Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.15.1 (ACE)
 18,300 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A glutamic acid residue at the active-site of bovine lung angiotensin I-converting enzyme was esterified with p-[N,N-bis-(chloroethyl)amino]phenylbutyryl-L-[U-14]-Proline (chlorambucyl-L-[U-14C]-L-Proline), an affinity label for this enzyme. The radiolabeled enzyme was digested with BrCN and only 1 of the 30 cleavage peptides resolved by reverse-phase HPLC contained the bound radiolabel. This active-site peptide (Mr approximately 16,000) was digested with trypsin, and the labeled peptide (T-2) was further degraded with thermolysin. The enzyme digest peptides were also resolved by reverse-phase HPLC. Only 1 of the 5 peptides obtained after thermolysin digestion (Th-1, Mr 1290) contained the bound radiolabel. Th-1 (12 residues) was subjected to manual Edman degradation and the following partial sequence was determined: H2N-Phe-Thr-Glu-Leu-Ala-Asp-Ser-Glu. The radiolabel was released at cycle 3 and the amount recovered was equivalent to the amount of PTH-Glu detected on HPLC. Thus, glutamic acid is esterified with chlorambucyl-L-[U-14C]-Proline which confirms our earlier findings. The sequence that we determined is homologous in five residues with the corresponding sequences of carboxypeptidase A and B, two other mammalian zinc-proteases. There is little sequence homology with thermolysin, a bacterial zinc-protease that also contains an essential active-site glutamic acid residue.
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PMID:Isolation and sequencing of an active-site peptide from angiotensin I-converting enzyme. 302 71

In order to investigate the role of the renal kallikrein-kinin (K-K) system in normal (NRH) and low renin (LRH) subgroups of essential hypertension (EHT), daily urinary excretions of renal K-K system components including kallikrein (KAL), total KAL, pre-KAL, kinin (KIN) and kininase (total, I and II), were measured in 21 normotensives (NT) and 45 patients with EHT (NRH: 29, LRH: 16). Urinary KAL and KIN quantities, KAL activity, total and pre-KAL, and kininase (total, I and II) were measured by direct RIA, kininogenase assay, direct RIA of KAL after trypsin treatment, and KIN destroying capacity, respectively. The daily excretions of KAL quantity and activity, total and pre-KAL, and KIN were significantly lower in EHT than in NT. That of total kininase and kininase I were significantly higher in EHT than in NT while no significant difference was found in kininase I between EHT and NT. In comparing NRH and LRH, the urinary KAL activity and KIN were lower in LRH than in NRH, and kininase I was higher in LRH than in NRH. No significant difference, however, was found in total and pre-KAL, KAL quantity and kininase II between NRH and LRH. The ratio of KAL quantity/total KAL which reflects the conversion rate from pre-KAL in the kidney, did not show any significant difference among NT, NRH and LRH.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Comprehensive studies on the renal kallikrein-kinin system in essential hypertension. 302 78

Bovine fetal aortic endothelial cells cultured in serum-containing medium accumulate angiotensin I-converting enzyme (ACE) activity and also release it into the culture medium. Following subcultivation of a confluent culture using trypsin-EDTA, cellular ACE activity falls 50% within 8 h, but no ACE activity is detected in the medium, suggesting intracellular loss of the enzyme activity. ACE activity reappears in both the cell lysate and culture medium after the culture becomes confluent. The rate of accumulation of ACE activity released into the medium is always greater than that for cellular activity. For example, 21 days following subcultivation 80-85% of the total culture activity is detected in the medium. Both cellular and medium-associated ACE decrease proportionately as the culture progresses through its in vitro lifespan.
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PMID:Release of angiotensin I-converting enzyme by endothelial cells in vitro. 303 89

Effects of condensed tannins isolated from Rhei Rhizoma on the activities of angiotensin converting enzyme (ACE) and various proteases were examined in vitro. Among the various condensed tannins tested, procyanidin B-5 3,3'-di-O-gallate and procyanidin C-1 3,3',3"-tri-O-gallate strongly inhibited the activity of ACE. The concentration of procyanidin B-5 3,3'-di-O-gallate required for 50% inhibition of ACE was 1.3 X 10(-6) M. The inhibition of ACE by condensed tannins was reversible and non-competitive, according to dialysis and to Dixon plots. However, over one hundred times the concentration was required to inhibit activities of other proteases such as trypsin, chymotrypsin, leucine aminopeptidase, carboxypeptidase A and urinary kallikrein. These results suggest that the inhibitory effects of condensed tannins on the activities of ACE are specific.
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PMID:Inhibitory effects of condensed tannins on angiotensin converting enzyme. 303 68

