UNIPROT:P50502 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Target Concepts:

Query: UNIPROT:P50502 (Hip)
7,003 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Angiotensin I converting enzyme (ACE) was purified to homogeneity from porcine kidney in order to determine whether iodobradykinins bind to the enzyme and, if so, whether pGlu-Trp-Pro-Arg-Pro-Gin-Ile-Pro-Pro, SQ20881, a competitive ACE inhibitor, changes the conformation of the enzyme in such a way that it binds kinins with an affinity and specificity expected of a bradykinin (BK) receptor, i.e. where the BK potentiating action of SQ20881 involves an increase in the number of BK receptors due to a conformational change in ACE. 125I-Labeled derivatives of [Tyr1]-kallidin and [Tyr-8]-bradykinin bound to the EDTA-inhibited enzyme, and binding was inhibited by nonradioactive BK. [125I-Tyr5]-BK was not bound by the enzyme. Specificity of [125I-Tyr5]-kallidin (T1K) binding was tested with forty-eight BK analogs, and the concentrations of analogs that inhibited 50% of T1K binding were determined. BK at 1.6 +/- 0.3 X 10(-8) M inhibited 505 of T1K binding. In addition, the concentrations of analogs that decreased by 50% the rate of [3H]-Hip-Gly-Gly ([3H]-HGG) hydrolysis by ACE were assessed. BK at 1.2 +/- 0.2 X 10(-6) M decreased the rate of [3H]-HGG hydrolysis by 50%. A comparison between these concentrations of analogs for inhibition of T1K binding and [3H]-HGG hydrolysis yielded a high correlation coefficient (r = 0.85). The specificity of ACE binding was clearly different from that expected of a BK receptor. Compounds structurally unrelated to BK, such as 5Q20881, pGlu-Lys-Trp-Ala-Pro-OH (BPP5a) and angiotensin I, inhibited T1K binding and [3H]-HGG hydrolysis by ACE.
...
PMID:Interactions of kinins with angiotensin I converting enzyme (kininase II). 614 Sep 24

Angiotensin-converting enzyme (ACE) was studied in preparations of microvessels isolated from rabbit cerebral cortex. Activity was determined by measuring the degradation of hippuryl-histidyl-leucine (Hip-His-Leu) by the intact microvessels in a physiological salt solution at pH 7.4. ACE activity was dependent on both substrate and chloride ion concentration and was inhibited by captopril in a manner similar to that observed previously with tissue homogenates. Angiotensin I was rapidly degraded by the intact microvessels, even in the presence of 10(-6)M captopril. An advantage of the methodology employed was the ability to pretreat the microvessels and then assess the effect of pretreatment by transfer to a postincubation assay system. Pretreatment with a hyperosmolar urea solution did not change ACE activity or cause release of ACE from the microvessels, although lactic dehydrogenase and lysosomal enzymes were released. Pretreatment with captopril caused a lag in the subsequent degradation of Hip-His-Leu, presumably reflecting dissociation of inhibitor from the cell-associated enzyme. ACE activity was unaffected by hypoxic or anoxic incubation conditions. The ability to measure ACE activity of the microvessels in vitro provides a unique opportunity to study the properties of the enzyme in intact cerebrovascular endothelial cells.
...
PMID:Properties of angiotensin-converting enzyme in intact cerebral microvessels. 626 Jun 46

The chemical properties of skin angiotensin-converting enzyme were characterized in mouse and human. In newborn mice, dermis contained almost all activity (1.3 mU/mg), of which 30% was in the 22,000 kappa g supernatant and 70% in the pellet which could be solubilized by Triton X-100. The activity increased sharply during the first 6 weeks after the birth. By gel filtration, the enzyme in the supernatant was Mr 330,000, but the solubilized enzyme was Mr 430,000 in the presence of Triton X-100. By electrophoresis, the 2 enzyme fractions demonstrated a charge difference. The enzymes showed the same pH optima of around 8.1 and 7.7, and Km values of 2.6 and 0.11 mm for Hip-His-Leu and angiotensin I, respectively. Sensitivity to known inhibitors and heat stability of the enzymes in 2 fractions were similar. In the human, 56% of the activity in skin homogenates (1.5 mU/mg) appeared in this supernatant and 44% in the pellet. Both soluble and solubilized preparations showed enzyme activity with 2 different molecular weights, 330,000 and 430,000. The human enzymes had chemical properties similar to the mouse enzymes, but their affinity for Hip-His-Leu and angiotensin I were 1.6 and 2 times higher than those of the mouse enzymes.
...
PMID:Partial purification and characterization of angiotensin-converting enzyme in mouse and human skin. 628 79

