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)

1. Met-enkephalin is degraded by peptidases present in the hemolymph fluid and hemocyte membrane suspension of Mytilus edulis. Degradation of Met-enkephalin is rapid in the fluid and slower in the membrane. 2. Aminopeptidase activity is bestatin sensitive in hemocyte membrane and highest in the fluid of the hemolymph, which appears to have a component which is insensitive to inhibitor. 3. ACE activity is found only in the fluid of the hemolymph. 4. Carboxypeptidase and NEP (CD10: "enkephalinase") are membrane bound and the former appears to predominate. Phosphoramidon inhibits not only NEP, as expected, but the invertebrate carboxypeptidase as well.
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PMID:Degradation of Met-enkephalin by hemolymph peptidases in Mytilus edulis. 133 5

We investigated the activity of bombesin (BN), neuromedin-C (NM-C) and neuromedin-B (NM-B) on serotonin (5-HT) release and reuptake in rat hypothalamus (HYP) in vitro. BN and NM-C but not NM-B (all 1 microM) decreased K+ evoked 3H-5-HT release from superfused HYP slices by 25%. Bacitracin (BCN, 2 micrograms/ml), a nonspecific peptidase inhibitor, reversed the inhibitory effect of BN on K+ evoked 3H-5-HT release. Phosphoramidon (PAN, 10 microM) an endopeptidase 24.11 inhibitor, abolished the inhibitory effect of BN, but not NM-C, on K+ evoked 3H-5-HT release. The peptidyl dipeptidase A inhibitor enalaprilat (ENP, 10 microM), enhanced both BN and NM-C inhibition of 3H-5-HT release. Bestatin (BST, 10 microM) had no effect on BN or NM-C inhibitory activity on 3H-5-HT release. Neither BN, NM-C nor NM-B affected reuptake of 3H-5-HT into HYP synaptosomes alone or in combination with any of the peptidase inhibitors, nor did these peptides alter the ability of fluoxetine to inhibit 3H-5-HT uptake. These data suggest: a) that BN-like peptides may alter neurotransmission in the HYP by acting presynaptically on the 5-HT release mechanism; b) a similarity in the structural requirements for the BN induced inhibition of 5-HT release and BN evoked thermoregulatory disturbances; and c) that peptidases may selectively augment or reduce pharmacologic activity of BN-like peptides upon CNS administration.
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PMID:Inhibition of serotonin release by bombesin-like peptides in rat hypothalamus in vitro. 254 89

To determine the role of endogenous neutral endopeptidase (NEP) (also called enkephalinase, EC 3.4.24.11) in regulating neurotensin-induced airway contraction, we used phosphoramidon, a specific NEP inhibitor, in the guinea pig. In studies in vitro, neurotensin and the COOH-terminal fragment neurotensin-(8-13) contracted strips of bronchial smooth muscle in a concentration-dependent fashion (P less than 0.001). In contrast, the NH2-terminal fragment neurotensin-(1-11) and the COOH-terminal fragment neurotensin-(12-13), the main fragments of neurotensin hydrolysis by NEP, had no effect. Phosphoramidon (10(-5) M) did not change resting tension but shifted the concentration-response curves to neurotensin to lower concentrations (P less than 0.001), whereas inhibitors of kininase II, aminopeptidases, serine proteases, and carboxypeptidase N were without effect. Removing the epithelium increased the contractile response to neurotensin (P less than 0.001), and phosphoramidon further increased the response to neurotensin in these tissues (P less than 0.001). Similar results were obtained in studies in vivo using aerosolized neurotensin and phosphoramidon. These results suggest that endogenous NEP in the airways modulates the effects of neurotensin on airway smooth muscle contraction by inactivating the peptide.
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PMID:Neutral endopeptidase modulates neurotensin-induced airway contraction. 274 98

