Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The angiotensin I-converting enzyme (kininase II, ECA) is a membrane bound enzyme anchored to the cell membrane through a single transmembrane domain located near its carboxyterminal extremity. Secretion of ACE by the cell occurs most likely as a result of a posttranslational cleavage of the membrane anchor and intracellular region. The ACE molecule is organized into two large highly homologous domains, each bearing consensus sequences for zinc binding in metallopeptidases. Site directed mutagenesis allowed to establish that both domains bear in fact a functional active site, able to convert angiotensin I into angiotensin II and to hydrolyze bradykinin or substance P. The two active sites of ACE, however, do not display the same sensitivity to anion activation (the C terminal active site being more chloride activatable) and also differs in kinetic parameters for peptide hydrolysis. The C terminal active site can hydrolyze faster angiotensin I and substance P and the N terminal active site is able to perform a peculiar endoproteolytic cleavage of an in vitro substrate of ACE, the luteinizing hormone releasing hormone. Both active sites bind with a high affinity, competitive inhibitors but the Kd of the reaction can vary up to 10 between the two active sites. All together, these observations suggest that ACE contains two active sites, whose structure is not exactly identical. They may have a different substrate specificity, however this remains speculative at the present time. Concerning the regulation of ACE gene expression in man, population studies indicated that the large interindividual variability in plasma ACE levels is genetically determined. An insertion/deletion polymorphism located in an intron of ACE gene is associated with differences in the level of ACE in plasma and cells. The physiological and clinical implications of these observations is discussed.
 ...
PMID:[Angiotensin converting enzyme (kininase II). Molecular and physiological aspects]. 133 89

The antihypertensive effect of inhibitors of the angiotensin I-converting enzyme (ACE = kininase II) results from their vasodilatory and natriuretic effects as well as their effect on baroreceptor function. In addition to the inhibition of systemic and local angiotensin II formation, other local hormonal systems may also be involved in this effect at multiple target sites. Thus, potentiation of the vasodilator and natriuretic kinin system following inhibition of kininase II is thought to contribute to the persistent hypotensive effect of ACE inhibitors despite normalization of circulating ACE activity. Although increased plasma bradykinin levels cannot be detected, we found that the enhanced kinin-dependent local vascular prostacyclin production can be blunted in vitro by aprotinin, a kallikrein inhibitor. ACE inhibition may affect the atrial natriuretic peptide (ANP) system as the renin-angiotensin system and ANP appear to play antagonistic roles at the peripheral and central nervous system levels. Inhibition of kallikrein or of kininase II were both shown to modulate the natriuretic and vasorelaxant effects of ANP. In hypertensive subjects, we found that ACE inhibition with blood pressure normalization reduces basal and stimulated plasma ANP and blunts the renal sodium excretion in response to saline loading. In contrast, we did not observe effects of acute ACE inhibition in healthy sodium-depleted volunteers on plasma vasopressin under basal conditions or in response to passive tilt. Finally, we investigated the interaction of ACE inhibition with substance P, a powerful endogenous diuretic and natriuretic peptide that may have a transmitter function in the baroreceptor reflex arch.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Kinin- and non-kinin-mediated interactions of converting enzyme inhibitors with vasoactive hormones. 169 69

