Angiotensin I-converting enzyme inhibitor peptides derived from the endostatin-containing NC1 fragment of human collagen XVIII.
Extracellular matrix and soluble plasma proteins generate peptides that regulate biological activities such as cell growth, differentiation and migration. Bradykinin, a peptide released from kininogen by kallikreins, stimulates vasodilatation and endothelial cell proliferation. Various classes of substances can potentiate these biological actions of bradykinin. Among them, the best studied are bradykinin potentiating peptides (BPPs) derived from snake venom, which can also strongly inhibit angiotensin I-converting enzyme (ACE) activity. We identified and synthesized sequences resembling BPPs in the vicinity of potential proteolytic cleavage sites in the collagen XVIII molecule, close to endostatin. These peptides were screened as inhibitors of human recombinant wild-type ACE containing two intact functional domains; two full-length ACE mutants containing only a functional C- or N-domain catalytic site; and human testicular ACE, a natural form of the enzyme that only contains the C-domain. The BPP-like peptides inhibited ACE in the micromolar range and interacted preferentially with the C-domain. The proteolytic activity involved in the release of BPP-like peptides was studied in human serum and human umbilical-vein endothelial cells. The presence of enzymes able to release these peptides in blood led us to speculate on a physiological mechanism for the control of ACE activities.
Farias
Shirley L
SL
Departamento de Biofísica, Escola Paulista de Medicina, Universidade Federal de São Paulo, 04044-020 São Paulo SP, Brazil.
Sabatini
Regiane A
RA
Sampaio
Tatiana C
TC
Hirata
Izaura Y
IY
Cezari
Maria Helena S
MH
Juliano
Maria A
MA
Sturrock
Edward D
ED
Carmona
Adriana K
AK
Juliano
Luiz
L
D000595:Amino Acid Sequence; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D001920:Bradykinin / Q000378:metabolism; D002403:Cathepsins / Q000037:antagonists & inhibitors / Q000378:metabolism; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D043170:Collagen Type XVIII / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D043169:Endostatins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D010447:Peptide Hydrolases / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D013379:Substrate Specificity
D000806:Angiotensin-Converting Enzyme Inhibitors; D043170:Collagen Type XVIII; D043169:Endostatins; D010446:Peptide Fragments; D002403:Cathepsins; D010447:Peptide Hydrolases; D007703:Peptidyl-Dipeptidase A; D001920:Bradykinin