The relative contributions of three kininases to total urinary kininase activity were determined by measuring the hydrolysis of kinins in the presence and absence of inhibitors of kininase I (2-mercaptomethyl-3-guanidinoethylthiopropanoic acid; MGTA), kininase II (captopril) and neutral endopeptidase 24.11 (NEP or enkephalinase A; phosphoramidon). Surprisingly, NEP was responsible for 68 +/- 2% (N = 18) of the total kininase in the rat while kininase I and II contributed only 9 +/- 0.4% and 23 +/- 1%, respectively. To study the effects of NEP inhibition on renal function, phosphoramidon (110 or 330 micrograms/hr/kg; N = 6) or saline (0.1 microliter/min; N = 6) was infused into rats. Urinary kinins, kininases, renal blood flow (RBF), glomerular filtration rate (GFR), UNaV, UKV and UV were measured during control, experimental and recovery periods. Phosphoramidon at the higher dose decreased total urinary kininase activity from 284 +/- 49 to 58 +/- 5 ng/min/kg (77%, P less than 0.01), and increased kinin excretion from 74 +/- 9 to 128 +/- 21 pg/min/kg (73%, P less than 0.02), UV from 72 +/- 10 to 82 +/- 10 microliters/min/kg (15%, P less than 0.01) and UNaV from 12 +/- 2 to 17 +/- 3 microEq/min/kg (37%, P less than 0.02), while BP, RBF, GFR and UKV did not change. 125I-Tyr0-bradykinin infused into the aorta did not appear in the urine intact during simultaneous phosphoramidon and captopril administration. This is the first demonstration of NEP having a major role in the catabolism of kinins. The increase in UNaV and UV after phosphoramidon administration may be due to the inhibition of intrarenal kinin destruction.
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PMID:Role of renal endopeptidase 24.11 in kinin metabolism in vitro and in vivo. 282 46

alpha-Human atrial natriuretic peptide, a 28-amino-acid-residue peptide, was rapidly hydrolysed by pig kidney microvillar membranes in vitro, with a t1/2 of 8 min, comparable with the rate observed with angiotensins II and III. The products of hydrolysis were analysed by h.p.l.c., the pattern obtained with membranes being similar to that with purified endopeptidase-24.11 (EC 3.4.24.11). No hydrolysis by peptidyl dipeptidase A (angiotensin I converting enzyme, EC 3.4.15.1) was observed. The contribution of the various microvillar membrane peptidases was assessed by including specific inhibitors. Phosphoramidon, an inhibitor of endopeptidase-24.11, caused 80-100% suppression of the products. Captopril and amastatin (inhibitors of peptidyl dipeptidase A and aminopeptidases respectively) had no significant effect. Hydrolysis at an undefined site within the disulphide-linked ring occurred rapidly, followed by hydrolysis at other sites, including the Ser25--Phe26 bond.
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PMID:The hydrolysis of alpha-human atrial natriuretic peptide by pig kidney microvillar membranes is initiated by endopeptidase-24.11. 303 78

The metabolism of Met-enkephalin and cholecystokinin (CCK) 8-(sulfated) by intact microslices was studied in rat brain regions. Incubation of brain slices with Met-enkephalin (400 microM) resulted in a linear rate of disappearance of parent peptide and appearance of metabolic fragments whose rate of accumulation was specific to brain region. The degradative rate (pmol/min/mg of protein) of Met-enkephalin was high in caudate-putamen (5,160 +/- 120) and lower in nucleus accumbens (3,630 +/- 110) and frontal cortex (3,180 +/- 120). Inhibition of aminopeptidases decreased Met-enkephalin degradation (50-97% vs. control) in frontal cortex but was less effective in caudate-putamen (20-34%). Tyr-Gly-Gly and Phe-Met were recovered in caudate-putamen and nucleus accumbens, whereas negligible quantities of these fragments were recovered from frontal cortex. Phosphoramidon, an inhibitor of neutral endopeptidase 24.11, decreased Met-enkephalin degradation in caudate-putamen (14%) but had no effect on that in frontal cortex. A cocktail of bestatin or leuhistin (inhibitors of aminopeptidases), phosphoramidon, and captopril (an inhibitor of angiotensin converting enzyme) protected Met-enkephalin from degradation (recovery > 95%) in caudate-putamen. CCK 8-(sulfated) degradation on slices from caudate-putamen, nucleus accumbens, and frontal cortex was not altered by inhibitors of neutral endopeptidase 24.11, metalloendopeptidase 24.15, angiotensin converting enzyme, or thiol proteases. Inhibitors of either aminopeptidases or serine proteases produced small reductions (13-30%) in CCK degradation in each region. These data provide evidence for regional and structural specificity in terminating the actions of neuropeptides.
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PMID:Regional metabolism of Met-enkephalin and cholecystokinin on intact ratbrain slices: characterization of specific peptidases. 759 77

