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PubMed1978

New chromogenic and fluorogenic substrates for pyrrolidonyl peptidase.

L-Pyroglutamyl derivatives of p-nitroaniline and 7-amino-4-methylcoumarin were synthesized as new sensitive substrates for pyrrolidonyl peptidase (pyrrolidonecarboxylyl peptidase) from Bacillus amyloliquefaciens. Their hydrolyses could be followed by conventional colorimetric and fluorometric procedures; i.e., in terms of the increase in absorbance at 410 nm caused by the liberation of p-nitroaniline and the emission at 440 nm after excitation at 370 nm depending on the liberation of 7-amino-4-methylcoumarin. Values of Km were estimated to be 0.69 mM for anilide substrate and 0.33 mM for methylcoumarin substrate in the pyrrolidonyl peptidase reaction at pH 8.0. The methylcoumarin compound was about one thousand fold more sensitive than the anilide substrate.

Aminopeptidases↗
PubMed1979

Do cleavages of amides by serine proteases occur through a stepwise pathway involving tetrahedral intermediates?

The mechanism of the serine protease-catalyzed cleavage of amides (acylation) was examined in terms of the basicity of the functional groups participating in the catalysis. It is proposed that the reaction does not proceed through a stepwise pathway, as opposed to the cleavage of esters and anilides, which start with general base-catalyzed formation of the tetrahedral intermediate followed by its general acid-catalyzed breakdown. Instead, the proton abstracted from the hydroxyl group of the serine by the imidazolyl group of the histidine is donated to the nitrogen atom of the leaving group of the amide before the bond between the carbonyl carbon atom of the amide and the attacking serine oxygen atom is completed. Reactions proceed by a SN2-like reaction through the cooperation of acid catalysis by the imidazolyl cation and nucleophilic attack by the serine. The mechanisms of the enzymatic hydrolyses of anilides and esters proceed through a discrete tetrahedral intermediate, but the enzymatic hydrolyses of amides probably do not.

Amides↗
PubMed1976

[Isolation and characterization of a microsomal arylaminopeptidase from rat kidney].

The isolation and characterization of a microsomal arylaminopeptidase from rat kidney is reported. By treatment of a microsomal arylaminopeptidase-phosphatase-complex with trypsin and subsequent gel filtration of the solubilized proteins on Sepharose 6B a electrophoretic homogeneous arylaminopeptidase was obtained (yield, 3%; enrichment, 900 times). The following properties of the purified enzyme were determined: 1. Molecular weight: 182000 (gel filtration on Sepharose 6B) to 192000 (SDS-polyacrylamide gel electrophoresis). 2. Subunit structure: In the presence of 6 M guanidine - HC1 + 1% BETA-mercaptoethanol the enzyme dissociates into subunits (MW 46700, ESTIMATED BY SDS gel electrophoresis method). 3. Isoelectric point: 4,71 (agarose gel electrophoresis method). 4. UV characteristics: E 280nm/E260NM=1.3. 5. Substrate specifity: optimal substrates L-alanyl derivatives (anilide, beta-naphthyl amide, p-nitroanilide, 4-(phenylazo)-phenylamide and hydrazide). Among these compounds the anilide derivative was hydrolyzed most rapidly. Furthermore, di- and tripeptides, especially L-methionyl-L-leucine, were also split. No hydrolysis was observed with hemoglobin (pH 4.5 and 7.5) and amino acid- or peptide-ester substrates. 6. Optimal pH: 7.5 +/- 0,1; optimal temperature: 45 to 50 degrees C. 7. The enzyme has no transamidation activity with L-alanyl amide both as aminoacyl donator and -acceptor. 8. Influence of effectors: Heavy metal ions (Ni2+, Cd2+, Cu2+, Zn2+), chelating agents (EDTA, o-phenanthroline) and puromycin inhibit the enzyme significantly. SH-group reagents are without any influence. 9. L-alanyl-L-alanyl-4 (phenylazo)-phenylamide, a dipeptide aryl aminopeptidase substrate, is hydrolyzed by the purified enzyme preparation according to a consecutive or step by step mechanism.

Aminopeptidases↗
PubMed1976

Thin-layer chromatography for detection of peptide cleavage or integrity during reactions of the Z-alanylglycines with aniline or phenylhydrazine under papain catalysis.

