Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.23.15 (renin)
 35,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Procedures for peptide bond formation using esters of L-amino acids as the acyl donor and secondary amines such as derivatives of D- or L-proline, or pyroglutamic acid as the nucleophile in anhydrous 2-methyl-2-propanol catalyzed by alcalase or subtilisin Carlsberg have been developed. Kinetic studies have shown that all secondary amines tested had catalytic efficiencies (kcat/km) in the range 84-423 min-1 M-1. Both enzymes have identical catalytic properties. The selectivity of the enzyme-catalyzed reaction in 2-methyl-2-propanol shows that at the s-1 subsite of the enzyme only L-amino acids are substrates as acyl donors, and at the s-1' subsite both D- and L-amino acids are substrates. Optimal conditions for preparing precursors of the renin inhibitors Z-Ala-Pro-OBzl, Z-Lys(Z)-Pro-OBzl and Z-Lys(TFA)-Pro-OBzl were studied.
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PMID:Alkaline protease catalysis of a secondary amine to form a peptide bond. 853 85

The intestinal oligopeptide transporter (OPT) mediates the absorption of di-/tripeptides, beta-lactam antibiotics, angiotensin converting enzyme (ACE) inhibitors and renin inhibitors. This suggests that the targeting of molecules to this transporter could result in orally-absorbed drugs. Results from a recent study with renal brush border membrane vesicles (BBMV) suggested that an alpha-NH2 group is required for interaction with the renal OPT. In general, structural requirements for interaction with the renal and intestinal OPT are similar. However, these recent findings do not agree with earlier studies, which showed that an alpha-NH2 group is not essential for interaction with the intestinal OPT. Thus, it appears that the renal and intestinal OPT may differ in their recognition of compounds containing an alpha-NH2 group. In this study, molecular modeling was used to determine the tridimensional structures of various cephalosporins for which Ki values had been determined using renal BBMV. All cephalosporins which interact with the OPT have two, energetically equivalent, conformations. Most compounds which do not interact with the OPT cannot adopt the two conformations. A key factor which influences the conformation seems to be the substituent group at the alpha position; an electron drawing group at that position alters the common conformations. For the OPT substrates, the distances between the -NH2 and -COOH groups are comparable to those of the tripeptide, GlyGlyGly; and the distances between -NH2 and carbonyl group in the beta-lactam ring are close to the distance between N-terminal and C-terminal in the dipeptide, GlyGly. The corresponding distances in cephamycin C (in which a -NH2 group is located in a different position) and the tetrapeptide, GlyGlyGlyGly, are longer than those in alpha-NH2 cephalosporins and GlyGlyGly. Cephamycin C and the tetrapeptide have low affinity for the renal OPT, suggesting that the distances between functional groups are critical for affinity. The alpha-NH2 group had no effect on the conformations of the molecules. We concluded that the alpha-NH2 group may interact directly with the renal oligopeptide transporter. Whether this is unique to the renal transporter or could be applied to the intestinal transporter will require further investigation.
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PMID:Molecular modeling study of structural requirements for the oligopeptide transporter. 879 74