Human skin fibroblasts produce in culture an elastase-type metalloendopeptidase which can hydrolyze synthetic elastase-substrate as Suc ala3 pNA and degrade also elastic fibers when injected in the dermis or deposited on cryostat-skin sections [3-8]. Here we describe further characterization of this enzyme activity using metallo-enzyme inhibitors as well as specific inhibitors of known Zn-endopeptidases such as angiotensin converting enzyme and enkephalinase. Among the metal complexing agents tested only EDTA and o-phenanthrolin could inhibit the elastase-type activity of fibroblasts, other known metal complexing substances capable of reacting with Zn (2,2' dipyridyl, diethyl dithiocarbamate and other metal chelators) were ineffective as was also lisinopril, an ACE-inhibitor [13]. Phosphoramidon and retrothiorphan, specific enkephalinase inhibitors [12] did strongly inhibit the elastase type activity of human skin fibroblasts (IC50 10(-8) M). Ethanol at conc-s used to dissolve organic, water insoluble inhibitors (50-100 microliters/ml) strongly inhibited the enzyme. It appears that the metal prosthetic group of fibroblast elastase (presumably, Zn) is not directly accessible to several of the low M. Wt complexing agents. The efficiency of enkephalinase inhibitors suggest a possible relationship between this enzyme and fibroblast-elastase.
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PMID:[Elastase-type endopeptidase of fibroblasts. Effect of metalloprotease inhibitors]. 775 12

The capillary endothelial cells of the median eminence represent a potential site for the degradation/modification of both circulating and hypothalamic peptides passing through the hypophysial portal system toward the pituitary. This study examines endothelial cell peptidase expression in vitro by monitoring the metabolism of gonadotropin-releasing hormone (GnRH) by cultured endothelial cells from sheep median eminence. Cleavage of GnRH by median eminence endothelial cell membranes generated GnRH1-5 as the primary stable product, which was then degraded to GnRH1-3 and free amino acids. Degradation of GnRH was completely inhibited by TPCK, ZnCl2 and N-ethylmaleimide, and partially inhibited by EDTA and by a specific inhibitor of the metalloendopeptidase EC 3.4.24.15, CFP-AAY-pAB. Interestingly, an increase in GnRH1-9 production was seen with the latter inhibitors, suggesting a two-step mechanism of GnRH degradation involving a primary cleavage at the Pro9-Gly10-NH2 bond, inhibitable by TPCK, ZnCl2, and NEM, followed by cleavage by EC 3.4.24.15 to generate GnRH1-5. Phosphoramidon and angiotensin converting enzyme inhibitors (as well as other non-specific inhibitors) were without effect, indicating that endopeptidase EC 3.4.24.11 and angiotensin converting enzyme are not involved. Neither bovine aortic endothelial cell nor AtT-20 cell membranes exhibited this pattern of peptidase activity. Degradation of GnRH by intact median eminence endothelial cells in culture was also observed, suggesting an extracellular orientation for these enzymes; the potential role of such peptidases in the fine regulation of both pituitary function and local blood flow is currently under investigation.
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PMID:Characterization of membrane-associated peptidase activities expressed by endothelial cells of the ovine median eminence. 804 22

Tachykinin-related peptides (TRP) are widely distributed in the CNS of insects, where they are likely to function as transmitters/modulators. Metabolic inactivation by membrane ecto-peptidases is one mechanism by which peptide signalling is terminated in the CNS. Using locustatachykinin-1 (LomTK-1, GPSGFYGVRamide) as a substrate and several selective peptidase inhibitors, we have compared the types of membrane associated peptidases present in the CNS of four insects, Locusta migratoria, Leucophaea maderae, Drosophila melanogaster and Lacanobia oleracea. A neprilysin (NEP)-like activity cleaving the G-F peptide bond was the major LomTK-1-degrading peptidase detected in locust brain membranes. NEP activity was also found in Leucophaea brain membranes, but the major peptidase was an angiotensin converting enzyme (ACE), cleaving the G-V peptide bond. Drosophila adult head and larval neuronal membranes cleaved the G-F and G-V peptide bonds. Phosphoramidon inhibited both these cleavages, but with markedly different potencies, indicating the presence in the fly brain of two NEP-like enzymes with different substrate and inhibitor specificity. In Drosophila, membrane ACE did not make a significant contribution to the cleavage of the G-V bond. In contrast, ACE was an important membrane peptidase in Lacanobia brain, whereas very little neuronal NEP could be detected. A dipeptidyl peptidase IV (DPP IV) that removed the GP dipeptide from the N-terminus of LomTK-1 was also found in Lacanobia neuronal membranes. This peptidase was a minor contributor to LomTK-1 metabolism by neuronal membranes from all four insect species. In Lacanobia, LomTK-1 was also a substrate for a deamidase that converted LomTK-1 to the free acid form. However, the deamidase was not an integral membrane protein and could be a lysosomal contaminant. It appears that insects from different orders can have different complements of neuropeptide-degrading enzymes. NEP, ACE and the deamidase are likely to be more efficient than the common DPP IV activity at terminating neuropeptide signalling since they cleave close to the C-terminus of the tachykinin, a region essential for maintaining biological activity.
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PMID:Inactivation of a tachykinin-related peptide: identification of four neuropeptide-degrading enzymes in neuronal membranes of insects from four different orders. 1189 92