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: UNIPROT:P20366 (substance P)
21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The angiotensin-converting enzymes (ACE) are involved in the regulation of the specific maturation or degradation of a number of mammalian bioactive peptides. A carboxydipeptidase similar to mammalian ACE has now been identified in the adult stage of the haematophagous fly, Haematobia irritans exigua (buffalo fly), a close relative of the horn fly of North America. The enzyme was purified by lectin-affinity chromatography and ion-exchange chromatography and migrated as a doublet of 70 kDa upon reducing SDS/PAGE. Unlike mammalian ACE, the fly carboxydipeptidase (HieACE) is not membrane bound. The amino acid sequence of an internal peptide from HieACE and a conserved amino acid region present in all mammalian ACE were used to design degenerate oligonucleotide primers suitable for PCR. A DNA fragment amplified from adult buffalo fly cDNA was used to identify a cDNA clone that encoded the enzyme. The cDNA sequence encodes a carboxydipeptidase with 41-42% amino acid identity to the mammalian testicular ACE. The active-site regions of mammalian ACE are conserved in the deduced amino acid sequence of HieACE. Enzymatically, HieACE is very similar to its mammalian counterparts, with comparable Km and V(max) values for the synthetic substrate, benzoylglycylglycylglycine, and similar patterns of inhibition by EDTA, ACE inhibitor peptide and captopril. HieACE also specifically activates angiotensin I to angiotensin II and degrades other mammalian ACE substrates such as bradykinin, substance P and cholecystokinin-8. In the adult fly, HieACE is expressed in the compound ganglion and in the posterior region of the midgut. Similar to the mammalian system, expression of this enzyme is induced in the maturing male reproductive system, which suggests conservation of ACE function in these species.
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PMID:Cloning and characterisation of angiotensin-converting enzyme from the dipteran species, Haematobia irritans exigua, and its expression in the maturing male reproductive system. 864 80

A soluble 67 kDa angiotensin-converting enzyme (ACE) has been purified by lisinopril-Sepharose affinity column chromatography from adult houseflies, Musca domestica. The dipeptidyl carboxypeptidase activity towards benzoyl-Gly-His-Leu was inhibited by captopril (IC50 50 nM) and fosinoprilat (IC50 251 nM), two inhibitors of mammalian ACE, and was activated by Cl- (optimal Cl- concentration 600 mM). Musca ACE removed C-terminal dipeptides from angiotensin I, bradykinin [Leu5]enkephalin and [Met5]enkephalin and also functioned as an endopeptidase by hydrolysing dipeptideamides from [Leu5]enkephalinamide and [Met5]enkephalinamide, and a dipeptideamide and a tripeptideamide from substance P. Musca ACE was also able to cleave a tripeptide from both the N-terminus and C-terminus of luteinizing hormone-releasing hormone, with C-terminal hydrolysis predominating. Maximal N-terminal tripeptidase activity occurred at 150 mM NaCl, whereas the C-terminal tripeptidase activity continued to rise with increasing concentration of Cl- (0-0.5 M). Musca ACE displays properties of both the N- and C-domains of human ACE, indicating a high degree of conservation during evolution of the substrate specificity of ACE and its response to Cl-.
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PMID:The endopeptidase activity and the activation by Cl- of angiotensin-converting enzyme is evolutionarily conserved: purification and properties of an an angiotensin-converting enzyme from the housefly, Musca domestica. 867 80

