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 angiotensin I-coverting enzyme (peptidyldipeptide hydrolase, EC 3.4.15.1) was isolated from both guinea pig lung and serum; Km and V values were determined using both angiotensin I and hippurylhistidylleucine as substrates. Km values for the lung enzyme were 3.1 mM for hippurylhistidylleucine hippurylhistidylleucine and 0.076 mM for angiotensin I. Inhibition studies were performed and I50 values were obtained with the following inhibitors: angiotensin II (lung, 1.9 - 10(-5) M; serum, 1.7 - 10(-5) M), bradykinin (lung, 2.6 - 10(-6) M; serum, 2.1 - 10(-6) M), and pyrrolidone-Lys-Trp-Ala-Pro (lung, 7.9 - 10(-8) M; serum, 5.6 - 10(-8) M). Both enzymes were glycoproteins and were inhibited by concanavalin A. A maximum inhibition of 35% initial enzymatic activity was observed for both enzymes at a concanavalin A concentration of 4 - 10(-4) M suggesting that the sugar moieties of each enzyme are similar. Both enzymes required NaCl for activity and were inhibited by EDTA. A comparison of kinetic and inhibition properties indicates that both enzymes are quite similar.
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PMID:Angiotensin I-converting enzyme from guinea pig lung and serum. A comparison of some kinetic and inhibition properties. 18 73

We studied a PDH deficient patient who is clinically responsive to thiamine. High Km and low Vmax values for the TPP were identified in the patient's cultured cells. Immunoblot analysis detected trace amount of mutant E1 alpha polypeptide which was 3.5 KD larger than normal in size. Four-nucleotide deletion in the E1 alpha gene causes a reading frame shift, producing an abnormal polypeptide with additional 31 amino acids at C-terminus of the E1 alpha subunit. The tryptophan (codon 383) and lysine (385) residues near the C-terminus might play a crucial role in the binding of TPP to the E1.
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PMID:Thiamine responsive pyruvate dehydrogenase deficiency. 129 18

Bradykinin (BK) receptor agonists and antagonists contain modifications that confer resistance to specific peptidases. In control studies, rat plasma degraded BK (10.3 +/- 0.3 nmol/min/ml) via angiotensin-converting enzyme (ACE; EC 3.4.15.1; 5.2 +/- 0.3 nmol/min/ml), carboxypeptidase N (CPN; EC 3.4.17.3; 3.2 +/- 0.4 nmol/min/ml), aminopeptidase P (APP; EC 3.4.11.9; 0.6 +/- 0.2 nmol/min/ml), and other (unidentified) activity (2.1 +/- 0.6 nmol/min/ml). In contrast, BK agonist analogs were hydrolyzed more slowly due to selective resistance to these plasma peptidases. In addition to Lys-Lys-BK (B1087), which is partially resistant to ACE, [Hyp3,Phe8-r-Arg9]BK (B7642) was completely resistant to ACE, CPN, and the unidentified plasma activity (1.9 +/- 0.3 nmol/min/ml), and D-Arg0[Hyp3,Phe8-r-Arg9]BK (B7644) was resistant to all plasma hydrolysis, including APP (less than 0.2 nmol/min/ml). In vivo ACE-resistant B1087 exhibited a depressor potency and duration of action greater than BK and equivalent to that of BK in the presence of the ACE inhibitor enalapril. Although the B7642 and B7644 agonists were also more potent and longer acting than BK, the increases were no more than that seen for B1087, despite their additional resistance to CPN (B7642) and CPN and APP (B7644). The duration of action of these analogs was, however, increased after renal ligation. These data demonstrate the importance of ACE to the metabolism of circulating BK and BK analogs. In contrast, resistance to CPN and APP are not associated with further potentiation. Beyond ACE resistance, it is likely that the development of more potent, longer-acting BK agonists and antagonists will relate to other factors, such as renal processing independent of CPN and APP.
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PMID:Depressor action of bradykinin agonists relative to metabolism by angiotensin-converting enzyme, carboxypeptidase N, and aminopeptidase P. 131 58

