & purification
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Membrane Proteins / metabolism*
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Metalloendopeptidases / antagonists & inhibitors
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Metalloendopeptidases / genetics
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Metalloendopeptidases / isolation & purification
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Metalloendopeptidases / metabolism*
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Molecular Sequence Data
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Protein Precursors / metabolism*
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RNA, Messenger / analysis
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Recombinant Proteins / metabolism
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Sequence Analysis
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Tissue Distribution
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Transfection
Substances
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Endothelin-1
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Endothelins
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Membrane Proteins
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Protein Precursors
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RNA, Messenger
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Recombinant Proteins
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Aspartic Acid Endopeptidases
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Metalloendopeptidases
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Endothelin-Converting Enzymes