Characterization of the metabolism of substance P and neurotensin by human angiotensin I converting enzyme and "enkephalinase".
Angiotensin I converting enzyme (ACE) and neutral endopeptidase ("enkephalinase"; NEP), were purified to homogeneity from human renal membranes. NEP hydrolyzed substance P (SP) at Gln6-Phe7, Phe7-Phe8, and Gly9-Leu10 and neurotensin (NT) at Pro10-Tyr11 and Tyr11-Ile12. ACE cleaved SP at Phe8-Gly9 and Gly9-Leu10 to release C-terminal tri- and dipeptide (ratio = 4:1). The hydrolysis was dependent on chloride ion and inhibited by captopril. Modification of arginine residues in ACE with cylcohexanedione or butanedione inhibited hydrolysis of SP, bradykinin and Bz-Gly-Phe-Arg (80-93%) indicating an active site arginine is required for hydrolysis of SP. ACE cleaved NT at Tyr11-Ile12 to release Ile12-Leu13. These studies indicate that ACE and NEP, two enzymes which are widely distributed in the body, may be involved in the metabolism of SP and NT.
Skidgel
R A
RA
D002462:Cell Membrane / Q000378:metabolism; D010450:Endopeptidases / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis; D007668:Kidney / Q000201:enzymology; D007700:Kinetics; D015260:Neprilysin; D009496:Neurotensin / Q000378:metabolism*; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D013373:Substance P / Q000378:metabolism*; D013379:Substrate Specificity
D013373:Substance P; D009496:Neurotensin; D010450:Endopeptidases; D007703:Peptidyl-Dipeptidase A; D015260:Neprilysin