Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.24.11 (CD10)
 9,792 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A double-stranded synthetic oligonucleotide that codes for an amino acid sequence specifically recognized and cleaved by the endopeptidase, renin, was inserted into a plasmid expression vector. The double-stranded oligonucleotide was placed at the junction between the sequences coding for two distinct domains of a fusion protein. The vector used for this analysis expressed a 190-kD Epstein-Barr virus membrane antigen (EBV-MA)-beta-galactosidase (beta-gal) fusion protein (Beisel et al., 1985). The resultant novel protein product expressed by the new construction can be cleaved specifically by renin to yield two distinct polypeptides, EBV-MA and beta-gal, corresponding to the two domains of the original fusion protein product.
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PMID:Site-specific cleavage of a fusion protein by renin. 282 77

The specificity of action of bovine brain cortex cathepsin D (EC 3.4.23.5) and high-Mr aspartic endopeptidase (EC 3.4.23.-) was studied with the vasoactive peptides renin substrate tetradecapeptide (RSTP), substance P (SP), and angiotensins I and II, and with model peptides--Lys-Pro-Ala-Glu-Phe-Phe (NO2)-Ala-Leu (I), Gly-Gly-His-Phe (NO2)-Phe-Ala-Leu-NH2 (II), and Abz-Ala-Ala-Phe-Phe-pNA (III). Cerebral aspartic peptidases show identical substrate specificity, cleaving the Leu10-Leu bond in RSTP and Phe-Phe in SP and peptide I-III, and not splitting angiotensins I and II. Because of the higher catalytic efficiency of cathepsin D (Kcat value), the specificity constants (Kcat/Km) for cathepsin D-catalyzed hydrolysis of substrates 1-111 are much higher than those for the high-Mr enzyme. High-Mr aspartic peptidase shares a number of properties with cathepsin D (sensitivity to pepstatin, substrate specificity, pH activity profile) and shows partial immunological identity; however, high-Mr aspartic peptidase has a specific activity 7-10 times lower than that of cathepsin D. The kinetic parameters of proteolysis of model peptides presented indicate that the high-Mr enzyme may be a complex of a single-chain cathepsin D with another polypeptide, although the possibility that it is an independent aspartic peptidase cannot be excluded.
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PMID:Substrate specificity of cerebral cathepsin D and high-Mr aspartic endopeptidase. 328 13

One of the esteroproteinases present in the submandibular glands of female mice was purified and characterized. The enzyme, designated proteinase F in this report, had a pI value of 4.6 and a molecular weight of 27600, being comprised of two subunits of 10000 and 18000 daltons. The amino acid composition of proteinase F resembled that of the epidermal growth factor-binding protein, but antiserum against proteinase F only reacted weakly against the binding protein. Proteinase F had an optimum pH at around 9.0 and was strongly inhibited by Cu2+ and Hg2+ (42 and 76% inhibition, respectively, at a concentration of 4 x 10(-6) M). It was also inhibited by aprotinin, phenylmethylsulfonylfluoride, iodoacetamide, leupeptin, antipain, and benzamidine but neither by trypsin inhibitors from pancrease, soybean, or ovomucoid, nor by TLCK, TPCK, and epsilon-amino-n-caproic acid. Although its actual physiological function has yet to be determined, these properties indicate that proteinase F is a new enzyme, being distinguished from known proteinases, kallikrein, plasmin, trypsin, chymotrypsin, tonin, angiotensin-converting enzyme, proteinase A (beta-nerve growth factor endopeptidase), proteinase D (epidermal growth factor-binding protein), P-esterase, renin A, and renin C. Proteinase F was present in the submandibular glands of female mice more abundantly than in those of males, but it increased in males following castration. Thus, proteinase F appears to be affected by male hormones in vivo.
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PMID:A new esteroproteinase (proteinase F) from the submandibular glands of female mice. 633 33

Secretory vesicles purified from the neural and intermediate lobes of the bovine pituitary contain acidic endopeptidases which are capable of converting renin tetradecapeptide (RTD) substrate to Angiotensin I (AI). Preliminary characterization of the neurosecretory vesicle (NSV) endopeptidase showed that it had a pH optimum of 4.0, and unlike renin was inactive at pHs greater than 6.0. It is inhibited by 10(-6) M pepstatin A, but not by PMSF, leupeptin, PMBS, or the specific renin inhibitor H-142. This NSV endopeptidase differed from cathepsin D in that it was unable to degrade alpha-casein, but was quite active in generating AI from RTD (Vmax = 5 moles/g protein/hour). No enzyme activity that could convert AI to Angiotensin II could be detected in the NSVs suggesting that the acidic endopeptidase is involved in processing neurosecretory vesicle proteins other than those associated with the renin angiotensin system in the brain.
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PMID:Angiotensin I-generating acid endopeptidase activity in neurosecretory vesicles isolated from bovine pituitary. 639 22

