Abstract
Endothelin-converting enzyme-1 (ECE-1) is one of the most important enzymes to convert big endothelin-1 (big ET-1) to ET-1. To identify the inhibitors of ECE-1, we examined the effects of variously substituted analogues of big ET-1 on ECE-1 activity using solubilized membranes prepared from human ECE-1-expressed CHO-K1 cells. Among the big ET-1 analogues tested, [Phe 21]big ET-1(18–34) and [Ala 31]big ET-1(18–34) exhibited a significant inhibition of ECE-1. A kinetic analysis revealed [Phe 21]big ET-1(18–34) to be a competitive inhibitor ( K i=20.6 μM) and [Ala 31]big ET-1(18–34) to be a non-competitive inhibitor ( K i=35.6 μM). These results not only support the concept that ECE-1 recognizes big ET-1 both at the P1 position and at the C-terminal region but also revealed that these two regions are recognized by this enzyme in a different manner.
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