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)

A rat blood pressure assay was used to perform a structure-activity relationship study (SAR) of Leu-Val-Val-hemorphin-7 (LVV-H7), a fragment of hemoglobin (Hb) beta-chain, elucidate the mechanisms of its cardiovascular effects, and test its potential involvement in the pressor activity of diaspirin crosslinked Hb (DCLHb), a recently developed Hb-based oxygen carrier. The SAR study revealed that the C-terminal-Arg-Phe-amino acid sequence of LVV-H7 contained the main determinants of the pressor activity of this peptide. Drug interaction studies using various inhibitory drugs (e.g., phentolamine, clonidine, etc.) and LVV-H7 showed that the pressor effect and tachycardia elicited by LVV-H7 involved the activation of the sympathetic nervous system (SNS). Additional studies using phenytoin (sodium channel blocker), [Tic7]H7(5-7)-NH2 (putative antagonist of receptors for LVV-H7) and H7(5-7)-NH2, an amidated C-terminal fragment of LVV-H7, suggested that LVV-H7 activated the SNS by interacting with specific receptors functionally coupled with phenytoin-sensitive sodium channels. The pressor effect and tachycardia caused by LVV-H7 were potentiated by captopril, suggesting that the angiotensin converting enzyme may contribute to the inactivation of LVV-H7 in rats. The pressor activity of DCLHb, in contrast to that elicited by LVV-H7, was not affected by animal pretreatment with LVV-H7 fragments shown to inhibit the pressor effect of LVV-H7. We conclude that: 1) LVV-H7 is unlikely to mediate the pressor activity of DCLHb in rats; 2) the pressor and tachycardic activities of LVV-H7 are mediated by the SNS; 3) the C-terminal-Arg-Phe-amino acid sequence of LVV-H7 contains the chemical groups responsible for the pressor effect of this peptide in rats; 4) LVV-H7 and FMRF amide-related peptides may share the same mechanism of pressor activity in rats.
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PMID:Structural requirements and mechanism of the pressor activity of Leu-Val-Val-hemorphin-7, a fragment of hemoglobin beta-chain in rats. 943 44

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

Inhibition of the renin-angiotensin system (RAS) has been shown to be beneficial in providing cardioprotective effects in humans, but the mechanism of these effects is not well understood. In this study, we examined the effects and mechanism of RAS inhibitors on ischemia/reperfusion (IR)-induced myocardial injury in rats. Rats were randomly divided into five groups and treated with vehicle (C), angiotensin converting enzyme inhibitor (ACE-I), angiotensin II type 1 receptor antagonist (AT1-A), angiotensin II type 2 receptor antagonist (AT2-A) or ACE-I plus bradykinin B2 antagonist. Ten minutes after administration, the left main coronary artery was ligated for 45 min, and then reperfused for 120 min. IR-induced cardiomyocyte apoptosis was assessed by terminal deoxyribonucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay and confirmed by typical DNA laddering. Mitogen-activated protein kinase, extracellular signal-regulated protein kinase (ERK) and c-Jun NH2-terminal protein kinase (JNK) activity in the ischemic zone were measured by an in vitro kinase assay. The duration of ventricular tachycardia (VT) during ischemia was reduced by AT2-A and ACE-I, and increased by AT1-A and ACE-I+icatibant. ACE-I and AT2-A reduced apoptosis (by 54% and 53%) and infarct size (by 42% and 41%), while AT1-A increased apoptosis (by 86%) and infarct size (by 45%). These changes were negatively correlated with the change in ERK activity. The effects of ACE-I on apoptosis and infarct size were abolished by the coadministration of icatibant. Apoptosis was correlated with the occurrence of VT (r=0.837, p<0.001). These results suggest that both the accumulation of bradykinin and inhibition of AT2 receptor are cardioprotective against IR injury through the activation of ERK, but not JNK.
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PMID:Mechanism of the cardioprotective effect of inhibition of the renin-angiotensin system on ischemia/reperfusion-induced myocardial injury. 1132 78