Angiotensin I-converting enzyme (ACE, E.C.3.4.15.1) has been recently shown to contain two very similar domains, each of which bears a functional active site hydrolyzing Hip-His-Leu or angiotensin I (AI). The substrate specificity of the two active sites of ACE was compared using wild-type recombinant ACE and mutants, where one active site is suppressed by deletion or inactivated by mutations of 2 histidines coordinating an essential zinc atom. Both active sites converted bradykinin (BK) to BK1-7 and BK1-5 with similar kinetics and with Kappm at least 30 times lower and kcat/kappm 10 times higher than for AI. The carboxyl-terminal active site, but not the amino-terminal site, was activated by chloride; however, chloride activation was minimal compared with AI. Both domains also hydrolyzed substance P and cleaved a carboxyl-terminal protected dipeptide and tripeptide. The carboxyl-terminal active site was more readily activated by chloride and hydrolyzed substance P faster. Luteinizing-hormone releasing hormone was hydrolyzed by both active sites, but hydrolysis by the amino-terminal active site was faster. It performed the endoproteolytic amino-terminal cleavage of this peptide at least 30 times faster than the carboxyl-terminal active site. Both active sites cleaved a carboxyl-terminal tripeptide from luteinizing hormone-releasing hormone. Thus, both active sites of ACE possess dipeptidyl carboxypeptidase and endopeptidase activities. However, only the carboxyl-terminal active site can undergo a chloride-induced alteration that greatly enhances the hydrolysis of AI or substance P, and the amino-terminal active site possesses an unusual amino-terminal endoproteolytic specificity for a natural peptide. This suggests physiologically important differences between the subsites of the two active centers, and different substrate specificity, despite the high degree of sequence homology.
...
PMID:Differences in the properties and enzymatic specificities of the two active sites of angiotensin I-converting enzyme (kininase II). Studies with bradykinin and other natural peptides. 768 54

The aim of the present study was to investigate whether a pathway for conversion of angiotensin I (ANG I) to angiotensin II (ANG II) other than that via angiotensin-converting enzyme (ACE) is present in the smooth muscle of the human detrusor. Isolated detrusor strips from 11 patients were contracted by ANG I (1 microM) in the absence or presence of enalaprilat (10 microM), soybean trypsin inhibitor (STI, 200 micrograms/ml), or both. The metabolic activity in detrusor membranes from four patients was studied separately using Hip-Gly-Gly or ANG I as a substrate, with or without various protease inhibitors. The contractile response to ANG I (1 microM) was depressed by enalaprilat from 66 +/- 22 (mean +/- SD) to 39 +/- 13% of the K+ (124 mM)-induced response (P < 0.01, n = 11), and the combination of enalaprilat and STI resulted in a further reduction in contractile amplitude to 25 +/- 14% (P < 0.01 vs. K+, and P < 0.05 vs. enalaprilat alone) and a significantly slower developing contraction with a time to peak of 3.7 +/- 1.7 vs. 1.1 +/- 0.3 min for ANG I alone (P < 0.01). In detrusor membranes, a low ACE activity, inhibitable by captopril, was demonstrated by the formation of hippuric acid (0.70 nmol.min-1.mg protein-1) from the synthetic ACE substrate, Hip-Gly-Gly. However, the conversion of ANG I (166 nmol.min-1.mg protein-1) to ANG II was not affected by ACE inhibition, while serine protease inhibitors, e.g., STI and chymostatin, completely prevented ANG II formation.(ABSTRACT TRUNCATED AT 250 WORDS)
...
PMID:Angiotensin I is converted to angiotensin II by a serine protease in human detrusor smooth muscle. 802 40

