Big endothelin‐1 structure important for specific processing by endothelin‐converting enzyme of bovine endothelial cells

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Abstract
Phosphoramidon‐sensitive endothelin‐converting enzyme of bovine endothelial cells showed substrate selectivity for big endothelin‐1 (ET‐1) when compared to big ET‐1(1–38), big ET‐2(1–37), big ET‐2(1–38) and big ET‐3(1–41). To investigate the big ET‐1 structure important for specific conversion by the endothelin‐converting enzyme, we synthesized a series of truncated analogues of big ET‐1, measured the hydrolysis of their Trp21–Val22 bonds, and found that a 16‐residue peptide, big ET‐1(19–34), is the minimal peptide sequence. This suggests that an unusually long carboxy‐terminal sequence is required for big ET‐1 conversion. Alanine substitution for individual amino acids in the carboxy‐terminal region of big ET‐1(19–34) demonstrated that His27, Val29, Pro30, Tyr31, Gly32, Leu33 and Gly34 are more important than Asn23, Thr24, Pro25, Glu26 and Val28 for eliciting efficient hydrolysis of the Trp21–Val22 bond, even though the former residues are located at more distant positions from the cleavage sites than are the latter. These results, together with the fact that big ET‐2 and big ET‐3 show heterogeneity in the big ET‐1 residues His27, Val28, Val29 and Gly34, suggest that the His27‐Val‐Val‐Pro‐Tyr‐Gly‐Leu‐Gly34 sequence in the carboxy‐terminal region of big ET‐1 plays the most important role in selective conversion by endothelin converting enzyme.

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