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)

Vasoactive peptides contain a high proportion of proline residues which make them resistant to hydrolysis by many peptidases. However, post proline cleaving enzyme (PPCE; EC 3.4.21.26), a proline specific endopeptidase which specifically hydrolyzes internal peptide bonds on the carboxyl side of proline residues, has been shown to inactivate numerous vasoactive peptides including angiotensins, kinins, substance P, vasopressin and oxytocin. In order to determine whether PPCE could be involved in vascular metabolism of vasoactive peptides, we carried out localization and characterization studies of PPCE-like activity in hog aorta and mesenteric artery. PPCE was assayed fluorometrically at pH 7.0 using the specific PPCE substrate CBZ-Gly-Pro-4-methyl-coumarinylamide. The subcellular distribution of vascular PPCE was essentially the same as that of the cytosolic marker enzyme lactic dehydrogenase (LDH). PPCE was enriched six-fold in the cytosolic fraction (11.4 +/- 2.7 units/mg) and unlike the plasma membrane-bound proline specific exopeptidase dipeptidyl-(amino)peptidase IV (DAP IV; EC 3.4.14.5), little or no activity could be detected in the microsomal or plasma membrane fractions. Similar to PPCE characterized from other sites, vascular PPCE was stabilized and activated by dithiothreitol and EDTA, and inhibited by DFP, p-chloromercuriphenyl sulfonic acid, L-1-tosylamido-2-phenylethylchloromethyl ketone, Cu++, Ca++, and Zn++. Vascular PPCE was unaffected by inhibitors of trypsin and kallikrein (Aprotinin, ABTI), aminopeptidase M (bestatin, amastatin), neutral endopeptidase (phosphoramidon), angiotensin I converting enzyme (captopril) or carboxypeptidase N (MERGETPA). These data demonstrate that PPCE is present in vascular endothelium and/or smooth muscle.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Vascular, post proline cleaving enzyme: metabolism of vasoactive peptides. 354 18

Neuronal and astroblast-rich cultures from rat brain degrade exogenously added substance P. The rate of degradation is decreased by diisopropylfluorophosphate, phosphoramidon and bacitracin, but not by N-ethylmaleimide or bestatin. When diisopropylfluorophosphate, phosphoramidon and bacitracin are simultaneously present in the culture medium, the degradation of substance P is completely inhibited. These results indicate that the hydrolysis of substance P by intact cells is catalyzed by the post-proline dipeptidylaminopeptidase (EC 3.4.14.5), the thermolysin-like metallopeptidase ("enkephalinase", EC 3.4.24.11) and a yet uncharacterized bacitracin-sensitive activity. While the thermolysin-like metallopeptidase is mainly associated with glial cells, the specific activity of the other enzymes is five times higher in the neuronal culture.
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PMID:Degradation of substance P by neurones and glial cells. 608 91

Dipeptidylpeptidase IV (EC 3.4.14.5), an enzyme which metabolizes substance P, is present in crude homogenates of hog mesenteric artery and aorta. Its subcellular localization is closely correlated with the plasma membrane marker enzyme 5'-nucleotidase (EC 3.1.3.5) in addition to the kinin and angiotensin metabolizing enzymes angiotensin I converting enzyme (EC 3.4.15.1) and aminopeptidase M (EC 3.4.11.2). The highest level of dipeptidylpeptidase IV is found on the surface membrane-enriched fraction and is immunologically identical to the kidney brush border-bound enzyme. Vascular dipeptidylpeptidase IV sequentially removes the N-terminal Arg1-Pro2 and Lys3-Pro4 dipeptides of substance P and exposes the biologically active C-terminal heptapeptide product to rapid degradation by vascular aminopeptidases.
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PMID:Mesentery vascular metabolism of substance P. 618 94

Dipeptidyl peptidase IV is a very specific protease that attracts growing scientific interest during the last few years. The enzyme has been purified to homogeneity from various human tissues. Histochemically, this protease is found at certain border lines of many organ compartments, as in the proximal tubuli of kidney, in the bile canaliculi of liver, in the capillary endothel, or in the myofibroblasts of placenta. In the blood, especially T-helper lymphocytes contain this enzyme. Dipeptidyl peptidase IV seems to be predestinated for regulatory functions, because it is located on the outer membranes of these cells. The peptidase very specifically degrades substance P. Thus, it is discussed whether the system substance P/dipeptidyl peptidase IV is involved in the regulation of blood pressure, especially in the placenta. On the other hand, the specific attack of the peptidase on the alpha-chain of monomeric fibrin considerably reduces the clotting potency of these molecules. Therefore, dipeptidyl peptidase IV may also be involved in the regulation of blood coagulation in intact vessels, especially because the capillary endothel is lined with this enzyme. The plasma zinc concentration seems to influence the peptidase activity. An increase in plasma zinc stimulates various factors that promote blood clotting.
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PMID:[Has dipeptidyl peptidase IV an effect on blood pressure and coagulation?]. 619 52

Substance P is rapidly converted by enzyme(s) in human plasma to des-[Arg1Pro2]-substance P (fragment 3-11) and to des-[Arg1Pro2Lys3Pro4]-substance P (fragment 5-11). These metabolites were isolated by HPLC and partially sequenced. No evidence was obtained for deamidation of substance P in plasma or for the formation of the N-terminal tetrapeptide [Arg-Pro-Lys-Pro]. The data suggest that substance P is metabolized in human plasma by an enzyme with the specificity of dipeptidyl-aminopeptidase IV. Consistent with this hypothesis, the rate of degradation of substance P measured with an antibody directed against the N-terminal region is 2-3-fold greater than measured with a C-terminally directed antibody. The degrading activity of plasma was purified 522-fold and was eluted from a gel filtration column in the molecular weight zone 150 000-170 000 and from a chromatofocusing column in the pH range 4.5 to 5.5.
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PMID:Conversion of substance P to C-terminal fragments in human plasma. 619 14