Z-l-Ala-gly and Z-dl-ala-gly can yield anilides and phenylhydrazides through peptide cleavage or peptide integrity during papain-catalyzed reactions with aniline (NH2Ph) or phenylhydrazine (NH2NHPh). Since Z-d-ala-gly yielded only uncleaved Z-d-ala-gly-NHPh or Z-d-ala-gly-NHNHPh, these were used as standards in thinlayer chromatography (TLC) for detecting integrity. Known Z-l-ala-NHPh and Z-l-ala-NHNHPh were the standards for cleavage. Depending on the time of incubation, cleaved or unsplit products, or both, were readily detected. The solvent systems that were used for TLC were also effectively employed for separations of reasonable amounts of mixtures of cleaved and uncleaved products through thick-layer chromatography on Chrom AR. This was followed by isolation of the separated components.

Alanine↗
PubMed1976

Mechanism of action of serine proteases: tetrahedral intermediate and concerted proton transfer.

Stopped-flow spectrophotometry and proton inventory experiments have been used to define the reaction pathway for hydrolysis of a specific peptide substrate, Ac-L-Ala-L-Pro-L-Ala p-nitroanilide, by the serine proteases elastase and alpha-lytic protease. The stopped-flow studies reveal the existence and buildup of a tetrahedral adduct between the active site serine hydroxyl group and the sensitive carbonyl group of the substrate. The decomposition of this tetrahedral intermediate to the acyl enzyme and p-nitroaniline is the rate-limiting step for the hydrolytic reaction. The proton inventory data suggest the simultaneous transfer of two protons (presumably from the catalytic carboxyl of Asp-102 to N pi of the catalytic imidazole of His-57 and from N pi of the imidazole to the anilide NH) in the transition state leading to breakdown of the tetrahedral complex. That these proton transfers occur in a concerted, rather than stepwise, process attests to the ability of enzymes to lower the enthalpy of activation most effectively when the precise alignment of a highly specific substrate and catalytic groups minimizes the entropy of activation.

Anilides↗
PubMed1979

Structural analogues of L-glutamic Acid gamma-(4-hydroxyanilide) and gamma-(3,4-dihydroxyanilde) as potential agents against melanoma.

Nine heretofore unknown mono- and dihydroxyanilide analogues of the cytotoxic mushroom metabolites L-glutamic acid gamma-(4-hydroxyanilide) (1) and L-glutamic acid gamma-(3,4-dihydroxyanilide) (3, agaridoxin) were synthesized and tested as inhibitors of the growth of B16 mouse melanoma cells in culture. The naturally occurring anilides 1 and 3 had ID50 values of 0.10 and 0.27 mM, respectively. The analogue of 1 in which the gamma-L-glutamyl moiety was replaced by beta-L-aspartyl showed only a threefold decrease in activity, whereas attachment of the phenolic OH group to the meta instead of the para position resulted in a tenfold decrease. Other structural modifications, such as O-methylation or deletion of the carboxyl or amino group in the side chain, led to compounds of still lower activity (ID50 greater than 1.0 mM). The only analogue in the series with more activity than either 1 or 3 against B16 cells was L-glutamic acid gamma-(2,5-dihydroxyanilide) (14), which had an ID50 value of 0.051 mM. These data suggest that the gamma-L-glutamyl side chain in 1 or 3 plays a significant role in the biological action of these compounds, though some flexibility appears to exist insofar as the positioning of OH groups on the aromatic ring is concerned.

Anilides↗
PubMed1976

Synthesis of N-acetylcysteine compounds.

The preparation of some anilides, esters and amides of N-acetyl and N,S-diacetyl-cysteine is described. Of the compounds synthesized, particular interest was aroused by the p-hydroxyanilide derivatives of N-acetyl and N,S-diacetyl-L-cysteine owing to their analgesic, antiinflammatory and antipyretic activity.

Acetylcysteine↗
PubMed1976

[Retrospective analysis of drug projection using correlative technics].

The problem of choosing substituents to allow correct correlative analysis according to the "Hausch Approach" is discussed. The problem of colinearity among parameters is considered in a case study on 296 anilides which inhibit the Hill reaction. The difficulty in of determining whether, pi or MR is the important variable in changes in activity is shown. "Cluster analysis" is discussed and proposed as a rational method for the selection of substituents to be introduced into biologically active structure in order to explore the scope of each defined physico-chemical parameter. An example of the use of this method conerning auxin activity of 1- and 2-benzotriazole derivatives is given.

Anilides↗
PubMed1975

Kinetic studies of carboxypeptidase Y. I. Kinetic parameters for the hydrolysis of synthetic substrates.