Stabilization of biologically active conformations of native peptides by cyclization or introduction of hindering residues led to peptidominetics endowed with high affinity and selectivity for one class of receptors and able to cross the blood brain barrier. This is the case of BUBU, Tyr-D-Ser(OtBu)-Gly-Phe-Leu-Thr(OtBu) and BUBUC, Tyr-D-Cys-(OtBu)-Gly-Phe-Leu-Thr(OtBu) for the opioid delta receptors and of BC 254, Boc-gamma-D-Glu-Tyr(SO3H)-Nle-D-Lys-Trp-Nle-Asp-PheNH2 and of BC 264, Boc-Tyr(SO3H)gNle-mGly-Trp-MeNle-Asp-PheNH2 for central CCK-B receptors. Inhibition of metabolizing peptidases such as aminopeptidase N and endopeptidase 24.11 (NEP) for enkephalins and of NEP and ACE for atrial natriuretic peptide and angiotensin I by mixed inhibitors such as kelatorphan and RB 101 or ES14, rationally designed by taking into account the structural differences in the active site of these zinc-metallopeptidases, led to potent analgesics devoid of the major morphine side effects or to new antihypertensives.
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PMID:Peptidomimetics as receptors agonists or peptidase inhibitors: a structural approach in the field of enkephalins, ANP and CCK. 132 Apr 19

Dried bonito (Katsuobusi), a Japanese traditional seasoning made of bonito muscle was hydrolyzed by various proteases and the inhibitory activity of the hydrolyzates for angiotensin I-converting enzyme (ACE) [EC 3.4.15.1] was measured. Among the digests, thermolysin digest showed the most potent inhibitory activity. Eight inhibitory peptides were isolated from the digest using HPLC. The amino acid sequences of inhibitory peptides were Ile-Lys-Pro-Leu-Asn-Tyr, Ile-Val-Gly-Arg-Pro-Arg-His-Gln-Gly, Ile-Trp-His-His-Thr, Ala-Leu-Pro-His-Ala, Phe-Gln-Pro, Leu-Lys-Pro-Asn-Met, Ile-Tyr, and Asp-Tyr-Gly-Leu-Tyr-Pro. By searching for the sequence homology in many proteins, four of them were found in the primary structure of actin. Asp-Met-Ile-Pro-Ala-Gln-Lys was obtained from the boiling water extract of dried bonito and this peptide was found in the primary structure of creatine kinase. Fragments of these peptides were prepared by further enzymatic digestion or chemical synthesis and their ACE-inhibitory activities were measured. Among them, Ile-Lys-Pro, Ile-Trp, Leu-Lys-Pro, and Leu-Tyr-Pro had higher inhibitory activity than their parental peptides. Ile-Lys-Pro suppressed the hypertensive activity of angiotensin I.
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PMID:Peptide inhibitors for angiotensin I-converting enzyme from thermolysin digest of dried bonito. 136 54

Inhibitors of the angiotensin converting enzyme (ACE, EC 3.4.15.1) are important in the treatment of the high blood pressure. The therapeutically used drugs captopril, enalapril and ramipril are enzymatic stable short pseudo-peptides. They are stabilized against enzymatic degradation and therefore usefully for oral application. But for some indications e.g. post operative treatment and shock therapy well dosed infusions are needed. For this purpose we attached nona-, penta- and tripeptide inhibitors of the ACE to immunologically inert dextran polymers. The inhibitors are derived as well from the bradykinin potentiating nonapeptide BPP9 alpha (Pyr-Trp-Pro-Arg-Pro-Gln-Ile-Pro-Pro) and the bradykinin potentiating pentapeptide BPP5 alpha (Pyr-Lys-Trp-Ala-Pro), both originally isolated from snake venoms, as from acylated tripeptides with the structure Acyl-AA1-Arg-Pro. We estimated the influence on the biological activity of two different linkers to the dextran polymers. The coupling to the polymer was achieved on the one hand via the aldehyd moiety (DAD-AK) and on the other hand by the carboxyl residue (KMD). In the case of DAD-AK-polymers the condensation of the peptides was performed by the N-hydroxysuccinimide ester of the polymer. Because of the instability of the KMD-OSU in this case water soluble carbodiimides are used. The polymer bound peptides inhibit the isolated ACE, but in the most cases with a reduced activity. Only the tripeptide DPhe-Arg-Pro has a enhanced activity in the polymer bound state. The polymer bound inhibitors show a prolongated action on normotensive rats by intravenous application.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Peptide inhibitors of the renin-angiotensin system. 2. Polymer-bound tri-, penta- and nonapeptide inhibitors of angiotensin converting enzyme]. 138 10