alpha2-HS glycoprotein is a major protein of human plasma whose function is still obscure. A proteolytically processed form of alpha2-HS glycoprotein lacking a segment of 40 amino acid residues bridging its heavy and light chain portions ("connecting peptide") has been described suggesting that this peptide is released by post-translational processing to fulfill biological role(s) of alpha2-HS glycoprotein. To test this hypothesis we investigated how the connecting peptide is released from the parental molecule by limited proteolysis. We developed monoclonal antibodies to various portions of the connecting peptide and its NH2-terminal flanking region which cross-react with the native alpha2-HS glycoprotein. Purified alpha2-HS glycoprotein from human plasma was subjected to limited proteolysis by proteinases including trypsin, chymotrypsin, elastase plasmin, kallikrein, thrombin, and renin. Immunoprint analysis of the proteolytic digests indicated that alpha2-HS glycoprotein is readily cleaved in its connecting peptide region. NH2-terminal amino sequence analysis of the generated fragments demonstrated that a single proteinase, chymotrypsin, cleaves the critical Leu-Leu bond flanking the NH2-terminal portion of the connecting peptide region. Most but not all of the other proteinase cleavage sites map to a short stretch of 9 residues located in the center portion of the connecting peptide region. Immunoprint analysis of plasma samples from patients with sepsis demonstrate that the connecting peptide region is cleaved under pathological conditions. Our results indicate that the connecting peptide and/or fragments thereof are readily releasable from alpha2-HS glycoprotein in vitro and in vivo.
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PMID:Limited proteolysis of human alpha2-HS glycoprotein/fetuin. Evidence that a chymotryptic activity can release the connecting peptide. 894 Jan 98

A novel method to monitor specific peptidase activities in biological samples as complex as undiluted plasma/blood is described. The approach is based on the design of synthetic polypeptide substrates in which di- or triarginine sequences are linked to each other via one or more other amino acids recognized specifically by the peptidase to be determined. Detection of chymotrypsin and renin activities using synthetic substrates P4 (F-R-R-R-F-V-R-R-F-NH2) and P5 (R-R-R-L-L-R-R-L-L-R-R-R), respectively, serves to demonstrate the principles of this new assay system. A polyion-sensitive membrane electrode, prepared by doping polymer films with dinonylnaphthalene-sulfonate (DNNS), is shown to exhibit significant nonequilibrium electromotive force (EMF) responses toward these and other polycationic substrates at microgram/milliliter levels under physiological conditions. The same electrode, however, exhibits much smaller total EMF response toward the shorter fragments of the synthetic peptides generated by peptidase activity; hence, the addition of peptidase to a solution containing the synthetic substrate yields a change in electrode EMF response, the rate of which is proportional to the activity of peptidase present. Other synthetic polycationic peptides as well as natural polycationic peptides (e.g., protamine) that lack specific cleavage sites for chymotrypsin and renin, yet are detected by the DNNS-based membrane electrode, do not elicit any significant change in EMF response in the presence of the peptidases, confirming the feasibility and utility of the proposed bioanalytical method.
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PMID:Selective monitoring of peptidase activities with synthetic polypeptide substrates and polyion-sensitive membrane electrode detection. 900 54

Solid-phase methodology has been used to synthesize a series of peptides based on the N-terminal sequence of human angiotensinogen in which statine (Sta) or the novel analogues (3S,4S)-3,4-diamino- or (3R,4S)-3,4-diamino-6-methylheptanoic acid (Ads or R-Ads) and (3S,4S)-4-amino-3-aminomethyl- or (3R,4S)-4-amino-3-aminomethyl-6-methylheptanoic acid (Amd or R-Amd) replace either residue 10 or both residues 10-11 at the P1-P1' cleavage site. The synthesis of these novel analogues of statine together with biological results on the inhibition of human and rat renin by peptides derived from them is reported. The absolute stereochemistry of the (3S,4S) Ads was determined by an X-ray crystallographic analysis of its N gamma-Boc, B beta-Z, R(+)-1-methyl benzamide derivative. Peptide Boc-His-Pro-Phe-His-Sta-Val-Ile-His-NH2 (VI) is the best inhibitor of human renin containing Sta at position 10. However, peptides containing Ads and Amd gave better rat renin inhibitors than the corresponding Sta-containing peptides. Peptides Boc-His-Pro-Phe-His-Ads-Val-Ile-His-NH2 (VII) having Ads at position 10 had an IC50 of 12 nM against rat renin. Although Sta has come to be accepted as an isosteric replacement for a dipeptide unit rather than for a single amino acid residue, in our series of inhibitors Sta is more effective when replacing only the amino acid at position 10 in the natural angiotensinogen sequence. None of the peptides gave any effect in vivo in a hypertensive rat model.
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PMID:New renin inhibitors containing novel analogues of statine. 927 95