Since both aminopeptidases and angiotensin I-converting enzyme are reported to degrade circulating enkephalins, we have examined the degradation of low-molecular-weight opioid peptides by a vascular plasma membrane-enriched fraction previously shown to contain both angiotensin I-converting enzyme (EC 3.4.15.1) and aminopeptidase M (EC 3.4.11.2). Except for an enkephalin analog resistant to amino-terminal hydrolysis, [D-Ala2]enkephalin, the purified vascular plasma membrane preferentially degraded low-molecular-weight opioids by hydrolysis of the N-terminal Tyr-1--Gly-2 bond. Enkephalin degradation was optimal at pH 7.0 and was inhibited by the aminopeptidase inhibitors amastatin (I50 = 0.08 microM), bestatin (9.0 microM) and puromycin (80 microM). Maximal rates of hydrolysis, calculated per mg plasma membrane protein, were highest for the shorter peptides (18.3, 15.6 and 16.6 nmol/min per mg for Met5-enkephalin, Leu5-enkephalin and Leu5-enkephalin-Arg6, respectively) and decreased with increasing peptide length (0.7 nmol/min per mg for dynorphin (1-13)). No significant hydrolysis of beta- and gamma-endorphin was detected. Km values decreased significantly with increasing peptide length (Km = 72.9 +/- 2.7, 43.6 +/- 4.7 and 21.4 +/- 0.9 microM for Met5-enkephalin, Leu5-enkephalin-Arg6 and Met5-enkephalin-Arg6-Phe7, respectively). However, no further decreases were seen with even larger sequences, i.e., dynorphin(1-13). Other peptides hydrolyzed by the plasma membrane aminopeptidase (angiotensin III, kallidin and hepta(5-11)-substance P) inhibited enkephalin degradation in a competitive manner. Thus, localization, specificity and kinetic data are consistent with identification of aminopeptidase M as a vascular enzyme with the capacity to differentially metabolize low-molecular-weight opioid peptides within the microenvironment of vascular cell surface receptors. Such differential metabolism may play a role in modulating the vascular effects of peripheral opioids.
 ...
PMID:Degradation of low-molecular-weight opioid peptides by vascular plasma membrane aminopeptidase M. 287 42

The purpose of this study was to determine the effects of bradykinin (BK), substance P (SP) and histamine on plasma exudation in the skin of conscious dogs with and without pacing-induced heart failure. We also determined the role tissue angiotensin I-converting enzyme (ACE) and neutral endopeptidase (NEP) play in modulating these responses. We found that intradermal injection of BK, SP and histamine induced a significant, concentration-dependent Evans blue exudation in normal dogs (p < 0.05). Bradykinin-induced responses were significantly potentiated by captopril (p < 0.05). In contrast, phosphoramidon potentiated BK-induced responses only at low concentrations of BK. Both captopril and phosphoramidon had no significant effects on SP- and histamine-induced Evans blue exudation. BK- and SP-induced responses were significantly attenuated, whereas histamine-induced Evans blue exudation was significantly potentiated in dogs with heart failure. We conclude that heart failure is associated with attenuation of BK- and SP-, but not histamine-induced plasma exudation in the peripheral microcirculation and that these responses are not modulated by tissue ACE and NEP.
 ...
PMID:Plasma exudation in conscious dogs with experimental heart failure. 753 20

Persistent dry cough is an occasional but clinically important adverse reaction to angiotensin I-converting enzyme (ACE) inhibitors (ACEI). Its reported incidence is variable, and why cough occurs in only certain individuals has been unclear. An insertion/deletion (I/D) polymorphism of the ACE gene is associated with serum ACE activity. We have previously shown that susceptibility to cough induced by ACEI is associated with this polymorphism such that patients with genotype II are more susceptible to cough than patients with other genotypes. In order to confirm and extend our previous observation, we conducted a randomized, placebo-controlled, double-blind, cross-over study in 10 healthy volunteers with genotype II and 10 with genotype DD. The cough threshold was determined by the concentration of inhaled capsaicin causing two or more coughs. After the usage of an ACEI, cilazapril, for 4 weeks, changes in the cough threshold in subjects with genotype II [before: 6.6+/-3.7 nM (mean+/-SD); after: 5.0+/-4.6 nM] significantly differed from those in subjects with genotype DD (before: 9.0+/-9.4 nM; after: 9.3+/-9.1 nM). Skin responses to intradermal bradykinin, which is a substrate of ACE and tussigenic, were significantly increased in subjects with genotype II (before: 1.6+/-0.6 vs. after: 2.6+/-0.5 cm2, P<0.05) but not in subjects with genotype DD (before: 1.4+/-0.5 vs. after: 1.6+/-0.6 cm2, n.s.) after usage of cilazapril. By contrast, skin responses to intradermal substance P did not change in subjects with either genotype. These findings provide further evidence of a link between ACEI-induced cough and I/D polymorphism of the ACE gene and suggest that ACEIs induce cough by modulating the tissue level of bradykinin.
 ...
PMID:The ACE gene polymorphism and cough threshold for capsaicin after cilazapril usage. 1121 9