Dipeptide and tripeptide derivatives containing a statine residue were synthesized as inhibitors of human renin. ES-305, bis[(1-naphthyl)methyl]acetyl(BNMA)-histidyl-statine 2(S)-methylbutylamide was found to be a highly potent inhibitor of human renin with a Ki value of 1.7 X 10(-9) M. Dipeptide derivatives with the BNMA group at the N-terminal (BNMA-Val-Sta-isoleucinol [ES-313], BNMA-Leu-Sta-isoleucinol [ES-316], and BNMA-Nle-Sta-isoleucinol [ES-317]) had potencies against human renin that were similar to the potency of ES-305. All these dipeptide derivatives competitively inhibited human renin. The inhibitors were also potent against monkey renin but were less effective against renins from pig, goat, dog, rabbit, and rat. ES-305 had little effect on cathepsin D and pepsin at the concentration of 10(-5) M. The other derivatives showed detectable inhibition of cathepsin D (IC50, 10(-6) - 10(-7) M) and pepsin (10(-5) - 10(-6) M). All the compounds had little or no effect on trypsin, chymotrypsin, angiotensin converting enzyme, and urinary kallikrein at the concentration of 10(-5) M. Our results indicate that ES-305 is a highly potent and specific inhibitor of human renin. This compound is superior to other, previously described statine-containing renin inhibitors with respect to molecular size and enzyme specificity.
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PMID:Statine-containing dipeptide and tripeptide inhibitors of human renin. 308 74

An orally active renin inhibitor, ES 6864 (N-[(2R)-3-morpholinocarbonyl-2-(1-naphthylmethyl)propionyl]-(4- thiazolyl)-L-alanyl-cyclostatine-(2-morpholinoethyl)amide), was synthesized. ES 6864 was found to be a highly potent inhibitor of human renin with a Ki value of 7.3 x 10(-9) M. The compound competitively inhibited human renin. The inhibitor was also potent against monkey renin but was less effective against renins from pig, goat, dog, rabbit, and rat. ES 6864 did not inhibit cathepsin D, pepsin, trypsin, chymotrypsin, angiotensin converting enzyme, and urinary kallikrein at a concentration of 10(-5) M. ES 6864 was resistant to proteolytic actions of the enzymes in rat tissue homogenates (liver, kidney, pancreas, and small intestine). Oral administration of ES 6864 at 30 mg/kg to conscious, sodium-depleted marmosets produced a significant blood pressure reduction and almost complete inhibition of plasma renin activity, which persisted for 5 hours. Oral administration of ES 6864 also produced dose-related decreases of blood pressure in hog renin-infused rats, but the duration of action was much shorter than that in conscious marmosets. The parent compound in the blood following oral administration of ES 6864 to marmosets was confirmed directly by measuring the plasma concentration of ES 6864. These results enhance the possibility of developing renin inhibitors that can be used clinically.
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PMID:A highly potent and long-acting oral inhibitor of human renin. 313 6

1. The results of this study indicates that the binding of insulin to brain plasma membranes activates a membrane protease which, by a trypsin like mechanism, produces a soluble factor that modulates the PDH behaviour when added to brain mitochondria. 2. The supernatant from brain plasma membranes incubated with 0.5 mg/ml trypsin added to mitochondria increases PDH activity levels and cancels PDH inhibition by NaF, as has already been seen when the plasma membranes are incubated with 25 microU/ml insulin. No such effects are obtained when the incubation is run out with 0.5 mg/ml chymotrypsin. 3. The supernatants from insulin or trypsin treated plasma membranes retain their activating properties on mitochondrial PDH also after dansylation; from these preparations a dansylated active on PDH material was separated by monodimensional chromatography on HPTLC silica Gel plates, using chloroform/1-butanol (93:7 v/v) as a solvent. 4. Insulin incubation of plasma membranes pretreated with protease inhibitors (leupeptin, phenylmethylsulfonylfluoride) or with exogenous trypsin, but not chymotrypsin substrates (esters of arginine and tyrosine) yields an inactive supernatant on PDH. 5. Insulin treated plasma membrane supernatants lose all stimulating properties on PDH after incubation for 1 hr with 2 mg/ml trypsin or chymotrypsin.
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PMID:Evidence of an insulin generated pyruvate dehydrogenase stimulating factor in rat brain plasma membranes. 331 49

