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: EC:3.4.15.1 (ACE)
18,300 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The proline requirement of Salmonella typhimurium strain proB25 can be satisfied by either of the peptides Leu-Pro or Gly-Pro-Ala. A mutant derivative of strain proB25 isolated by penicillin selection in medium containing Leu-Pro as proline source fails to use either Leu-Pro or Gly-Pro-Ala as a source of proline. This strain is a double mutant that lacks two aminoacyl-proline-specific peptidases. One of these enzymes (peptidase Q) catalyzes the rapid hydrolysis of Leu-Pro but does not hydrolyze Gly-Pro-Ala or poly-l-proline. Mutations at a site (pepQ) near metE lead to loss of this activity. The other peptidase (peptidase P) catalyzes the hydrolysis of Gly-Pro-Ala and poly-l-proline but is only weakly active with Leu-Pro as substrate. This enzyme is similar to aminopeptidase P previously described in Escherichia coli (16). Mutations at a locus (pepP) near serA lead to loss of this enzyme.
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PMID:Isolation and characterization of proline peptidase mutants of Salmonella typhimurium. 460 25

In a study of changes in digestive enzymes after massive intestinal resection and the mechanisms by which such changes occur, rats were sacrified 4 wk after removal of the proximal two-thirds of the small intestine. Alterations in the mucosal levels of sucrase, enterokinase, and dipeptide hydrolase (L-leucyl-L-alanine substrate) were examined in the light of associated changes in protein. DNA and wet mucosal weight, measured in standardized gut segments from various regions of intestine. Metabolic studies showed that normal growth patterns were reestablished after the operation but significant elevations in stool weight and fecal nitrogen occurred in the second postoperative week, falling towards normal by the 4th wk. In standard gut segments wet weight of mucosa, protein, and DNA rose, especially in distal segments, DNA increasing disproportionately. Mucosal levels of the proximally distributed and membrane-bound enzymes, sucrase and enterokinase, showed similar patterns of change: when enzyme activity was expressed in terms of the total per segment, proximally there were considerable increases in both enzymes, but, expressed in terms of specific activity, that of sucrase fell and that of enterokinase was unaltered. By contrast, the largely soluble and more distally distributed dipeptide hydrolase increased more in distal segments and the increases in total activity were accompanied by lesser increases in specific activity. However, in spite of increases in total activity, enzyme activity per milligram DNA fell by over 50% in postanastomotic segments. Subcellular distribution studies showed no change in the percentage of the total activity which was membrane-bound and zymograms confirmed that no new dipeptide hydrolase had appeared after resection. It is concluded that increases in the segmental totals of various enzymes seen after resection are achieved by disproportinate increases in the number of mucosal cells per segment and that the greatest change in a particular enzyme occurs in the region where the enzyme is normally found in highest concentration.
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PMID:Changes in sucrase, enterokinase, and peptide hydrolase after intestinal resection. The association of cellular hyperplasia and adaptation. 469 57

Two "ACE" mutants of Bacillus subtilis which require acetate for growth on glucose minimal medium have been isolated. They do not grow with acetoin, 2,3-butanediol, fatty acids, isoleucine, lipoic acid, malic acid, pyruvic acid, succinic acid, thiamine, or valine, but respond somewhat to glutamate or citrate. The mutants lack the activity of the pyruvate dehydrogenase complex; they excrete pyruvate and later acetoin. They grow in nutrient sporulation medium (NSMP) to one-half the normal turbidity and do not sporulate subsequently. When acetate is added to NSMP (at the optimal concentration of 0.07 m), the ACE mutants grow to the normal turbidity and then sporulate normally. Growth but not sporulation is restored in NSMP upon addition of 2,3-butanediol, citrate, glucose, glutamate, glycerol, or ribose, but not upon addition of acetoin, malate, oxaloacetate, pyruvate, and several other compounds. After growth in NSMP has stopped, the mutants incorporate uracil only at a very low rate, which can be increased by the addition of acetate, citrate, or glutamate. Furthermore, the metabolism of acetoin is prevented after growth has stopped but can be restored by the addition of acetate. All these results can be explained by a lack of reduced nicotinamide adenine dinucleotide (NADH) resulting from the deficiency in acetylcoenzyme A. In fact, after growth of the ACE mutants had stopped, the NADH concentration was at the borderline of measurability, whereas it increased significantly upon addition of glucose. The growing standard strain contains, at the same bacterial turbidity, at least 20 times more NADH (230 pmole/optical density unit at 600 nm) than the nongrowing ACE mutants. The isolated spores, obtained after growth in NSMP plus acetate, can be initiated to germinate in the presence of either l-alanine or the combination of l-asparagine, fructose, glucose, and potassium; addition of acetate is not required and has no effect.
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PMID:Growth and sporulation of Bacillus subtilis mutants blocked in the pyruvate dehydrogenase complex. 498 74