1. Microinjection of angiotensin (Ang) II or substance P (SP) into the medial nucleus tractus solitarii (nTS) produces similar decreases in arterial pressure and heart rate. We previously reported that some medial nTS neurons responsive to SP were also excited by Ang II, and that Ang II increased the release of SP from medulla slices. Both electrophysiological and anatomic data suggest that the cardiovascular effects of these peptides may be mediated by a common neuronal pathway consisting of SP-containing vagal afferent fibers with presynaptic Ang II receptors that innervate medial nTS neurons with SP receptors. To evaluate the validity of this model, we established the presynaptic or postsynaptic location of the receptors for Ang II and SP that mediate excitation of medial nTS neurons by determining the capacity of each peptide to activate the cell before and after blocking synaptic transmission in rat dorsal medulla slices. 2. Extracellular recordings were obtained from 55 medial nTS neurons responsive to Ang II or SP in 400-microns horizontal slices of the dorsal medulla. Neuronal excitation by Ang II and SP was tested before, during, and after reversal of synaptic blockade with low-Ca2+ (0.2 mM), high Mg2+ (5 mM) artificial cerebrospinal fluid (aCSF). Elimination of synaptically evoked short latency responses of the neuron to current pulses applied to afferent fibers in the solitary tract (TS) documented blockade of synaptic transmission by low-Ca2+ aCSF. In most cases, the basal firing rate of the cell increased slowly during perfusion with low-Ca2+ aCSF and stabilized after approximately 30 min at a higher level of spontaneous activity. Responses to the peptides and TS stimulation were also documented after synaptic blockade had been reversed by adding aCSF containing 2-mM Ca2+. 3. Of the 55 medial nTS neurons, 41 were responsive to Ang II; whereas, 50 of the 55 cells were responsive to SP. The neurons were divided into three subgroups on the basis of their responsiveness to Ang II and SP. Although most neurons were responsive to both Ang II and SP (n = 36), five other cells were excited only by Ang II, and 14 neurons were activated only by SP. Of the 55 neurons, 26 were also responsive to L-glutamate: 14 of 17 cells responsive to both Ang II and SP, all 5 neurons excited by Ang II but not by SP, and 7 of 10 neurons responsive only to SP were also excited by L-glutamate. The latency of the action potentials evoked by TS stimulation was much shorter in those neurons responsive only to Ang II (3.6 ms) than in cells excited by both Ang II and SP (6.8 ms) or responsive only to SP (7.4 ms). 4. In 21 of the 36 medial nTS neurons responsive to both Ang II and SP, Ang II continued to excite the cell when synaptic responses to TS stimulation were prevented by low-Ca2+ aCSF, but had no effect on the firing rate of the other 15 neurons during synaptic blockade. Excitation induced by Ang II was also prevented in two of the five medial nTS neurons responsive only to Ang II when synaptic transmission in the slice was blocked. Low-Ca2+ aCSF failed to prevent excitation by SP or L-glutamate in all medial nTS cells responsive to these agonists (n = 50 and n = 26, respectively). In contrast to these observations in medial nTS neurons, Ang II-induced excitation was not altered during synaptic blockade in any of the six dmnX cells studied. No responses to SP or L-glutamate were blocked in dmnX neurons, as also seen in the medial nTS. 5. When all medial nTS neurons responsive to Ang II were examined, the latencies of the response to TS stimulation were significantly shorter in those neurons with presynaptic Ang II receptors than in the group of cells with postsynaptic receptors. In addition, neurons with presynaptic Ang II receptors were distributed differently within the medial nTS than cells with postsynaptic Ang II receptors.(ABSTRACT TRUNCATED)
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PMID:Presynaptic or postsynaptic location of receptors for angiotensin II and substance P in the medial solitary tract nucleus. 879 36

Angiotensin-converting enzyme (ACE; EN 3.4.15.1) is a peptidyl dipeptide hydrolase that removes the carboxyl terminal His-Leu from angiotensin I to produce the octapeptide angiotensin II. In addition, ACE inactivates bradykinin, a vasodilator peptide/mediator of inflammation, as well as substance P, enkephalins and endorphins. Because of the importance of ACE and its active site-directed inhibitors in the pathogenesis and treatment of cardiovascular disorders such as hypertension and heart failure, ACE purification and assay are of clinical and commercial, as well as scientific interest. This review summarizes the historical development of ACE purification and assay methods and presents some innovative high-performance liquid chromatography-based techniques developed in our own laboratory for high yield and efficient purification and sensitive and specific assay of ACE.
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PMID:Purification and assay methods for angiotensin-converting enzyme. 881 75

