TY - JOUR
T1 - Endothelins are more sensitive than sarafotoxins to neutral endopeptidase
T2 - Possible physiological significance
AU - Sokolovsky, M.
AU - Galron, R.
AU - Kloog, Y.
AU - Bdolah, A.
AU - Indig, F. E.
AU - Blumberg, S.
AU - Fleminger, G.
PY - 1990
Y1 - 1990
N2 - Incubation of endothelins (ETs) with bovine kidney neutral endopeptidase (NEP) resulted in a selective two-step degradation with loss of biochemical activity. The K(m) of the enzyme indicated high-affinity binding, and hydrolysis was completely inhibited by phosphoramidon. The first step was nicking of the Ser5-Leu6 bond, followed by cleavage at the amino side of Ile19. The nicked peptide exhibited biochemical activities comparable to those of the intact peptide - i.e., binding to the ET receptor, induction of inositol phospholipid hydrolysis, and toxicity. The twice-cleaved product was inactive. The sarafotoxins (SRTXs) were more resistant than the ETs to NEP: for example, the half-time for ET-1 was ~ 1 hr, while it was ~ 4 hr for SRTX-b and even higher for SRTX-c. These in vitro findings may indicate a regulatory role of NEP (or similar enzymes) in the physiological inactivation of ETs. They might also help to explain why under certain physiological conditions ETs may be less toxic than SRTXs.
AB - Incubation of endothelins (ETs) with bovine kidney neutral endopeptidase (NEP) resulted in a selective two-step degradation with loss of biochemical activity. The K(m) of the enzyme indicated high-affinity binding, and hydrolysis was completely inhibited by phosphoramidon. The first step was nicking of the Ser5-Leu6 bond, followed by cleavage at the amino side of Ile19. The nicked peptide exhibited biochemical activities comparable to those of the intact peptide - i.e., binding to the ET receptor, induction of inositol phospholipid hydrolysis, and toxicity. The twice-cleaved product was inactive. The sarafotoxins (SRTXs) were more resistant than the ETs to NEP: for example, the half-time for ET-1 was ~ 1 hr, while it was ~ 4 hr for SRTX-b and even higher for SRTX-c. These in vitro findings may indicate a regulatory role of NEP (or similar enzymes) in the physiological inactivation of ETs. They might also help to explain why under certain physiological conditions ETs may be less toxic than SRTXs.
KW - inositol phospholipid turnover
KW - neutral endopeptidase
KW - proteolysis
KW - receptor binding sites
KW - structure activity relationship
UR - http://www.scopus.com/inward/record.url?scp=0025321142&partnerID=8YFLogxK
U2 - 10.1073/pnas.87.12.4702
DO - 10.1073/pnas.87.12.4702
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C2 - 2191299
AN - SCOPUS:0025321142
SN - 0027-8424
VL - 87
SP - 4702
EP - 4706
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 12
ER -