Three series of bidentates bearing an hydroxamic or an N-Acyl-N-hydroxy amino group on structures related to Phe-Gly or Phe-Ala exhibit strong inhibitory potency against purified enkephalinase with IC50 values in the 4 to 15 nM range. As with thiol-containing inhibitors, such as thiorphan, the most active compounds are those in which a methylene spacer separates the benzyl P1' moiety from the Zn coordinating residue. Formation of a bidentate complex with the metal enzyme is clearly demonstrated by a loss of potency of three order of magnitude following the removal of one component of the bidentate group. All the compounds studied are unable to interact with angiotensin converting enzyme (IC50 greater than 10,000 nM). Moreover, compounds of the general formula HONHCO-CH2-CH(CH2 phi)-CONH-CH(R)-COOH belonging to the most active series of enkephalinase blockers (IC50 approximately 4 nM) behave also as highly potent and competitive inhibitors (IC50 approximately 10 nM) of a Tyr-Gly releasing dipeptidylaminopeptidase purified from rat brain. The pure steroisomer [(R)-3-(N-hydroxy)carboxamido-2-benzylpropanoyl]-L-alanine designated kelatorphan, exhibits also a relatively good inhibitory potency against aminopeptidases (IC50 approximately 10 microM) and can be considered as the first virtually complete inhibitor of enkephalin metabolism. This very interesting property of inhibiting all three enzymes of enkephalin metabolism could enhance the required selectivity for a possible clinical use of these inhibitors as new analgesic and psychoactive drugs.
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PMID:Bidentate peptides: highly potent new inhibitors of enkephalin degrading enzymes. 608 32

It is known that the serum level of glycylproline aminopeptidase (Gly-Pro-AP) is decreased in the patients with rheumatoid arthritis. In the present study, the serum levels of various hydrolytic enzymes were tested in such patients. In comparison to the controls, many enzymes, including Ala-AP, Ser-AP, Phe-AP, Gly-Pro-AP, Gly-Pro-Leu-AP, dipeptidyl carboxypeptidase (angiotensin converting enzyme), and esterase, showed significantly decreased activities in the patients' sera. Only the activity of Trp-AP was significantly increased. Of these enzymatic activities in serum, several ones including those of Gly-Pro-AP, Ala-AP, Phe-AP, trypsin-like enzyme, and esterase, were significantly correlated with the severity of the disease. Although a part of these findings are compatible with previous observations, they suggest rather more extensive disorders of peptide metabolism in this immunological disease.
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PMID:Decreased serum levels of various hydrolytic enzymes in patients with rheumatoid arthritis. 608 27

The interaction of angiotensin converting enzyme with six metal-coordinating [(D-3-mercapto-2-methylpropanoyl)-L-Pro (captopril), N-[1(S)-carboxy-3-phenylpropyl]-L-Ala-L-Pro (MK-422), N-(phenylphosphoryl)-L-Phe-L-Phe, N alpha-(3-mercaptopropanoyl)-L-Arg, N alpha-[1(S)-carboxy-3-phenylpropyl]-Ala-L-Lys, and N-[1(S)-carboxy-5-aminopentyl]-L-Phe-Gly] and three dipeptide inhibitors (Gly-L-Trp, L-Phe-L-Arg, and L-Ala-L-Pro) was examined at pH 7.5 in the presence of 300 mM NaCl. Inhibition modes, apparent Ki [Ki(app)] values, and shapes of 1/v vs. [I] plots were found to vary with the substrate employed. All inhibitors except Phe-Arg were competitive with the substrate furanacryloyl (Fa)-Phe-Gly-Gly, while five of seven tested with Fa-Phe-Phe-Arg as substrate produced mixed patterns. Ki-(app) values for N-[1(S)-carboxy-5-aminopentyl]-L-Phe-Gly, N-(phenylphosphoryl)-L-Phe-L-Phe, Gly-Trp, and MK-422 were 8.3-, 5.5-, 4.7-, and 2.6-fold lower, respectively, when Fa-Phe-Gly-Gly was substrate, compared with values measured with Fa-Phe-Phe-Arg. In contrast, Ki(app) values for Phe-Arg and (3-mercaptopropanoyl)-Arg were lower (2.8- and 2.2-fold, respectively) when Fa-Phe-Phe-Arg was the substrate. Plots of 1/v vs. [I] for most of the inhibitors were nonlinear, to an extent which was also substrate dependent.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibition of angiotensin converting enzyme: mechanism and substrate dependence. 609 93