We have purified and characterized human brain endopeptidase 3.4.24.16. The enzyme behaved as a 72 kDa protein and belonged to the metalloprotease family. Human endopeptidase 3.4.24.16 cleaved neurotensin at a unique site at the Pro10-Tyr11 bond, leading to the formation of neurotensin(1-10) and neurotensin(11-13). The kinetic parameters displayed by human endopeptidase 3.4.24.16 towards a series of natural neuropeptides indicated that bradykinin was the most efficiently proteolysed. Angiotensin I, dynorphins 1-8 and 1-9 and substance P also behaved as good substrates while neuromedin N, angiotensin II, leucine and methionine enkephalin and neurokinin A resisted degradation by human endopeptidase 3.4.24.16. We have purified the porcine counterpart of endopeptidase 3.4.24.16 and compared its ability to cleave neurotensin with that of the enzyme from human origin. It appeared that, besides a major production of neurotensin(1-10), an additional formation of neurotensin(1-8) was observed with the pig enzyme, suggesting a cleavage of neurotensin not only at the Pro10-Tyr11 bond but also at the Arg8-Arg9 peptidyl bond. The latter cleavage appeared reminiscent of endopeptidase 3.4.24.15 since this peptidase was reported to cleave neurotensin at the Arg8-Arg9 bond. Our study indicated that neurotensin(1-10) formation by porcine endopeptidase 3.4.24.16 could be potently blocked with the selective endopeptidase 3.4.24.16 dipeptide inhibitor Pro-Ile without interfering with neurotensin(1-8) formation. By contrast, the formation of the latter product was highly potentiated by dithiothreitol and inhibited by the endopeptidase 3.4.24.15 inhibitor Cpp-Ala-Ala-Tyr-pAB, two effects that were not observed for neurotensin(1-10) production. Altogether, our results indicate that porcine endopeptidase 3.4.24.16 cleaves neurotensin at a unique site, leading to the formation of neurotensin(1-10) and that the production of neurotensin(1-8) is due to contaminating endopeptidase 3.4.24.15.
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PMID:Purification and characterization of human endopeptidase 3.4.24.16. Comparison with the porcine counterpart indicates a unique cleavage site on neurotensin. 886 56

Phase I human studies can be used to differentiate a novel agent from existing drugs that influence the same pathway (eg, angiotensin-converting enzyme [ACE] inhibitors). Human forearm vasculature provides a useful experimental model for such studies because antagonism of local effects of agonists on resistance vasculature can be quantified, unconfounded by reflex cardiovascular responses to systemically applied agonists. In this model, inhibition of ACE with enalapril (given orally) or its active metabolite enalaprilat (given into the brachial artery) influences responses to some, but not all, vasoactive peptides that are substrates of ACE in vitro. Vasoconstrictor responses to angiotensin I (A I) are antagonized, while vasodilator responses to bradykinin are potentiated. Responses to vasoactive intestinal peptide (VIP), substance P (SP), and atrial natriuretic peptide (ANP) are unaltered by ACE inhibition. Vasodilator responses to bradykinin are antagonized by the B2-receptor icatibant and are blunted (but not abolished) by inhibition of the L-arginine/NO pathway with L-NG-monomethyl arginine. In contrast to inhibition of ACE with enalapril, blockade of the AT1 receptor with losartan results in similar inhibition of vasoconstrictor responses to both A I and angiotensin II but has no significant effect on the vasodilator action of bradykinin. The implication is that losartan provides more specific blockade of the renin-angiotensin pathway than does inhibition of ACE. The in vivo methods described in the study confirm the mechanistically relevant differentiation between AT1-receptor antagonism and ACE inhibition in humans.
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PMID:Angiotensin II-receptor (AT1) blockade in the human forearm. 891 43

Sheep mast cell proteinase 1 (SMCP-1), which is abundantly expressed in gastrointestinal but not skin mast cells, was isolated and its substrate specificity was investigated. Peptide substrates, including angiotensin I, substance P, bradykinin and oxidized insulin B chain were hydrolysed at P1 Phe, Leu or Tyr residues, conforming to the known chymotrypsin-like properties of the enzyme. However, SMCP-1 was found to hydrolyse some chromogenic substrates with P1 Lys and Arg residues. The enzyme also demonstrated trypsin-like activity against protein substrates, cleaving BSA at Lys114-Leu115, Lys238-Val239, Lys260-Tyr261 and Lys376-His377. Bovine fibrinogen beta-chain was cleaved at Lys28-Lys29. To ensure homogeneity of the enzyme, the ratio of chymotrypsin-like to trypsin-like activity was observed; it was found to be constant during purification and between different preparations of SMCP-1. Treatment of SMCP-1 with a range of inhibitors decreased chymotrypsin-like and trypsin-like activities by similar extents, supporting the assertion that both activities are the property of a single enzyme. In terms of activity, and by N-terminal amino acid sequencing, SMCP-1 strongly resembles the similarly dual-specific bovine duodenal proteinase, duodenase. It is proposed that SMCP-1 and duodenase represent a new class of ruminant chymases with unusual dual specificities.
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PMID:Sheep mast cell proteinase-1: characterization as a member of a new class of dual-specific ruminant chymases. 903 51