Incubation of substance P in human plasma at 37 degrees C resulted in rapid conversion to des (Arg1-Pro2) substance P (fragment 3-11) and to des (Arg1-Pro2-Lys3-Pro4) substance P (fragment 5-11). The metabolites were purified by high-performance liquid chromatography and identified by sequence analysis. These data are consistent with the hypothesis that substance P is metabolized by enzyme(s) with the specificity of dipeptidyl aminopeptidase IV (EC 3.1.14.5). Analysis by high-performance liquid chromatography of plasma extracts following intravenous infusion of Substance P (300-350 nmoles) into anaesthetized rats showed that the peptide was cleared from the circulation within 1-2 minutes. No circulating metabolites could be identified.
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PMID:Metabolism of substance P in human plasma and in the rat circulation. 620 88

Proline-containing dipeptidyl-4-nitroanilides have been synthesised and subjected to dipeptidyl peptidase IV-catalysed hydrolysis at high enzyme concentrations to collect information on the conformational specificity of the enzyme active site for a nonscissile bond. Descriptions of the biphasic kinetics were carried out in terms of cis/trans interconversion of the substrates. The results show that the enzyme can cleave only the trans-conformation of the substrate. The competitive inhibition by Gly-Pro-OH and Ala-Pro-OH is also specific for the trans form of the dipeptides. The interpretation of the results obtained from these kinetic studies has led to proposals for the stepwise cleavage of biologically active peptides like substance P and beta-casomorphine by dipeptidyl peptidase IV.
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PMID:The conformation around the peptide bond between the P1- and P2-positions is important for catalytic activity of some proline-specific proteases. 634 Jul 41

Dipeptidyl peptidase IV (dipeptidyl-peptide hydrolase, EC 3.4.14.5), an enzyme that participates in the catabolism of bradykinin and Substance P as well as the post-translational processing of various other peptides, has been purified from human and pig kidney. The assay reaction involved the cleavage of p-nitroaniline (pNA) from various dipeptidyl p-nitroanilides. The specific activities of the human and pig enzyme (with Gly-Pro-pNA at pH 7.6) were 49.2 and 45.8, respectively. The dependence of initial reaction velocity on substrate concentration was determined for a variety of dipeptidyl p-nitroanilides over the concentration range 0.05 to 2.0 mM. Most of the substrates tested produced significant non-hyperbolic behavior for the function v vs. S at concentrations above 0.5 mM. As to differences between the two enzymes, the pig enzyme exhibited featureless (i.e., hyperbolic) behavior with Glu-Pro-pNA concentrations as high as 2.0 mM, whereas the human enzyme produced significant non-hyperbolic behavior for the function v vs. S, beginning at S = 0.4 mM. Thus, the human and pig dipeptidyl peptidases IV are kinetically distinct enzyme forms.
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PMID:Kinetic investigation of the hydrolysis of aminoacyl p-nitroanilides by dipeptidyl peptidase IV from human and pig kidney. 636 69

In the human placenta, besides the fetal blood vessel system a second extravascular contractile system exists. It is localized in the chorionic plate and runs in a longitudinal direction and adjacent to fetal blood vessels into the stem villi, where it forms perivascular contractile sheaths. Characteristically, cells of the extravascular contractile system are extremely long and spindle-shaped and give rise to fine cell processes, by which they obviously contact each other or insert into the basement membrane of the trophoblast. They show immunoreactivity with desmin, vimentin, alpha-actin, myosin, nitric oxide synthase type I (brain form) and dipeptidyl peptidase IV. The ultrastructure suggests that cells of the extravascular contractile system are related to smooth muscle cells, including subpopulations with myofibroblastic features. In stem villi a few cells are nitric oxide synthase type I immunoreactive. These cells are thought to be specialized smooth-muscle-like cells of the extravascular contractile system or cells of the extravascular contractile system related to paraneurons that generate nitric oxide, which, in turn, may modulate the tone of perivascular contractile sheaths. The high dipeptidyl peptidase IV activity suggests that modulation of the extravascular contractile system may also occur by substance P.
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PMID:The extravascular contractile system in the human placenta. Morphological and immunocytochemical investigations. 753 54

A recent study determined that cultured human skeletal muscle adult myoblasts, myotubes, and fibroblasts degraded angiotensins and kinins via neutral endopeptidase-24.11 (NEP-24.11: EC 3.4.24.11) and aminopeptidase N (APN: EC 3.4.11.2). Due to the possible importance of other peptides to skeletal muscle blood flow and function, the present study looked specifically at the metabolism of the neurokinins substance P (SP) and neurokinin A (NKA) by skeletal muscle peptidases. The results show that SP is degraded not only by NEP-24.11, but also sequentially by dipeptidyl(amino)peptidase IV (DAP IV: EC 3.4.14.5)/APN. NKA is unaffected by DAP IV but is metabolized by NEP-24.11 and APN. NEP-24.11 was inhibited by phosphoramidon (IC50 = 80 nM), thiorphan and ZINCOV, DAP IV by diprotin A (IC50 = 8 microM), and APN by amastatin (IC50 = 50 nM) and bestatin (IC50 = 100 microM). Skeletal muscle myocyte and fibroblast metabolism of SP and NKA may regulate local skeletal muscle vascular and extravascular functions including SP- and NKA-mediated nerve-induced vasodilation. Inhibition of both NEP-24.11 and DAP IV/APN may increase skeletal muscle blood flow and decrease peripheral vascular resistance via potentiation of local neurokinin levels.
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PMID:Substance P and neurokinin A metabolism by cultured human skeletal muscle myocytes and fibroblasts. 897 37


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