Using solid-phase methodology we have synthesised peptides based on the 8-14 or 6-14 human and rat angiotensinogen sequences, containing the following different isosteric units at the P1-P1' cleavage site: Leu-psi[CH2NH]Leu; Leu-psi[CH(OH)CH2]Val; Leu-psi[CH(OH)CH2]Leu and Leu-psi[CH(NH2)CH2]Val. In vitro, peptide Piv-His-Pro-Phe-His-Leu-psi[CH(OH)CH2]Leu-Tyr-Tyr-Ser-NH2(XXI) is the most potent inhibitor of rat plasma renin reported having an IC50 of 0.21 nM; it is a much weaker inhibitor of human renin (IC50 45 nM). Peptide Boc-His-Pro-Phe-His-Leu-psi[CH(OH)CH2] Leu-Val-Ile-His-NH2 (XX) was a highly effective inhibitor of rat renin in vivo. When infused (1 mg/kg/h) into two-kidney, one-clip chronic renal hypertensive rats, it lowered blood pressure and suppressed both plasma renin and angiotensin II. When given as a bolus (1 mg/kg) there was a divergence between the rapid rebound of renin levels and blood pressure, which remained suppressed. These results indicate that potent in vivo inhibitors of rat renin could be useful not only in examining the role of circulating renin but also in elucidating the equally important involvement of extracirculatory renin pools.
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PMID:Potent in vivo inhibitors of rat renin: analogues of human and rat angiotensinogen sequences containing different classes of pseudodipeptides at the scissile site. 935 62

A series of renin inhibitors containing the dipeptide transition state mimics (2R,4S,5S)-5-amino-4-hydroxy-2-methyl-6-cyclohexyl hexanoic acid (Cha-psi[CH(OH)CH2]Ala) and (2R,4S,5S)-5-amino-4-hydroxy-2-isopropyl-6-cyclohexyl hexanoic acid (Cha-psi[CH(OH)CH2]Val) were prepared. A structure-activity study, using pseudopeptide (Boc-Phe-His-Leu-psi[CH(OH)CH2]Val-Ile-His-OH) as our lead structure, led to a new series of inhibitors, which correspond to tripeptides and contain no natural amino acids. For example, R,S-Bpma-Ape-Cha-psi[CH(OH)CH2]Ala-NH2 (IC50 = 1.26 nM against human plasma renin at pH 6.0; molecular weight = 564) has only two thirds of the molecular weight but twice the potency of our original lead. This new class of low molecular weight renin inhibitor displays excellent specificity toward human renin versus the related aspartic proteinase pepsin and angiotensin-1-converting enzyme. Examples are given of selected inhibitors showing encouraging evidence for intestinal absorption after intracolonic and oral administration in male Sprague-Dawley rats.
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PMID:Synthesis and biological activity of potent, low molecular weight renin inhibitors. 935 63