In a previous report [Shapiro, R., Holmquist, B., & Riordan, J. F. (1983) Biochemistry 22, 3850], it was demonstrated that activation of angiotensin converting enzyme (ACE) by chloride is strongly dependent on substrate structure, and three substrate classes were identified on the basis of activation behavior. The present study examines the chloride dependence of the inhibition of ACE by nine inhibitors [(D-3-mercapto-2-methylpropanoyl)-L-Pro (captopril), N-[1(S)-carboxy-3-phenylpropyl]-L-Ala-L-Pro (MK-422), L-Ala-L-Pro, N-(phenylphosphoryl)-L-Phe-L-Phe, Gly-L-Trp, N-[1(S)-carboxy-5-aminopentyl]-L-Phe-Gly, L-Phe-L-Arg, N alpha-(3-mercaptopropanoyl)-L-Arg, and N alpha-[1(S)-carboxy-3-phenylpropyl]-L-Ala-L-Lys] containing structural features characteristic of the three classes of substrates. Apparent Ki values for all inhibitors are markedly (70-250-fold) decreased by 300 mM chloride. However, the enhancement of inhibition is achieved at significantly lower chloride concentrations with those inhibitors having an ultimate arginine or lysine than with the remainder. This variability parallels that previously found for activation of substrate hydrolysis. The effect of chloride on the individual steps in the formation and dissociation of the steady-state enzyme-inhibitor complexes was determined with the slow-binding inhibitor MK-422. Pre-steady-state analysis indicates that binding of both MK-422 and captopril follows a (minimally) two-step mechanism: (formula; see text) in which rapid formation of an enzyme-inhibitor complex is followed by a slow isomerization.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibition of angiotensin converting enzyme: dependence on chloride. 609 94

Endopeptidase-24.11 (EC 3.4.24.11), purified to homogeneity from pig kidney, was shown to hydrolyse a wide range of neuropeptides, including enkephalins, tachykinins, bradykinin, neurotensin, luliberin and cholecystokinin. The sites of hydrolysis of peptides were identified, indicating that the primary specificity is consistent with hydrolysis occurring at bonds involving the amino group of hydrophobic amino acid residues. Of the substrates tested, the amidated peptide substance P is hydrolysed the most efficiently (Km = 31.9 microM; kcat. = 5062 min-1). A free alpha-carboxy group at the C-terminus of a peptide substrate is therefore not essential for efficient hydrolysis by the endopeptidase. A large variation in kcat./Km values was observed among the peptide substrates studied, a finding that reflects a significant influence of amino acid residues, remote from the scissile bond, on the efficiency of hydrolysis. These subsite interactions between peptide substrate and enzyme thus confer some degree of functional specificity on the endopeptidase. The inhibition of endopeptidase-24.11 by several compounds was compared with that of pig kidney peptidyldipeptidase A (EC 3.4.15.1). Of the inhibitors examined, only N-[1(R,S)-carboxy-2-phenylethyl]-Phe-p-aminobenzoate inhibited endopeptidase-24.11 but not peptidyldipeptidase. Captopril (D-3-mercapto-2-methylpropanoyl-L-proline), Teprotide (pGlu-Trp-Pro-Arg-Pro-Gln-Ile-Pro-Pro) and MK422 [N-[(S)-1-carboxy-3-phenylpropyl]-L-Ala-L-Pro] were highly selective as inhibitors of peptidyldipeptidase. Although not wholly specific, phosphoramidon was a more potent inhibitor of endopeptidase-24.11 than were any of the synthetic compounds tested.
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PMID:The metabolism of neuropeptides. The hydrolysis of peptides, including enkephalins, tachykinins and their analogues, by endopeptidase-24.11. 614 47