1. The aim of the present study was to determine the effect of nitric oxide (NO) on angiotensin-converting enzyme (ACE) activity. 2. A biochemical study was performed in order to analyse the effect of the NO-donors, SIN-1 and diethylamine/NO (DEA/NO), and of an aqueous solution of nitric oxide on the ACE activity in plasma from 3-month old male Sprague-Dawley rats and on ACE purified from rabbit lung. SIN-1 significantly inhibited the activity of both enzymes in a concentration-dependent way between 1 and 100 microM. DEA/NO inhibited the activity of purified ACE from 0.1 microM to 10 microM and plasma ACE, with a lower potency, between 1 and 100 microM. An aqueous solution of NO (100 and 150 microM) also inhibited significantly the activity of both enzymes. Lineweaver-Burk plots indicated an apparent competitive inhibition of Hip-His-Leu hydrolysis by NO-donors. 3. Modulation of ACE activity by NO was also assessed in the rat carotid artery by comparing contractions elicited by angiotensin I (AI) and AII. Concentration-response curves to both peptides were performed in arteries with endothelium in the presence of the guanylyl cyclase inhibitor, ODQ (10 microM), and the inhibitor of NO formation, L-NAME (0.1 mM). NO, which is still released from endothelium in the presence of 10 microM ODQ, elicited a significant inhibition of AI contractions at low concentrations (1 and 5 nM). In the absence of endothelium, 1 microM SIN-1 plus 10 microM ODQ, as well as 10 microM DEA/NO plus 10 microM ODQ induced a significant inhibition on AI-induced contractions at 1 and 5 nM and at 1-100 nM, respectively. 4. In conclusion, we demonstrated that (i) NO and NO-releasing compounds inhibit ACE activity in a concentration-dependent and competitive way and that (ii) NO release from endothelium physiologically reduces conversion of AI to AII.
...
PMID:Modulation of angiotensin-converting enzyme by nitric oxide. 964 45

Angiotensin I-converting enzyme (ACE) is a zinc metallopeptidase that plays a major role in blood pressure regulation. The demonstration that the hemoregulatory peptide acetyl-Ser-Asp-Lys-Pro (AcSDKP) is a natural and specific substrate of the N-active site of ACE suggests that this enzyme may have a new physiological role such as the modulation of hematopoietic stem cells. In vitro studies have shown that ACE inhibitors displayed various potencies in inhibiting the degradation of different natural or synthetic substrates of ACE, among which captopril inhibits AcSDKP hydrolysis more potently than angiotensin I hydrolysis. To look for this selectivity in vivo, we investigated the pharmacodynamic effect of increasing doses of captopril (0.01-10 mg/kg) during the 90 min after i.v. administration to spontaneously hypertensive rats. Plasma and urinary AcSDKP levels were measured. The renin-angiotensin system was evaluated by measurements of ACE activity in plasma samples, using the synthetic substrate Hip-His-Leu, by determinations of plasma renin concentrations and measurements of arterial blood pressure. The results showed that captopril (0.01-0.3 mg/kg) selectively inhibited AcSDKP hydrolysis, with limited effects on the renin-angiotensin system. AcSDKP levels in plasma and urine rose to a plateau 4 times the basal level for doses more than 0.3 mg/kg. All of the parameters reflecting the renin-angiotensin system were significantly affected at doses of 1 and 10 mg/kg. The present study therefore confirms that captopril can be used to protect hematopoietic stem cells during antitumor chemotherapy while having only a limited effect on cardiovascular homeostasis.
...
PMID:In vivo assessment of captopril selectivity of angiotensin I-converting enzyme inhibition: differential inhibition of acetyl-ser-asp-lys-pro and angiotensin I hydrolysis. 1033 14

We used a vasoreactivity assay to examine the functional significance of angiotensin I-converting enzyme overexpression in smooth muscle cells after vascular injury. Rat carotid arteries isolated at days 2 to 14 after in vivo endothelial denudation were compared with the contralateral freshly denuded (control) vessels. Arterial rings were constricted ex vivo with angiotensin I in the absence or presence of the angiotensin I-converting enzyme inhibitors captopril (300 nM and 3 microM) or perindoprilate (1 nM). Angiotensin I-converting enzyme activity was determined by cleavage of the chromogenic substrate Hip-His-Leu. Angiotensin I-converting enzyme activity in injured arteries was increased (2-fold) at day 7 only after vascular injury. Contractions to angiotensin I were unaffected after injury. Inhibition by captopril and perindoprilate of angiotensin I-induced contractions was significantly less potent in injured arteries at day 7 as compared to control vessels. Mechanical removal of neointimal smooth muscle cells normalized the inhibition by captopril in injured arteries at day 7. Captopril did not affect angiotensin II-induced contractions. Thus, upregulation of angiotensin I-converting enzyme after arterial injury confers resistance to angiotensin I-converting enzyme inhibitors.
...
PMID:Angiotensin I-converting enzyme activity and vascular sensitivity to angiotensin I in rat injured carotid artery. 1077 Dec 96

