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

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Query: EC:3.4.15.1 (ACE)
18,300 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The physiological functions of angiotensin I-converting enzyme (ACE) are not limited to its cardiovascular role. ACE constantly degrades N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP), a natural circulating regulator of the hematopoietic stem cell proliferation, and thereby may be involved in hematopoietic stem cell regulation. AcSDKP is hydrolyzed 50-fold faster by the N-domain active site compared to the C-domain active site. The aim of the present study was to investigate which aminoacid residues from AcSDKP are required to ensure N-domain specificity. Several peptides were designed by progressively increasing the length of the peptidic chain from a tripeptide to a pentapeptide. Kinetic studies of the wild-type ACE and of the two ACE mutants containing a single active domain (N- or C-domain) were performed using Bz (benzoyl) Asp-Lys-Pro, benzoyl-glycyl (Bz-Gly)-Asp-Lys-Pro, and Bz-Gly-Ser-Asp-Lys-Pro (with its intermediate product Bz-Gly-Ser-Asp) as substrates. The unexpected importance of an aspartic acid in the P1 position was discovered, as well as the interaction of the P2 and P3 positions in the substrate to increase or decrease N-domain specificity. Substrates longer than five residues may involve interdependence between subsites. Finally, the discovery of highly specific and novel N-domain substrates cannot be predicted from single subsite mapping, but may require other approaches such as combinatorial peptide libraries.
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PMID:N-domain selectivity of angiotensin I-converting enzyme as assessed by structure-function studies of its highly selective substrate, N-acetyl-seryl-aspartyl-lysyl-proline. 1003 45

The tetrapeptide Acetyl-N-Ser-Asp-Lys-Pro (AcSDKP), an inhibitor of hematopoietic stem cell proliferation, is known to reduce in vivo the damage resulting from treatment with chemotherapeutic agents or ionizing radiation on the stem cell compartment. Recently, AcSDKP has been shown to be a physiological substrate of the N-active site of angiotensin I-converting enzyme (ACE). Four analogs of the tetrapeptide expressing a high stability towards ACE degradation in vitro have been synthesized in order to provide new molecules likely to improve the myeloprotection displayed by AcSDKP. These analogs are three pseudopeptides with a modified peptidic bond, Ac-Serpsi(CH2-NH)Asp-Lys-Pro, Ac-Ser-Asppsi(CH2-NH)Lys-Pro, Ac-Ser-Asp-Lyspsi(CH2-N)Pro, and one C-terminus modified peptide (AcSDKP-NH2). We report here that these analogs reduce in vitro the proportion of murine colony-forming units-granulocyte/macrophage in S-phase and inhibit the entry into cycle of high proliferative potential colony-forming cells. The efficacy of AcSDKP analogs in preventing in vitro primitive hematopoietic stem cells from entering into cycle suggests that these molecules could be new candidates for the powerful inhibition of hematopoietic stem and progenitor cell proliferation in vivo.
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PMID:In vitro effect of acetyl-N-Ser-Asp-Lys-Pro (AcSDKP) analogs resistant to angiotensin I-converting enzyme on hematopoietic stem cell and progenitor cell proliferation. 1019 70

The human somatic angiotensin converting enzyme (ACE) contains two homologous domains, each bearing a zinc-dependent active site. All of the synthetic inhibitors of this enzyme used in clinical applications interact with these two active sites to a similar extent. Recently, several lines of evidence have suggested that the N-terminal active site of ACE might be involved in specific hydrolysis of some important physiological substrates, like Acetyl-Seryl-Aspartyl-Lysyl-Proline, a negative regulator of hematopoietic stem cell differentiation and proliferation. These findings have stimulated studies aimed at identifying new ACE inhibitors able to block only one of the two active sites of this enzyme. By screening phosphinic peptide libraries, we discovered a phosphinic peptide Ac-Asp-(L)Phepsi(PO2-CH2)(L)Ala-Ala-NH2, called RXP 407, which is able to differentiate the two ACE active sites, with a dissociation constant three orders of magnitude lower for the N-domain of the enzyme. The usefulness of a combinatorial chemistry approach to develop new lead structures is underscored by the unusual chemical structure of RXP 407, as compared with classical ACE inhibitors. As a highly potent and selective inhibitor of the N-terminal active site of wild ACE (Ki = 12 nM), RXP 407, which is metabolically stable in vivo, may lead to a new generation of ACE inhibitors able to block in vivo only a subset of the different functions regulated by ACE.
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PMID:RXP 407, a phosphinic peptide, is a potent inhibitor of angiotensin I converting enzyme able to differentiate between its two active sites. 1020 Feb 62