To compare the effects of a potent rat renin inhibitor peptide (RIP) and angiotensin-converting enzyme (ACE) inhibitor on the intrarenal and plasma renin-angiotensin systems, anesthetized Sprague-Dawley rats were treated with an infusion of vehicle, ramipril or graded doses of the rat RIP (acetyl-His-Pro-Phe-Val-statine-Leu-he-NH2) for 30 min. Kidney and plasma samples were processed rapidly, and angiotensin peptides were separated by high-pressure liquid chromatography before measurement by a double-antibody radioimmunoassay. Blood pressure fell identically, by approximately 15 mm Hg, after either the RIP or ACE inhibitor. Plasma Ang II was 83 +/- 20 fmol/ml in vehicle-treated rats and fell to 28 +/- 3 fmol/ml with ramipril (10 mg/kg), the dose-response zenith. Plasma Ang II was significantly lower, 9 +/- 2 fmol/ml, with the highest RIP dose used. Control renal tissue Ang II was 183 +/- 18 fmol/g, fell with ramipril to 56 +/- 6 and then fell to a similar level (47 +/- 10 fmol/g) after RIP. Ang I/Ang II ratios indicated the expected sharp drop in Ang I conversion after ramipril in plasma and tissue. RIP did not influence conversion rate in plasma but was associated with an unanticipated fall in Ang I conversion in renal tissue, perhaps reflecting local aspartyl protease inhibition, which contributes to normal Ang II formation. Also unanticipated was a rise in tissue Ang I concentration during RIP administration. Renin inhibition is more effective than ACE inhibition in blocking systemic Ang II formation, supporting studies suggesting that quantitatively important non-ACE-dependent pathways participate in Ang II formation.
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PMID:Renin vs. angiotensin-converting enzyme inhibition in the rat: consequences for plasma and renal tissue angiotensin. 935 83

To examine chronic changes in mitogen-activated protein (MAP) kinases in cardiac hypertrophy, we determined the activities of two subfamilies of MAP kinases, including extracellular signal-regulated kinases (ERKs) and c-Jun NH2-terminal kinases (JNKs), in the heart of stroke-prone spontaneously hypertensive rats (SHRSP) and Wistar-Kyoto rats (WKY) aged 5, 8, 14, and 24 weeks. MAP kinases were determined by using in-gel kinase assay. In both the left and right ventricles of WKY, the activities of ERKs (p44ERK and p42ERK) and JNKs (p46JNK and p55JNK) decreased significantly with age, indicating that aging remarkably downregulated cardiac MAP kinase activities. In SHRSP, left ventricular ERK and JNK activities were already significantly higher at the mild hypertensive phase than they were in the same age of WKY, and they remained higher until development of left ventricular hypertrophy. On the contrary, the right ventricle of SHRSP, which did not exhibit cardiac hypertrophy, had no significant increase in ERK or JNK activities compared with WKY, except for the slight increase in p55JNK in 24-week-old SHRSP. Antihypertensive treatment of SHRSP with imidapril, an angiotensin-converting enzyme inhibitor, decreased the left ventricular JNK activities (P<.01) but did not affect ERK activities, suggesting the contribution of hypertension or the renin-angiotensin system to the increase in JNKs. Our observations provide the first evidence that both ERK and JNK activities are higher in the left ventricle of SHRSP than WKY. However, further study is needed to elucidate the mechanism and the significance of the increased cardiac MAP kinases in SHRSP.
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PMID:Cardiac mitogen-activated protein kinase activities are chronically increased in stroke-prone hypertensive rats. 944 90

The substrate specificities and kinetic properties of proteinase A, an intracellular aspartic proteinase from the yeast Saccharomyces cerevisiae, were determined using a series of synthetic chromogenic peptides with the general structure P5-P4-P3-P2-Phe-(NO2)Phe-P2'-P3' [P5, P4, P3, P2, P2', P3' are various amino acids; (NO2)Phe is p-nitro-L-phenylalanine]. The nature of the residues occupying the NH2-terminal region of the substrate had a strong influence on the kinetic constants. Among those tested, Ala-Pro-Ala-Lys-Phe-(NO2)-Phe-Arg-Leu had the best kinetic constants (Km = 0.012 mM, kcat = 14.4 s-1, kcat/Km = 1,200 M-1.s-1). Compared with such aspartic proteinases as pepsin, cathepsin D, and renin, the substrate specificity of proteinase A was unique. Based on these results, a novel fluorescent substrate, MOCAc-Ala-Pro-Ala-Lys-Phe-Phe-Arg-Leu-Lys(Dnp)-NH2, was developed for the sensitive measurement of proteinase A.
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PMID:Substrate specificities and kinetic properties of proteinase A from the yeast Saccharomyces cerevisiae and the development of a novel substrate. 964 56


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