The exact mechanism of action of angiotensin converting enzyme (ACE) inhibitors in reducing blood pressure is not known, although inhibition of angiotensin II formation is the generally accepted mechanism. Experiments were performed in two models of experimental hypertension to determine whether or not inhibition of the pressor response to angiotensin I, 300 ng/kg i.v., would correlate with the antihypertensive response to single oral doses of N-[(S)-1-(ethoxycarbonyl)-3-phenylpropyl]-L-Ala-L-Pro (MK-421), a new ACE inhibitor. Captopril, given as a single oral dose, was studied in spontaneously hypertensive rats (SHR) for comparative purposes. In SHR, MK-421 at 0.1-3 mg/kg p.o. and captopril at 0.1-3 mg/kg p.o. were approximately equipotent with regard to inhibiting the pressor response to angiotensin I (relative potency=1.7; 95% C.I.=0.7-4.5). The magnitude of ACE inhibition and onset of action were similar with both agents, but MK-421 had a longer duration of action. The decrement in systolic pressure following each ACE inhibitor consisted of an initial decrease in blood pressure corresponding to the maximal inhibition of angiotensin I pressor response and a secondary fall in blood pressure which was evident 5-6 h after treatment. At this time, the inhibition of the pressor response to angiotensin I was minimal. Thus, the time course for blockade of angiotensin I and the blood pressure reduction did not correspond. The dose-response regression lines for the antihypertensive effect of each inhibitor, unlike those for ACE inhibition, were flat. The potency ratio computed on the basis of the maximum fall in blood pressure over 6 h revealed that MK-421 was 11.5 times (P less than 0.05) more potent thant captopril. In 2-kidney Grollman renal hypertensive rats (RHR), MK-421 at 0.3-10 mg/kg p.o. inhibited the pressor response to angiotensin I by 65-95%, but produced significant decrements in blood pressure only at 10 mg/kg p.o. The finding that MK-421 was more potent than captopril in lowering blood pressure in SHR, yet equally active in its ability to block angiotensin I pressor responses, suggests that a mechanism(s) other than inhibition of plasma ACE is involved in the decrease in blood pressure was not reduced. However, a higher dose which produced a similar degree of blockade was associated with a significant decrease in blood pressure.
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PMID:Relationship between angiotensin I blockade and antihypertensive properties of single doses of MK-421 and captopril in spontaneous and renal hypertensive rats. 617 51

The disposition of converting enzyme (kininase II) on the luminal surface of pulmonary endothelial cells is well established. Further, it is known that there is a net conversion of angiotensin I into angiotensin II as blood passes through the lungs. However, little is known about modulations of converting enzyme activity that may arise through, e.g., changes in the quality of inhalants, blood flow, or blood oxygenation. There are few data on the effects of lung disease. A major barrier to studies to examine for pathophysiologic modulations of converting enzyme is that of assay. The enzyme can be measured in terms of the rate of formation of angiotensin II from a known quantity of angiotensin I. However, both peptides are biologically active, and lungs contain other enzymes capable of degrading them. We have developed a series of radiolabeled, acylated tripeptides to improve our ability to examine for changes in the net converting enzyme of intact lungs. The enzyme, a dipeptidyl carboxypeptidase, is capable of removing C-terminal dipeptides from a variety of oligopeptides. We have prepared benzoyl-Gly-Gly-Gly (I), benzoyl-Pro-Phe-Arg (II), benzoyl-Gly-His-Leu (III), benzoyl-Phe-Ala-Pro (IV), and benzoyl-Phe-His-Leu (V), each containing a (3)H-atom in the para position of the benzoyl moiety. Substrates I and III have been used previously in photometric assays of low sensitivity. II is the acylated C-terminal tripeptide of bradykinin, IV is an acylated tripeptide analog of BPP(5a) (<Glu-Lys-Trp-Ala-Pro) and V is the acylated C-terminal tripeptide of angiotensin I. These substrates can be used in vitro or in vivo to measure converting enzyme. The (3)H-labeled product is separable by partitioning between an organic solvent and acidified aqueous solution. The product is quantified by scintillation counting of the organic phase. The choice of substrate depends on the goals of the experiment: substrate I or III when wide variations in substrate concentrations are needed but high sensitivity is not; substrate IV when high sensitivity is needed.
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PMID:Angiotensin-converting enzyme: I. New strategies for assay. 625 Aug 9


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