N-Acetyl-Ser-Asp-Lys-Pro-OH (AcSDKP-OH), a negative regulator of hematopoietic stem cell proliferation, is shown to be a physiological substrate of angiotensin I-converting enzyme (ACE), a zinc-dipeptidyl carboxypeptidase, involved in cardiovascular homeostasis. Recently, a study carried out on captopril-treated volunteers revealed that the kinetics of [3H]AcSDKP-OH hydrolysis in vitro in the plasma of donors correlates closely to the plasmatic ratio angiotensin II/angiotensin I, which characterized the conversion activity of ACE. This prompted us to design a fluorescent substrate, 2-[7-(dimethylamino)-2-oxo-2H-chromen-4-yl]acetyl-SDKP-OH, or coumarin-SDKP-OH, which could be an alternative to the radiolabeled analogue used in that study, allowing an easier and more rapid determination of enzyme activity. We report here the synthesis and the determination of the kinetics constants of this fluorescent derivative compared with those of [3H]AcSDKP-OH with human plasma ACE (133 and 125 microM, respectively), which are in the same range as those of the physiological substrate angiotensin I. Furthermore, the hydrolysis of the fluorescent substrate shows the same sensitivity toward chloride concentration as the natural substrate, demonstrating its specificity for N-domain hydrolysis. This fluorescent derivative was used to develop a sensitive assay for the determination of ACE activity in human plasma.
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PMID:Coumarin-Ser-Asp-Lys-Pro-OH, a fluorescent substrate for determination of angiotensin-converting enzyme activity via high-performance liquid chromatography. 1080 21

Endothelin-1 has vasoconstrictor and mitogenic properties and may contribute to the pathogenesis of hypertension by enhancing vasoconstrictor mechanisms. In this study, we investigated the ability of endothelin-1 decrease the hypotensive effects of the vasodilator bradykinin in anesthetized rats. We also studied the effects a two-week oral pre-treatment with losartan (10 mg/kg/day) or enalapril (25 mg/kg/day) on endothelin-1-induced changes in the hypotensive responses to bradykinin. Bradykinin (0.4, 1.6, 6.4, and 25 mcg/kg, i.v.) induced dose-dependent hypotensive responses which were attenuated (P<0.05) by endothelin-1 (2 mcg/kg, i.v.). This effect of endothelin-1 was abolished by the mixed endothelin receptor antagonist N-Acetyl-alpha-[10,11-Dihydro-5H-dibenzo[a, d]cycloheptadien-5-yl]-D-Gly-Leu-Asp-Ile-Ile-Trp (PD145065, 1 mg/kg, i.v.). Endothelin-1 also decreased (P<0.05) the responses to bradykinin in rats pre-treated with losartan, but had no effect in rats pre-treated with enalapril. These results suggest that endothelin-1 may contribute to the development of hypertension by decreasing the responses to bradykinin through a mechanism not involving angiotensin AT(1) receptors, although the inhibition of angiotensin converting enzyme blunted the effect of endothelin-1.
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PMID:Endothelin-1 attenuates bradykinin-induced hypotension in rats. 1084 36

Angiotensin I-converting enzyme (ACE) activity was analyzed in human urine collected from mild hypertensive untreated patients. DEAE-cellulose chromatography using linear gradient elution revealed two forms of angiotensin I-converting enzyme, eluted in the conductivity of 0.75 and 1.25 mS. The fractions of each conductivity were pooled and submitted to direct gel filtration in an AcA-34 column, and the apparent molecular weights of urinary ACEs were estimated as 90 kDa (for ACE eluted in 0.75 mS) and 65 kDa (for ACE eluted in 1.25 mS). Both enzymes have a K(i) of the order of 10(-7) M for the specific inhibitors studied, and are able to hydrolyze luteinizing hormone-releasing hormone and N-acetyl-Ser-Asp-Lys-Pro as described for N-domain ACE. By Western blot analysis, both peaks were recognized by ACE-specific antibody Y4, confirming the molecular weight already described. A plate precipitation assay using monoclonal antibodies to the N-domain of ACE showed that both forms of ACE binds with all monoclonal antibodies to the active N-domain ACE, suggesting that these forms of human urine ACEs resemble the N-fragment of ACE. The HP2 ACE (65 kDa) is similar to low molecular weight (LMW) ACE from normal subjects, and the HP2 ACE (90 kDa) is different from high molecular weight (190 kDa) and LMW (65 kDa) normal ACEs. The 90 kDa ACE could have an important role in development of hypertension. It will be fundamental to elucidate the molecular mechanism responsible for the genesis of this isoform.
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PMID:Angiotensin converting enzymes from human urine of mild hypertensive untreated patients resemble the N-terminal fragment of human angiotensin I-converting enzyme. 1116 34