A novel human zinc metalloprotease that has considerable homology to human angiotensin-converting enzyme (ACE) (40% identity and 61% similarity) has been identified. This metalloprotease (angiotensin-converting enzyme homolog (ACEH)) contains a single HEXXH zinc-binding domain and conserves other critical residues typical of the ACE family. The predicted protein sequence consists of 805 amino acids, including a potential 17-amino acid N-terminal signal peptide sequence and a putative C-terminal membrane anchor. Expression in Chinese hamster ovary cells of a soluble, truncated form of ACEH, lacking the transmembrane and cytosolic domains, produces a glycoprotein of 120 kDa, which is able to cleave angiotensin I and angiotensin II but not bradykinin or Hip-His-Leu. In the hydrolysis of the angiotensins, ACEH functions exclusively as a carboxypeptidase. ACEH activity is inhibited by EDTA but not by classical ACE inhibitors such as captopril, lisinopril, or enalaprilat. Identification of the genomic sequence of ACEH has shown that the ACEH gene contains 18 exons, of which several have considerable size similarity with the first 17 exons of human ACE. The gene maps to chromosomal location Xp22. Northern blotting analysis has shown that the ACEH mRNA transcript is approximately 3. 4 kilobase pairs and is most highly expressed in testis, kidney, and heart. This is the first report of a mammalian homolog of ACE and has implications for our understanding of cardiovascular and renal function.
...
PMID:A human homolog of angiotensin-converting enzyme. Cloning and functional expression as a captopril-insensitive carboxypeptidase. 1092 99

Angiotensin-(1-7) [Ang-(1-7)] has biological actions that can often be distinguished from those of angiotensin II (Ang II). Recent studies indicate that the effects of Ang-(1-7) are mediated by specific receptor(s). We now report the partial characterization of a new antagonist selective for Ang-(1-7), D-Pro7-Ang-(1-7). D-Pro7-Ang-(1-7) (50 pmol) inhibited the hypertensive effect induced by microinjection of Ang-(1-7) [4+/-1 vs 21+/-2 mm Hg, 25 pmol Ang-(1-7) alone] into the rostral ventrolateral medulla without changing the effect of Ang II (16+/-2.5 vs 19+/-2.5 mm Hg after 25 pmol Ang II alone). At 10(-7) mol/L concentration, it completely blocked the endothelium-dependent vasorelaxation produced by Ang-(1-7) (10(-10) to 10(-6) mol/L) in the mouse aorta. The antidiuresis produced by Ang-(1-7) (40 pmol/100 g body weight) in water-loaded rats was also blocked by its analog [1 microg/100 g body weight; 3.08+/-0.8 vs 1.27+/-0.33 mL in Ang-(1-7)-treated rats]. D-Pro7-Ang-(1-7) at a molar ratio of 40:1 did not change the hypotensive effect of bradykinin. Moreover, D-Pro7-Ang-(1-7) did not affect the dipsogenic effect produced by intracerebroventricular administration of Ang II (11.4+/-1.15 vs 8.8+/-1.2 mL/h after Ang II) and did not show any demonstrable angiotensin-converting enzyme inhibitory activity in assays with the synthetic substrate Hip-His-Leu and rat plasma as a source of enzyme. Autoradiography studies with 125I-Ang-(1-7) in mouse kidney slices showed that D-Pro7-Ang-(1-7) competed for the binding of Ang-(1-7) to the cortical supramedullary region. In Chinese hamster ovary cells stably transfected with the AT1 receptor subtype, D-Pro7-Ang-(1-7) did not compete for the specific binding of 125I-Ang-II in concentrations up to 10(-6) mol/L. There was also no significant displacement of Ang II binding to angiotensin type 2 receptors in membrane preparations of adrenal medulla. These data indicate that D-Pro7-Ang-(1-7) is a selective antagonist for Ang-(1-7), which can be useful to clarify the functional role of this heptapeptide.
...
PMID:Characterization of a new selective antagonist for angiotensin-(1-7), D-pro7-angiotensin-(1-7). 1262 89

<< Previous 1 2 3 Next >>