The imaginal discs of Drosophila melanogaster give rise to the adult epidermis during metamorphosis. During this developmental period several peptidase genes are expressed in disc cells, but there is a paucity of biochemical information regarding substrate specificity. We have used peptides and peptidyl 7-amino-4-methylcoumarin (AMC) substrates to detect several peptidases either positioned on the surface of wing discs or secreted by the imaginal cells. Using [Leu(5)]enkephalin as a substrate, a captopril sensitive dipeptidyl carboxypeptidase (angiotensin I-converting enzyme) and an amastatin-sensitive aminopeptidase were detected as prominent activities associated with intact discs. The formation of [Leu(5)]enkephalin-derived Phe was attributed to the concerted action of the D. melanogaster angiotensin I-converting enzyme (Ance) and a dipeptidase. The disc Ance also showed endopeptidic activity towards locust tachykinin-1 (LomTK-I) by cleaving the Gly-Val peptide bond, but this enzyme was not the sole endopeptidase activity associated with discs. Complete inhibition of the endopeptidic hydrolysis of the LomTK-1 by a disc homogenate required a combination of captopril and the neprilysin inhibitor, phosphoramidon, providing biochemical evidence for a neprilysin-like peptidase, in addition to Ance, in imaginal discs of D. melanogaster. Peptidyl AMC substrates for furin, prohormone convertase and tryptase provided evidence for trypsin-like serine endopeptidases in addition to the metalloendopeptidases. We conclude that imaginal discs are endowed with a variety of peptidases from different families that together are capable of hydrolyzing a broad range of peptides and proteins. Some of these peptidases might be responsible for the metabolic activation/inactivation of signaling peptides, as well as being involved in the production of dipeptides and free amino acids required for protein synthesis and osmotic balance during adult morphogenesis.
 ...
PMID:Extracellular peptidases of imaginal discs of Drosophila melanogaster. 1243 39

Drosophila melanogaster angiotensin converting enzyme (Ance) and angiotensin converting enzyme related (Acer) are single domain homologs of mammalian peptidyl dipeptidase A (angiotensin I-converting enzyme) whose physiological substrates have not as yet been identified. We have investigated the in vitro substrate specificities of the two peptidases towards a variety of insect and mammalian peptides. Ance was generally much better than Acer at hydrolyzing peptides of 5-13 amino acids in length. Only two of the peptides, [Leu(5)]enkephalinamide and leucokinin-I were cleaved faster by Acer. Increasing NaCl concentration had opposite affects on the cleavage of [Leu(5)]enkephalin and [Leu(5)]enkephalinamide by Acer, decreasing the activity towards [Leu(5)]enkephalin but increasing the activity towards [Leu(5)]enkephalinamide. Of the insect peptides tested, the tachykinin-related peptide, Lom TK-1, proved to be the best substrate for Ance with a k(cat)/K(m) ratio of 0.122s(-1) microM(-1). However, in comparison, the D. melanogaster tachykinins, DTK-1, DTK-2, DTK-3 and DTK-4 were poor Ance substrates. DTK-5 was the best substrate of this family, but the apparent high K(m) for hydrolysis by Ance suggested that this peptide would not be a natural Ance substrate. This low affinity for DTK-5 is the likely reason why the peptide was not rapidly degraded in D. melanogaster hemolymph, where Ance was shown to be a major peptide-degrading activity.
 ...
PMID:Peptidyl dipeptidases (Ance and Acer) of Drosophila melanogaster: major differences in the substrate specificity of two homologs of human angiotensin I-converting enzyme. 1243 41