In addition to angiotensin I converting enzyme (ACE; EC 3.4.15.1) and carboxypeptidase N (CPN; EC 3.4.17.3), other peptidases contribute to bradykinin (BK) degradation in plasma. Rat plasma degraded BK by hydrolysis of the N-terminal Arg1-Pro2 bond, and the characteristics of hydrolysis are consistent with identification of aminopeptidase P (APP; EC 3.4.11.9) as the responsible enzyme. BK and BK[1-5] N-terminal hydrolysis was optimal at neutral pH, was inhibited by 2-mercaptoethanol, dithiothreitol, o-phenanthroline and EDTA, but was unaffected by the aminopeptidase inhibitors amastatin, puromycin and diprotin A, the endopeptidase-24.11 inhibitors phosphoramidon and ZINCOV, and the ACE and CPN inhibitors captopril and D,L-mercapto-methyl-3-guanidinoethylthiopropanoic acid (MERGETPA), respectively. Although kallidin (Lys-BK) was not metabolized directly by APP, conversion to BK by plasma aminopeptidase M (EC 3.4.11.2) resulted in subsequent degradation by APP. BK analogs containing N-terminal Arg1-Pro2 bonds, including [Tyr8-(OMe)] BK and [Phe8 psi(CH2NH)Arg9]BK (B2 agonists), des-Arg9-BK and [D-Phe8]des-Arg9-BK (B1 agonists), and [Leu8]des-Arg9-BK (B1 antagonist), were degraded by APP with Km and Vmax values comparable to those found for BK (Km = 19.7 +/- 2.6 microM; Vmax = 12.1 +/- 1.2 nmol/min/mL). In contrast, B2 antagonists containing D-Arg0 N-termini, including D-Arg[Hyp3,Thi5.8,D-Phe7]BK and D-Arg[Hyp3,D-Phe7,Phe8 psi(CH2NH)Arg9]BK, were resistant to APP-mediated hydrolysis. These data support a role for plasma aminopeptidase P in the degradation of circulating kinins, and a variety of B2 and B1 kinin agonists and antagonists. However, APP does not participate in the degradation of D-Arg0-containing antagonists.
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PMID:Metabolism of bradykinin agonists and antagonists by plasma aminopeptidase P. 165 Oct 78

Close to 95% of patients with established clinical, biochemical and histologic features of primary biliary cirrhosis (PBC) possess antimitochondrial M2 antibodies reacting with the E2 component, dihydrolipoamide acetyltransferase, of the pyruvate dehydrogenase complex. We examined the ability of synthetic peptides of E2 to be recognized in ELISA by sera from patients with PBC and autoimmune-related disorders. Sera from 14 PBC M2+ patients, 1 PBC M2- patient, 5 non-PBC M2+ patients, and 6 patients with chronic active hepatitis were studied. Among the seven E2 synthetic peptides tested (namely peptides 87-119, 167-184, 169-202, 267-302, 456-477, 498-513 and 530-543), only peptide 167-184 used as OVA conjugate and prepared with lipoic acid (LA) located on lysine 173 (natural inner lipoyl-binding site) was recognized in direct ELISA by PBC M2+ sera. The conjugated peptide 167-184 LA was not recognized in direct ELISA by non-PBC M2+ sera or by sera from patients with chronic active hepatitis. The free peptide 167-184 LA inhibited the ELISA reaction of PBC antibodies to PDH and totally abolished the typical immunofluorescence reaction of PBC sera on rat kidney, stomach and liver, or human HEp-2 cell substrates. No inhibition of ELISA or immunofluorescence reaction was found with the other E2 fragments including peptide 167-184 without LA. Our results show that the lipoyl moiety forms an integral part of a dominant conformational epitope recognized by PBC sera. Inasmuch as the peptide 167-184 LA was not recognized by non-PBC sera in direct ELISA, it could be used as a valuable probe for PBC diagnosis.
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PMID:A lipoyl synthetic octadecapeptide of dihydrolipoamide acetyltransferase specifically recognized by anti-M2 autoantibodies in primary biliary cirrhosis. 172 64