Kinetic parameters for carboxypeptidase Y [EC 3.4.12.1], characterized as a nonspecific enzyme, are given for the hydrolysis of a series of acylated peptides, acylated amino acid esters, and amides. We confirmed that the enzyme released COOH-terminal proline and beta-alanine at an appreciable rate, as well as neutral amino acids with aromatic and aliphatic side chains at a very high speed. The rates of hydrolysis of ester and amide substrates were compatible with those produced by chymotrypsin [EC 3.4.21.1]. Stereospecificity was also demonstrated by the failure to hydrolyze peptide, ester, amide, and anilide substrates containing a D-amino acid. The effects of pH, solvents, and salt concentrations on the kinetic parameters of hydrolysis of peptide and ester substrates are also described.

Anilides↗
PubMed1979

Components of the kallikrein-kinin system in urine.

The excretion of kallikrein in urine varies, but the pathophysiologic implications are not clear. To help clarify the role of the urinary kallikrein-kinin system, we have begun to define components of the system as they occur in urine. To minimize artifacts which may arise through extensive purification procedures, we studied urinary protein concentrates prepared by ultrafiltration. The concentrates were separated by chromatography on Sephacryl. Urine contains abundant kininase activity, but in strongly inhibited forms. Kininase II is separable into at least two forms. Another major kininase can hydrolyze benzoyl-Pro-Phe-Arg and is inhibited by arginine but not by BPP9a or SQ 14,225. Its molecular weight is approximately 63,000. A third kininase, not inhibited by BPP9a, is excluded from Sephacryl. Human urine appears to contain only one kallikrein-like enzyme (MW 45,000). In addition, urine contains a protein (MW approximately 80,000) which reacts with trypsin to release bradykinin and which inhibits the hydrolysis of Pro-Phe-Arg-[3H]anilide by urinary kallikrein. Thus, in addition to kallikrein and kinins, urine contains kininogen and at least three kininase enzymes. Urinary ultrafiltrate contains an inhibitory substance (approximately MW 400).

Animals↗
PubMed1979

Isolation and characterization of an enkephalin-degrading aminopeptidase from rat brain.

An enkephalin-degrading aminopeptidase from rat brain extracts has been purified to apparent homogeneity. This enzyme cleaves the N-terminal tyrosine from Leu-enkephalin and hydrolyzes some beta-naphthylamides and p-nitro-anilides of neutral, basic and aromatic, but not acidic, amino acids. The enzyme requires a free amino group on the substrate and has a neutral pH optimum. After dialysis against EDTA, the enzyme requires a divalent cation (Zn2+, Co2+ greater than Mn2% greater than Mg2+) for activity. The enzyme is inhibited by puromycin, o-phenanthroline, p-chloromercuribenzoate and EDTA, but not by puromycin, methylsulfonyl fluoride or a specific peptide inhibitor of leucine amino-peptidase. The aminopeptidase consists of two subunits and has a molecular weight of about 100 000.

Aminopeptidases↗
PubMed1979

Characteristics of lithium iodide-containing poly(ethylene glycol) as a gas chromatographic stationary phase, and its application to analysis of amidic drugs.

The characteristics of lithium iodide-containing poly(ethylene glycol) as a gas chromatographic stationary phase have been evaluated in terms of partial free energy of transfer (delta G t0) from poly(ethylene glycol) to the lithium iodide-poly(ethylene glycol) system for a variaty of amides (n-fatty acid amides, lactams, benzamides, anilides, nicotinamides, isonicotinamides, barbiturates, pyrazolones) and several amines. The changes in relative retention and resolution of two solute peaks caused by the addition of lithium iodide to poly)ethylene glycol) are correlated with the difference in their delta Gt0 values. The application to the specific separation of some amidic drugs is demonstrated.

Amides↗
PubMed1977

Studies on the catalytic action of poly-alpha-amino acids. VII. Stereospecificity in the enzyme-like hydrolysis of benzoyl-L-(D)-arginine-p-nitroanilides by copoly (Cys, Glu).