The dipsogenic activity of two artificial renin substrates, tetradecapeptide and tridecapeptide, was studied. The dose-response curves obtained with these peptides, following intracerebroventricular administration, were similar to that of angiotensin I. The angiotensin II antagonist, Sar1, Ala8-angiotensin II, inhibited the dipsogenic effect of tetradecapeptide, indicating the conversion of the latter peptide into angiotensin II. The lower dipsogenic activity of tridecapeptide points to a conversion of this renin substrate into angiotensin III. Specific inhibition of tetradecapeptide induced drinking by the endopeptidase inhibitor N-acetyl-pepstatin suggests the involvement of an endopeptidase in the conversion of the renin substrates in the brain. Two endopeptidases present in the brain (cathepsin D and renin), were compared with respect to their capacity to generate angiotensin I from artificial renin substrate in vitro. Cathepsin D was active under only acidic pH conditions, whereas renin showed a wider pH range with maximal activity in the non-acidic region. Moreover, cathepsin D did not generate angiotensin I from natural, cerebrospinal fluid-angiotensinogen in vitro, and lacked dipsogenic activity following central administration. Small amounts of renin, however, were able to release angiotensin I from cerebrospinal fluid in vitro. In addition, this enzyme induced high dipsogenic activity upon intracerebroventricular injection. These results support the existence of a functionally active central renin-angiotensin system and provide an argument against the involvement of cathepsin D in the formation of angiotensin I in the brain.
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PMID:Angiotensin generation in the brain and drinking: indications for the involvement of endopeptidase activity distinct from cathepsin D. 702 65

A porcine kidney microsomal metalloendopeptidase has been enriched 3900-fold. Gel filtration on a calibrated Toyo-Soda G-3000 SW column indicated an appropriate molecular weight for the endopeptidase of 88,000 +/- 2000. The purified enzyme is inhibited by a number of synthetic inhibitors of thermolysin. The endopeptidase hydrolyzes the succinyl (Suc)-containing fluorogenic peptide substrate Suc-Ala-Ala-Phe-(7-amino-4-methylcoumarin) at the Ala-Phe position with a Km of 2.9 X 10(-4) M. The endopeptidase also hydrolyzes a variety of peptides including corticotropin, substance P, angiotensin I and II, neurotensin, somatostatin, bradykinin, and the renin tetradecapeptide substrate. The endopeptidase hydrolyzes both [Leu]- and [Met]enkephalin at the Gly-Phe bond.
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PMID:Purification of a membrane-bound metalloendopeptidase from porcine kidney that degrades peptide hormones. 703 58

The generation of angiotensin I from the artificial renin substrate tetradecapeptide by proteolytic enzymes in rat brain tissue was studied. The involvement of endopeptidase activity in the enzymatical cleavage of the renin substrate was inferred from the simultaneous accumulation of both angiotensin I and the complementary tetrapeptide Leu-Val-Tyr-Ser on incubation of tetradecapeptide with rat brain tissue. This endopeptidase activity was active over a pH range of 3.5--7.5. In contrast, cathepsin D released angiotensin I from tetradecapeptide only at acidic pH. The angiotensin I accumulation on incubation of tetradecapeptide with brain endopeptidase activity was only partly inhibited in the presence of an excess of the carboxyl protease inhibitor N-acetyl pepstatin. Further, the brain endopeptidase activity displayed a subcellular localization different from that of acid protease activity. It is concluded that angiotensin I can be generated in the brain by soluble endopeptidases, which are distinct from cathepsin D.
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PMID:Subcellular localization in rat brain of angiotensin I-generating endopeptidase activity distinct from cathepsin D. 703 49