1. Somatic angiotensin I-converting enzyme (ACE) is a protein that contains two similar domains (N- and C-terminal), each possessing an active site. We have examined the effects of a generator of hydroxyl radicals (g*OH: 2,2'-azo-bis(2-amidinopropane)) and hydrogen peroxide (H2O2) on ACE using an in vitro approach. 2. The generator of hydroxyl radicals inactivated ACE in a time (2-6 h)- and concentration (0.3-3 mmol/L)-dependent manner at 37 degrees C. When ACE was coincubated for 4 h with g*OH (3 mmol/L), its activity decreased by 70%. Addition of dimethylthiourea or mannitol + methionine, two *OH scavengers, resulted in a significant protection of ACE activity. Mercaptoethanol and dithiotreitol, two thiol-reducing agents, also efficiently protected ACE activity. 3. The hydrolysis of two natural and domain-specific substrates was explored. The hydrolysis of angiotensin I, preferentially cleaved by the C-domain, was significantly inhibited (57-58%) after 4 h exposure to g*OH (0.3-1 mmol/L). Under the same conditions of exposure, the hydrolysis of N-acetyl-Ser-Asp-Lys-Pro, a specific substrate for the N-domain, was only slightly inhibited by 1 mmol/L g*OH. 4. Hydrogen peroxide, another source of *OH, was used. After exposure to H2O2 (3 mmol/L; 4 h), an 89% decrease in ACE activity was observed. Pretreatment with the iron chelator deferoxamine (1 mmol/L) attenuated H2O2-mediated ACE inactivation, demonstrating that the effect of H2O2 was partly due to its conversion into *OH (Fenton reaction). 5. In summary, our findings demonstrate that g*OH and H2O2 inhibit ACE activity and suggest a preferential action of g*OH on the C-domain of the enzyme.
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PMID:Inhibitory effect of reactive oxygen species on angiotensin I-converting enzyme (kininase II). 1120 78

Coronary artery disease is among the leading causes of death worldwide. Clinical trials show a protective effect of statins against the sequelae of coronary artery disease. The mean risk reductions for subjects using statins compared with placebo found in these trials is about 30%. These are average reductions for all patients included in the trials. Important factors in interpreting the variability in the outcome of drug therapy include the patient's health profile, prognosis, disease severity, quality of drug prescribing, compliance with prescribed pharmacotherapy and the genetic profile of the patient. This review aims to give an overview of the known polymorphisms (Cholesteryl Ester Transfer Protein polymorphism, Stromelysin-1 polymorphism, -455G/A and TaqI polymorphisms of the beta-fibrinogen gene, apoE4, Asp(9)Asn mutation in the lipoprotein lipase gene, the -514 CT polymorphism in the hepatic lipase gene and the ACE deletion type gene) that have an influence on the effects of statins in the general population. The expectation is that in the future a subject's genotype may determine whether he will be treated with statins or not. Determining the genotype will not deny therapy to a subject, but will help in deciding the therapy that will suit the patient best.
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PMID:Genetic polymorphisms: importance for response to HMG-CoA reductase inhibitors. 1205 67

N-Acetyl-Ser-Asp-Lys-Pro (AcSDKP) is a specific substrate for the N-terminal site of ACE and increases 5-fold during ACE inhibitor therapy. It is known to inhibit the proliferation of hematopoietic stem cells and has also recently been reported to inhibit the growth of cardiac fibroblasts. We investigated its mode of action in cardiac fibroblasts by assessing its influence on transforming growth factor beta(1) (TGFbeta1)-mediated Smad signaling. AcSDKP inhibited the proliferation of isolated cardiac fibroblasts (P<0.05) but significantly stimulated the proliferation of vascular smooth muscle cells. Flow cytometry of rat cardiac fibroblasts treated with AcSDKP showed significant inhibition of the progression of cells from G0/G1 phase to S phase of the cell cycle. In cardiac fibroblasts transfected with a Smad-sensitive luciferase reporter construct, AcSDKP decreased luciferase activity by 55+/-9.7% (P=0.01). Moreover, phosphorylation and nuclear translocation of Smad2 was decreased in cardiac fibroblasts treated with AcSDKP. To conclude, AcSDKP inhibits the growth of cardiac fibroblasts and also inhibits TGFbeta1-stimulated phosphorylation of Smad2. Because AcSDKP increases substantially during ACE inhibitor therapy, this suggests a novel pathway independent of angiotensin II, by which ACE inhibitors can inhibit cardiac fibrosis.
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PMID:N-acetyl-Ser-Asp-Lys-Pro inhibits phosphorylation of Smad2 in cardiac fibroblasts. 1215 6

Two monohydroxamates of l-aspartic acid beta-hydroxamate (AAH) and l-glutamic acid gamma-hydroxamate (GAH) were used for testing antioxidant and angiotensin converting enzyme (ACE) inhibitory activities in comparison with those of asparagine and glutamine, respectively. The half-inhibition concentrations, IC(50), of scavenging activity against 1,1-diphenyl-2-picrylhydrazyl (DPPH) were 36 and 48 microM and against superoxide radicals were 18.99 and 6.33 mM, respectively, for AAH and GAH. However, no activities of asparagine and glutamine were found. AAH and GAH also exhibited activities against peroxynitrite-mediated dihydrorhodamine 123 oxidations and hydroxyl radical-mediated DNA damage. For ACE inhibitory activities, the IC(50) values were 4.92 and 6.56 mM, respectively, for AAH and GAH. The ACE hydrolyzed products on the TLC chromatogram also confirmed the inhibitory activities of the two amino acid hydroxamates on ACE. When 1.23 mM AAH was added, AAH showed competitive inhibitions against ACE, and the apparent inhibition constant (K(i)) was 2.20 mM.
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PMID:Monohydroxamates of aspartic acid and glutamic acid exhibit antioxidant and angiotensin converting enzyme inhibitory activities. 1508 Jun 51


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