The interactions between pathogenic bacteria and extracellular matrix (ECM) components markedly influence the initiation and establishment of infection. We have identified two surface proteins of virulent Mycoplasma pneumoniae with molecular masses of 45 and 30 kDa that bind to the ECM constituent, fibronectin (Fn). These Fn-binding proteins (FnBPs) were purified to near homogeneity using Fn-coupled Sepharose 4B-affinity column chromatography, and amino acid sequence analysis of the 45 and the 30 kDa proteins identified them as elongation factor Tu (EF-Tu) and pyruvate dehydrogenase E1 beta subunit (PDH-B) respectively. The genes for EF-Tu and PDH-B were cloned, and the entire EF-Tu gene and NH2-terminus of PDH-B (NPDH (pyruvate dehydrogenase E1 beta subunit from amino acid 1-244)-B) gene were overexpressed in Escherichia coli. The recombinant proteins, rEF-Tu and rNPDH-B, were purified to homogeneity by His-tag affinity column chromatography and used to immunize rabbits. Purified rEF-Tu and rNPDH-B bound to Fn using a ligand immunoblot assay and ELISA. Immunogold electron microscopy with polyclonal antibodies reactive against rEF-Tu (antirEF-Tu) and rNPDH-B (antirNPDH-B) and whole cell radioimmunoprecipitation (WCRIP) revealed the surface location of these proteins. Adherence of viable M. pneumoniae to immobilized Fn was inhibited by antirEF-Tu and antirNPDH-B antisera in a dose-dependent and cumulative manner. These results demonstrate that M. pneumoniae EF-Tu and PDH-B, in addition to their major cytoplasmic biosynthetic and metabolic roles, can be surface translocated, which confers additional important biological functions.
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PMID:Elongation factor Tu and E1 beta subunit of pyruvate dehydrogenase complex act as fibronectin binding proteins in Mycoplasma pneumoniae. 1242 10

The magnitude of the in vitro and in vivo resistance of 3 synthetic enkephalin analogs, [D-Ala2,Met5]-enkephalin (DAME), [D-Ala2,Met5]-enkephalinamide (DAME-NH2) and [D-Ala2,D-Met5]enkephalin (DADME), to 3 enkephalin-hydrolyzing enzymes, amastatin-sensitive aminopeptidase (AsA), phosphoramidon-sensitive endopeptidase-24.11 (PsE) and captopril-sensitive dipeptidyl carboxypeptidase I (CsD), was estimated by comparing the potency of enkephalins in the absence of the peptidase inhibitor (PI) with that in the presence of the PI. The enhancement of the potency of enkephalins in the isolated mouse vas deferens preparation by 3 PIs, amastatin, phosphoramidon, and captopril, indicated that the resistance of enkephalins to AsA, PsE, or CsD was DADME [symbol: see text] DAME-NH2 [symbol: see text] DAME > [Met5]-enkephalin (ME), DADME > DAME-NH2 > DAME [symbol: see text] ME, or DADME [symbol: see text] DAME-NH2 > DAME > ME, respectively. Additionally, the data obtained by the s.c. administration of enkephalin analogs to 10-day-old rats with or without PI, showed that PsE played the most important role in the inactivation of both DAME and DAME-NH2. In addition to PsE, both AsA and CsD, or AsA alone, played the significant role in the inactivation of DAME, or DAME-NH2, respectively. In the inactivation of DADME, AsA alone played the significant role. These results showed that the 3 peptidases all played important roles in the inactivation of enkephalins, and therefore only an analog like DADME, which was quite resistant to the 3 enzymes, was able to produce the effect without PIs after its systemic administration. Since even DADME was not completely resistant to the 3 enzymes; however, its potency was further increased by pretreatment of infant rats with the PIs.
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PMID:The in vitro and in vivo resistance of synthetic enkephalin analogs to three enkephalin-hydrolyzing enzymes. 1250 18

We investigated the ability of cathepsin L to induce a hypotensive effect after intravenous injection in rats and correlated this decrease in blood pressure with kinin generation. Simultaneously with blood pressure decrease, we detected plasma kininogen depletion in the treated rats. The effect observed in vivo was abolished by pre-incubation of cathepsin L with the cysteine peptidase-specific inhibitor E-64 (1 microM) or by previous administration of the bradykinin B2 receptor antagonist JE049 (4 mg/kg). A potentiation of the hypotensive effect caused by cathepsin L was observed by previous administration of the angiotensin I-converting enzyme inhibitor captopril (5 mg/kg). In vitro studies indicated that cathepsin L excised bradykinin from the synthetic fluorogenic peptide Abz-MTSVIRRPPGFSPFRAPRV-NH2, based on the Met375-Val393 sequence of rat kininogen (Abz = o-aminobenzoic acid). In conclusion, our data indicate that in vivo cathepsin L releases a kinin-related peptide, and in vitro experiments suggest that the kinin generated is bradykinin. Although it is well known that cysteine proteases are strongly inhibited by kininogen, cathepsin L could represent an alternative pathway for kinin production in pathological processes.
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PMID:A possible alternative mechanism of kinin generation in vivo by cathepsin L. 1620 91