An intracellular oligopeptidase from Lactobacillus paracasei Lc-01 has been purified to homogeneity by Fast Flow Q Sepharose, hydroxyapatite, and Mono Q chromatography. The molecular mass of the enzyme was determined to be 140 kDa by gel filtration and approximately 30 kDa by sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis and SDS-capillary electrophoresis. The pI of the enzyme was at pH 4.5. The enzyme expressed maximum activity at pH 8.0 and 40 degrees C. Oligopeptidase activity on bradykinin was inhibited strongly by 1,10-phenantroline and EDTA and partly by p-chloromercuribenzoic acid but not by phosphoramidon or phenylmethylsulfonyl fluoride. Marked inhibition by beta-casein fragment 58 to 72 was demonstrated. The enzyme showed neither general aminopeptidase nor caseinolytic activity, and it degraded only oligopeptides between 8 and 13 amino acids. The enzyme readily hydrolyzed the Phe-Ser and Pro-Phe bonds of bradykinin; the Phe-His bond of angiotensin I; the Pro-Gln, Gln-Phe, and Phe-Gly bonds of substance P; and the Pro-Tyr bond of neurotensin. Weak activity toward the Ala-Tyr and Pro-Ser bonds of alpha(s1)-casein fragment 157 to 164, was observed. The N-terminal amino acid sequence of the oligopeptidase showed a high degree of homology to the lactacin B inducer from Lactobacillus acidophilus.
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PMID:Characterization of an intracellular oligopeptidase from Lactobacillus paracasei. 909 25

The presence in insect tissues of peptides with structural similarities to angiotensin I and to bradykinin, the two best known substrates of mammalian angiotensin-converting enzyme, has not been reported. As part of our study to identify potential substrates for insect angiotensin-converting enzyme, we have investigated the susceptibility of a number of known insect peptide hormones and neurotransmitters to hydrolysis by Musca domestica angiotensin-converting enzyme. Insect peptides belonging to the red pigment-concentrating hormone, leucokinin, locust tachykinin, and depolarizing peptide families were hydrolyzed by housefly angiotensin-converting enzyme, whereas proctolin and crustacean cardioactive peptide were not substrates. Cus-DP II, LK I, LK II, and Lom-TK I were all cleaved at the penultimate C-terminal peptide bond to release a dipeptide amide as a major fragment with Km values of 94 +/- 11, 634 +/- 8, and 296 +/- 35 microM for Cus-DP II, LK I, and Lom-TK I, respectively. The ability of insect angiotensin-converting enzyme to hydrolyze C-terminally amidated peptides in vitro might be of functional significance because the enzyme has been localized to neuropile regions of the insect brain and is present in the hemolymph of houseflies.
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PMID:Hydrolysis of insect neuropeptides by an angiotensin-converting enzyme from the housefly, Musca domestica. 911 51

The effect on thermonociceptive threshold of intrathecally (i.t.) administered angiotensin II (Ang II) was assessed in the rat tail-flick test. Rats were pretreated, 15 min earlier, with i.t. naloxone (opiate antagonist), losartan (Ang II selective antagonist at AT1 receptor) or [Sar1, Leu8] Ang II (non selective Ang II receptor antagonist) to define the mechanism of action and the nature of the receptor subtype. Ang II (0.65-6.5 nmol) induced antinociceptive effects that peaked at 1 min post-injection and returned to baseline after 5-10 min. Naloxone (10 microg) completely inhibited the response to 6.5 nmol Ang II. Losartan (65 pmol) and [Sar1, Leu8] Ang II (6.5 nmol) blocked the antinociception induced by Ang II but were inactive against [MePhe7]neurokinin B. Furthermore, losartan failed to affect the hyperalgesic responses induced by substance P (6.5 nmol) or [beta-Ala8]neurokinin A (6.5 nmol). This study provides the first functional evidence that Ang II inhibits the transmission of thermal nociceptive information through an endogenous opioid mechanism and the activation of an AT1 receptor in the rat spinal cord.
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PMID:Effect of angiotensin II on a spinal nociceptive reflex in the rat: receptor and mechanism of action. 924 20


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