Combined neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE) inhibition produces greater acute hemodynamic effects than either treatment alone. We investigated whether BMS-182657 (BMS), which bears inhibitory activities against both NEP and ACE, elicited similar enhanced effects. BMS inhibited NEP and ACE, in vitro (IC50 = 6 and 12 nM, respectively) and the pressor response to Ang I in rats. In deoxycorticosterone acetate (DOCA)-salt hypertensive rats sensitive to NEP inhibition but not to ACE inhibition, BMS at 100 mumol/kg i.v. lowered mean arterial pressure (MAP) from 180 +/- 6 to 151 +/- 5 mm Hg. In sodium-depleted, spontaneously hypertensive rats (SHR) sensitive to ACE inhibition but not to NEP inhibition, BMS at 100 mumol/kg p.o. lowered MAP from 151 +/- 4 to 123 +/- 5 mm Hg. Cardiomyopathic hamsters with heart failure were administered vehicle or one of the following (30 mumol/kg i.v.): the ACE inhibitor enalaprilat; the NEP inhibitor SQ-28603; or BMS. Enalaprilat and SQ-28603 had minimal hemodynamic effects. BMS decreased left ventricular end-diastolic pressure by 12 +/- 2 and 10 +/- 1 mm Hg and left ventricular systolic pressure by 27 +/- 2 and 23 +/- 3 mm Hg at 30 and 60 min, respectively (P < .05 vs. each other group). These changes were associated with a 40% increase in cardiac output, a 47% decrease in peripheral vascular resistance and a lowering of MAP by 21 +/- 3 mm Hg at 60 min (P < .05 vs. each other group). There were no significant differences in the changes in heart rate or left ventricular stroke work index among the four groups. Hence, BMS-182657 is a dual inhibitor of NEP and ACE, is antihypertensive irrespective of the activity of the renin-angiotensin system and has acute hemodynamic effects in hamsters with heart failure greater than those produced by selective inhibition of NEP or ACE. The NEP and ACE inhibitory activities of BMS-182657 act synergistically and mimic the interaction resulting from combining selective inhibitors of these enzymes.
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PMID:Cardiovascular effects of the novel dual inhibitor of neutral endopeptidase and angiotensin-converting enzyme BMS-182657 in experimental hypertension and heart failure. 747 62

The natriuretic peptide family consists of three members: atrial natriuretic peptide, brain natriuretic peptide, and C-type natriuretic peptide. Atrial and brain natriuretic peptides possess similar effects, causing natriuresis, vasodilation, and suppression of the renin-angiotensin-aldosterone system. C-type natriuretic peptide has been suggested to exert its predominant effect on the vasculature, eliciting vasodilation and inhibiting the proliferation of vascular smooth muscle cells. Numerous studies have broadened our current knowledge of the regulation of natriuretic peptide gene expression, biosynthesis, and secretion, as well as structure of specific receptors. This has led to a better understanding of the renal, cardiovascular, and endocrine actions of natriuretic peptides in both normal and pathophysiological states, including hypertensive disease. Development of nonpeptide neutral endopeptidase inhibitors and antagonists for natriuretic peptide receptors may reveal the range of potential therapeutic application of atrial and other natriuretic peptides in hypertension.
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PMID:The natriuretic peptides in hypertension. 749 58

The acute renal effects of neutral endopeptidase 24.11 (E-24.11) inhibition induced by a single oral dose of sinorphan (100 mg) were investigated in 10 healthy normotensive subjects on normal sodium diet. Sinorphan inhibited 90% of E-24.11 activity and increased plasma atrial natriuretic peptide (ANP) and urinary guanosine 3',5'-cyclic monophosphate (cGMP) by 70 and 100%, respectively. Sinorphan increased urinary sodium output by 50% (P < 0.001) and decreased fractional distal reabsorption by 4% (P < 0.01). Sinorphan increased glomerular filtration rate (GFR) and filtration fraction by 10% 1 h after administration and decreased renal plasma flow by 10%. Mean arterial pressure, renal vascular resistance, plasma aldosterone concentration, and renin activity were unmodified. Sinorphan decreased fractional clearance of neutral dextrans over the 34- to 52-A radius range. Applying the changes along with a hydrodynamic isopore with shunt model, sinorphan significantly increased capillary pressure gradient (delta P; 39 +/- 1 vs. 34 +/- 1 mmHg; P < 0.01), whereas ultrafiltration coefficient was unchanged. In conclusion, endopeptidase inhibition increased endogenous plasma ANP and cGMP generation and induced natriuresis through both an increase in filtered load and a decrease in distal tubular reabsorption of sodium. Sinorphan increases GFR, filtration fraction, and delta P, probably through an increase in efferent over afferent arteriolar resistance ratio.
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PMID:Acute renal effects of neutral endopeptidase inhibition in humans. 751 5


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