A selection of lactoferricin B (LfcinB)-related peptides with an angiotensin I-converting enzyme (ACE) inhibitory effect have been examined using in vitro and ex vivo functional assays. Peptides that were analyzed included a set of sequence-related antimicrobial hexapeptides previously reported and two representative LfcinB-derived peptides. In vitro assays using hippuryl-L-histidyl-L-leucine (HHL) and angiotensin I as substrates allowed us to select two hexapeptides, PACEI32 (Ac-RKWHFW-NH2) and PACEI34 (Ac-RKWLFW-NH2), and also a LfcinB-derived peptide, LfcinB17-31 (Ac-FKCRRWQWRMKKLGA-NH2). Ex vivo functional assays using rabbit carotid arterial segments showed PACEI32 (both D- and L-enantiomers) and LfcinB17-31 have inhibitory effects on ACE-dependent angiotensin I-induced contraction. None of the peptides exhibited in vitro ACE inhibitory activity using bradykinin as the substrate. In conclusion, three bioactive lactoferricin-related peptides exhibit inhibitory effects on both ACE activity and ACE-dependent vasoconstriction with potential to modulate hypertension that deserves further investigation.
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PMID:Lactoferricin-related peptides with inhibitory effects on ACE-dependent vasoconstriction. 1684 12

An increase in bradykinin has been suggested to contribute to the enhanced insulin sensitivity observed in the presence of ACE inhibitors. To investigate a potential direct, nonvascular effect on an insulin target tissue, the effect of bradykinin on glucose uptake and insulin signaling was studied in primary rat adipocytes. Whereas basal glucose uptake was not altered, bradykinin augmented insulin-stimulated glucose uptake twofold, which was blocked by HOE-140, a bradykinin B2 receptor antagonist. The bradykinin effect on glucose uptake was nitric oxide (NO) dependent, mimicked by NO donors and absent in adipocytes from endothelial NO synthase-/- mice. Investigation of insulin signaling revealed that bradykinin enhanced insulin receptor substrate-1 (IRS-1) Tyr phosphorylation, Akt/protein kinase B phosphorylation, and GLUT4 translocation. In contrast, insulin-stimulated extracellular signal-regulated kinase1/2 and Jun NH2-terminal kinase (JNK) activation were decreased in the presence of bradykinin, accompanied by decreased IRS-1 Ser307 phosphorylation. Furthermore, bradykinin did not enhance insulin action in the presence of the JNK inhibitor, SP-600125, or in adipocytes from JNK1-/- mice. These data indicate that bradykinin enhances insulin sensitivity in adipocytes via an NO-dependent pathway that acts by modulating the feedback inhibition of insulin signaling at the level of IRS-1.
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PMID:Bradykinin augments insulin-stimulated glucose transport in rat adipocytes via endothelial nitric oxide synthase-mediated inhibition of Jun NH2-terminal kinase. 1700 31

The purpose of the present paper was to study at physiological pH the affinity between vasoactive intestinal peptide (VIP) and four poly(amidoamine) dendrimers (PAMAMs) designed for drug delivery. Therefore, a fast and reproducible CE method was first developed to analyze the strongly basic peptide. To allow an accurate determination of binding constant (K) values, the ability to suppress peptide adsorption onto the silica capillary of nonpermanent coatings (poly(ethylene oxide) (PEO), low and medium relative molecular masses poly(diallyldimethylammonium chloride) (PDDA)) or poly(acrylamide) permanent coating (PAA) was evaluated. Very good intraday repeatability of VIP migration times and peak areas (0.1-0.6 and 2.9-4.9% RSD, respectively) was obtained using two of the investigated coatings (PEO and PDDA with medium molecular mass). ACE combined with these dynamic coatings was then employed to evaluate K between VIP and two amine-terminated PAMAM dendrimers of generation 2 and 5 (G2.NH2, G5.NH2) and two carboxyl-terminated PAMAM derivatives of generation 2 and 5 (G2.COOH, G5.COOH). Binding constant of (6.7 +/- 1.1) x 10(4)/M could be determined for the couple VIP/G5.NH2, while no affinity was evidenced between VIP and all other dendrimers investigated. These results suggest that G5.NH2 might be an interesting carrier for the delivery of VIP.
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PMID:Determination of binding constants of vasoactive intestinal peptide to poly(amidoamine) dendrimers designed for drug delivery using ACE. 1755 62


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