Kininase II (EC 3.4.15.1) (KII) and kininase I (KI) (EC 3.4.12.7) activities of rat plasma were characterized by the hydrolysis of hippuryl-L-histidyl-L-leucine (HHL), hippuryl-L-arginine (HLA) [expressed as carboxypeptidase N1 (CN1) activity] and hippuryl-L-lysine (HLL) [expressed as carboxypeptidase N2 (CN2) activity]. Using a spectrophotometric assay, biochemical characteristics of the three enzymes were investigated. The Michaelis-Menten constants were as follows: KII: Km 2.55 +/- 0.22 mM, Vmax 0.357 +/- 0.017 mumol/min/mL; CN1: Km 6.93 +/- 0.32 mM, Vmax 0.748 +/- 0.019 mumol/min/mL; and CN2: Km 35.8 +/- 1.52 mM, Vmax 13.11 +/- 0.40 mumol/min/mL. EDTA and O-phenanthroline inhibited the three enzyme assays at the same Ki, whereas captopril and 2-mercaptomethyl-3-guanidinoethylthiopropanoic acid (MERGETPA), allowed for the demonstration of the specificity of each assay. Furthermore, Ki values of MERGETPA against both CN1 (4.75 microM) and CN2 (2.36 microM) activities do not support the hypothesis that KI activity may be accounted for by the presence of isoenzymes in rat plasma.
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PMID:A micromethod for the determination of the activities of kininases in rat plasma. Kinetics and inhibitory characteristics. 184 16

Captopril ((2S)-1-(3-mercapto-2-methyl-propionyl)-L-proline) inhibited the bifunctional, Zn(2+)-containing enzyme leukotriene A4 hydrolase/aminopeptidase reversibly and competitively with Ki = 6.0 microM for leukotriene B4 formation and Ki = 60 nM for L-lysine-p-nitroanilide hydrolysis at pH 8. Inhibition was independent of pH between pH 7 and 8, the optimum range for each catalytic activity. Half-maximal inhibition of leukotriene B4 formation by intact erythrocytes and neutrophils required 50 and 88 microM captopril, respectively. In neutrophils and platelets neither 5(S)-hydroxyeicosatetraenoic acid, 12(S)-hydroxyeicosatetraenoic acid, nor leukotriene C4 formation were reduced, indicating selective inhibition of leukotriene A4 hydrolase/aminopeptidase, not 5-lipoxygenase, 12-lipoxygenase, or leukotriene C4 synthase. In whole blood, captopril inhibited leukotriene B4 formation with an accompanying redistribution of substrate toward formation of cysteinyl leukotrienes. The decrease in leukotriene B4 was more substantial than the corresponding increase in cysteinyl leukotrienes suggesting that nonenzymatic hydration predominates over transcellular metabolism of leukotriene A4 by platelets during selective inhibition of leukotriene A4 hydrolase. Enalapril dicarboxylic acid and Glu-Trp-Pro-Arg-ProGln-Ile-Pro-Pro which inhibit angiotensin-converting enzyme: angiotensin I, bradykinin, and N-[3-(2-furyl)acryloyl]Phe-Gly-Gly which are substrates; and chloride ions which activate angiotensin-converting enzyme did not modulate leukotriene A4 hydrolase/aminopeptidase activity. The results indicate that: (i) the sulfhydryl group of captopril is an important determinant for inhibition of leukotriene A4 hydrolase/aminopeptidase, probably by binding to an active site Zn2+; (ii) aminopeptidase and leukotriene A4 hydrolase display differential susceptibility to inhibition; (iii) there is minimal functional similarity between angiotensin-converting enzyme (peptidyl dipeptidase) and leukotriene A4 hydrolase/aminopeptidase; (iv) captopril may be a useful prototype to identify more potent and selective leukotriene A4 hydrolase inhibitors.
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PMID:Inhibition of leukotriene A4 hydrolase/aminopeptidase by captopril. 188 82


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