The substrate specificity in the hydrolysis of L-, DL-, and D-BAPA (benzoylarginine-p-nitro-anilide) by copoly (L-Cys, L-Glu) and copoly (D-Cys, D-Glu) was studied, and enzyme-like stereospecific hydrolyses by poly-alpha-amino acids were identified for the first time. The L-type copolymer hydrolyzed L-BAPA faster than D-BAPA and the rates (v) of BAPA hydrolyses by L-type copolymer were found to be in the order vL greater than vDL greater than vD. On the other hand, the D-type copolymer hydrolysed D-BAPA faster than L-BAPA and the rates of BAPA hydrolyses by D-type copolymer were in the order vD greater than vDL greater than vL. In all cases, the reaction followed Michaelis-Menten kinetics when the substrate concentration was corrected, and the optimum conditions of the reaction were pH 6.0 and 40 degrees. The activity appeared after a certain amount of BAPA had combined with the polymer. D- and L-substrates combine competitively with the polymer and the different rates of hydrolysis are presumably due to the different substrate configurations in relation to the conformation of the active site in the polymer. The polymer shows activity near the range of random coil conformation, where some alpha-helical conformation is still present. Only some of the cysteine residues in the copolymer are involved in the hydrolytic activity.

Arginine↗
PubMed1979

Endothelial cells and components of the kallikrein-kinin system.

Endothelial cells are a major source of kininase enzymes including kininase II. Kininase II is situated along the plasma membrane, not as an ecto-enzyme but as an enzyme synthesized by the endothelial cells themselves. However, it is likely that endothelial cells do more than degrade kinins. These cells are contractile and may possess kinin receptors; a possibility supported by the fact that kinins stimulate endothelial cells to form and release prostaglandin-related substances. In addition, we have found that endothelial cells in culture are reactive with antibodies to alpha 2-macroglobulin. Endothelial cells can hydrolyze [3H]Pro-Phe-Arg-anilide, a kallikrein substrate, but the reaction is not inhibited by soya bean trypsin inhibitor (SBTI) or Trasylol. Possibly kallikrein or a related trypsin-like enzyme is bound to alpha 2-macroglobulin and is not free to react with the inhibitors. Thus, endothelial cells can bind and inhibit kallikrein-like enzymes, degrade kinins and respond to kinin stimulation.

Animals↗
PubMed1978

Gamma glutamyl transferase: application of a new radiochemical assay to the analysis of its subcellular distribution in the rat liver.

gamma-Glutamyl transferase (gamma-GT) is a key catalyst in the metabolism of glutathione. Its activity in the rat liver is usually very low but it increases significantly during the process of chemical hepatocarcinogenesis. A new radiochemical assay is reported which measures the amount of 3H-aniline liberated from gamma-glutamyl-3H-anilide. This assay is highly specific and no biological substances interferes. By applying this new assay to the analysis of the subcellular distribution of the rat liver gamma-GT, it is shown that it distributes between two pools, one which corresponds to a membrane-bound enzyme, the other to a soluble enzyme. The subcellular distribution of gamma-GT is discussed by comparison with the patterns of distribution of classical marker enzymes.

Animals↗
PubMedDate not supplied

[Influence of the structure of photoreactive ATP analogs on the affinity modification of phenylalanyl-tRNA synsthetase. Modification of the enzyme at two types of nucleotide sites].

ATP gamma-(p-azidoanilidate) (1) and ATP gamma-(p-azidobenzyl)-methylanilidate (2) were shown to be competitive inhibitors for ATP and amino acid in tRNA aminoacylation catalyzed by E. coli MRE-600 phenylalanyl-tRNA synthetase (E.C.6.1.1.20). Low concentration (10(-5)--10(-6) M) of either ATP, gamma-anilidate or GMP stimulates the aminoacylation of tRNA suggesting their interaction with some nucleotide binding sites of the enzyme other than catalytic ones. Covalent photobinding of (1) to the enzyme does not inhibit aminoacylation, nor does it prevent nucleotides from activating the enzyme. UV-irradiation of the synthetase in the presence of (2) results in complete inactivation of the enzyme which can be prevented by phenylalanine or phenylalanine-ATP to save 50% of the enzyme activity but not ATP and tRNA. The photobinding of (2) to the enzyme in the presence of phenylalanine and ATP removes the activation of the enzyme by nucleotides suggesting that both the catalytic and effector sites of the synthetase are blocked in the same manner by compound (2).

Adenosine Triphosphate↗
PubMed1979

[Aminopeptidase activity in "Corynebacterium vaginale" (author's transl)].

Aminopeptidase activity can only be detected in significant amounts in Gram-negative bacteria with a test reaction using L-alanine-4-nitro-anilide as substrate. Corynebacterium vaginale show no aminopeptidase activity even after prolonged reaction times. This indicates surely that this microorganism is nt a Gram-negative bacteria.

Aminopeptidases↗