Cathepsins M and B from rabbit liver lysosomes were separated by chromatography on Ultrogel AcA34 at low ionic strength and purified to homogeneity, and their catalytic and molecular properties were compared. Cathepsin M was relatively inactive with synthetic peptide substrates. Thus, it hydrolyzed benzoyl arginine naphthylamide at only one-fifth the rate observed with cathepsin B, and no activity was detected with Gly-Phe naphthylamide which is a relatively good substrate for cathepsin B. On the other hand, cathepsin M exhibited a preference for protein substrates. It was more active than cathepsin B in catalyzing the inactivation of the following enzymes: rabbit muscle or liver fructose-1,6-bisphosphate aldolases, rabbit liver fructose-1,6-bisphosphatase and pyruvate kinase, yeast glucose-6-phosphate dehydrogenase, and rabbit muscle glyceraldehyde-3-phosphate dehydrogenase. With glucagon as substrate, both enzymes showed similar peptidyl dipeptidase activities with some minor differences in peptide bond specificity. Cathepsins M and B are similar in size, with apparent molecular weights of 30,200 for cathepsin M and 28,800 for cathepsin B, and in amino acid composition and carbohydrate content. Each contains approximately 2-3 equivalents/mol glucosamine, 3 equivalents/mol mannose, and no fucose or galactosamine. They also show similar microheterogeneity in sodium dodecylsulfate-gel electrophoresis and isoelectric focusing; this microheterogeneity is probably related to differences in glycosylation. Extensive homology in primary structure for the two proteins was indicated by the similar patterns of peptides formed on digestion with trypsin.
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PMID:Purification and properties of rabbit liver cathepsin M and cathepsin B. 406 7

It is known that the serum level of glycylproline aminopeptidase (Gly-Pro-AP) is decreased in the patients with rheumatoid arthritis. In the present study, the serum levels of various hydrolytic enzymes were tested in such patients. In comparison to the controls, many enzymes, including Ala-AP, Ser-AP, Phe-AP, Gly-Pro-AP, Gly-Pro-Leu-AP, dipeptidyl carboxypeptidase (angiotensin converting enzyme), and esterase, showed significantly decreased activities in the patients' sera. Only the activity of Trp-AP was significantly increased. Of these enzymatic activities in serum, several ones including those of Gly-Pro-AP, Ala-AP, Phe-AP, trypsin-like enzyme, and esterase, were significantly correlated with the severity of the disease. Although a part of these findings are compatible with previous observations, they suggest rather more extensive disorders of peptide metabolism in this immunological disease.
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PMID:Decreased serum levels of various hydrolytic enzymes in patients with rheumatoid arthritis. 608 27

Roles of kininogens in the development of potentiation of carrageenan edema in rats by angiotensin converting enzyme (ACE, = kininase II) inhibitor were studied. Carrageenan-induced edema was potentiated by oral administration of YS980, an ACE inhibitor, at a dose of 1 mg/kg 0.5 h before carrageenan injection. Intravenous injection of bromelain, a kininogen (KGN) depletor, at 3 mg/kg produced reduction of plasma KGN (total and high molecular weight KGN), which resulted in suppression of carrageenan edema and suppression of edema potentiation induced by YS980. Even after the plasma KGN level and inflammatory response to carrageenan returned to normal 24 h after the administration of bromelain, the potentiative effect of YS980 on the carrageenan edema remained suppressed. Thus, some factor other than plasma KGN is thought to be involved in the potentiation mechanisms on the carrageenan edema by YS980. Partially purified KGN from rat plasma (0.1 mg/site: liberated 4.4 X 10(-8) g bradykinin eq by trypsin digestion) completely restored the suppressed potentiation to normal by local preinjection to the inflamed site. In addition, such restoration was not observed in the animal in which plasma KGN was reduced 3 h after administration of bromelain. These results suggest that KGN, not only in plasma but also in tissue, play an active role in the development of potentiation of carrageenan edema by ACE inhibitor.
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PMID:Potentiative effect of angiotensin converting enzyme inhibitor on carrageenan edema in rats and the role of tissue kininogen. 609 Jun 35


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