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PubMed1978

New observations concerning the chloroacetaldehyde reaction with some tRNA constituents. Stable intermediates, kinetics and selectivity of the reaction.

The stable intermediates formed in the reaction of cytosine, cytidine and adenosine with chloracetaldehyde were isolated. The -CH2CH/OH/- bridge between the exo and endo nitrogen atoms of the parent base was found in these compounds by means of PMR spectroscopy. Their acid-induced dehydration resulted in formation of appropriate ethenoderivatives. The rate constants of the intermediate formation and its dehydration were found to be 38x10(-4) and 47x10(-4) /min-1/ for adenosine, and 33x10(-4) and 10x10(-4) /min-1/ for cytidine. The PH range of 4.5--5.0 was found to be optimum for both adenosine and cytidine reactions. The quantitative modification of these two nucleosides in the presence of guanosine may be achieved with high selectivity only at a low pH of 3.0--4.0 N6-methyladenosine and N4-methylcytidine react quantitatively with chloroacetaldehyde and the reaction rate is higher than in the case of the parent nucleosides. The structure of the reaction products was assigned on the basis of PMR spectroscopy.

Acetaldehyde↗
PubMed1978

Recognition of individual procaryotic and eucaryotic transfer-ribonucleic acids by B subtilis adenine-1-methyltransferase specific for the dihydrouridine loop.

Bulk tRNA from yeast and Rat liver can be methylated in vitro with -adenosylmethionine and B, subtilis extracts. The sole product formed is 1-methyladenosine (m1A). This tRNA (adenine-1) methyltransferase converts quantitatively the 3'-terminal adenosine-residue in the dihydrouridine-loop of tRNAThr and tRNATyr from yeast into m1A. Out of 16 eucaryotic tRNAs with known sequences 6 accepted methyl groups, all at a molar ratio of 1. These tRNAs have in common an unpaired adenosine-residue at the specific site in the sequence Py-A-A+-G-G-C-m2G. Out of 12 tRNAs from E. coli 6 served as specific substrates. These E. coli tRNAs also have an unpaired adenosine-residue at the 3'-end of the D-loop. Besides restrictions in primary structure intact secondary and tertiary structure is important for recognition of the specific tRNAs by the enzyme.

Bacillus subtilis↗
PubMed1977

Spontaneous deamidation of a protein antibiotic, neocarzinostatin, at weakly acidic pH. Conversion to a homologous inactive preneocarzinostatin due to change of asparagine 83 to aspartic acid 83 accompanied by conformational and biological alterations.

The amide content of neocarzinostatin (NCS), an antitumor protein, has been determined by analysing asparagine and glutamine in the Pronase-aminopeptidase M digests of tetra-S-carboxymethyl-NCS and carboxyl-modified NCS (modified with a water-soluble carbodiimide and [14C]glycine methyl ester). Preneocarzinostatin (PRE) was separated and purified from a crude NCS preparation by CM-cellulose column chromatography. PRE was found to contain one mole less asparagine than NCS, and asparagine was deamidated to aspartic acid in PRE. A time-dependent conversion of NCS to PRE at pH 3.2 at 4 degrees or in 0.1 M acetic acid at 26 degrees was studied in two ways; first, by quantitative determination of NCS and PRE by CM-cellulose column chromatography and second, by following the release of free NH3 during dialysis in an air-tight container. Within experimental error, PRE was indistinguishable from NCS in amino acid content after acid hydrolysis, as well as in apparent molecular weight as determined by SDS-disc gel electrophoresis (10% acrylamide), and N- and C-terminal amino acid residues. Both NCS and PRE shared a common antigenicity as determined by Ouchterlony's agar diffusion method. Only a slight difference between the two in electrophoresis on a cellulose acetate membrane and on a peptide map of the tryptic digest was demonstrated. PRE, however, was completely devoid of biological activity. In addition to the chromatographic difference, a conformational difference was observed by CD spectroscopy, namely, an apparently looser structure of PRE was indicated by the shallowness of the trough in the 240-265 nm region. This interpretation was supported by the finding that digestions by Pronase were more extensive with PRE than with NCS. These results indicate an important role of the single asparagine residue (Asn 83) of NCS in the biological activity, which is evidently governed by the conformation.

Amino Acids↗
PubMed1976

Coenzyme properties of NAD+ bound to different matrices through the amino group in the 6-position.

A method for the synthesis of N6-(2-aminoethyl)-NAD+ is given. The binding of this NAD+ derivative to different soluble and insoluble supports and the direct coupling of NAD+ to epoxyactivated Sepharose are described. Proofs are given that NAD+ is bound through the amino group in 6- position and the NAD+ derivative through the aliphatic amino group of the side chain. Non-enzymic reduction of the bound coenzyme to an almost quantitative extent is possible in all cases, but the enzymic reduction is largely influenced by the support. While N6-(2-aminoethyl)-NAD+ coupled to soluble dextran is nearly completely reducible by different dehydrogenases with a velocity of about 40% of that for free NAD+, the coenzyme bound to different insoluble matrices is very slowly reduced. Only 5% of the coenzyme derivative bound to BrCN-activated Sepharose are reducible, but 40% when it is bound through a spacer. From capacity determinations evidence is given that, even in this coenzyme gel, only those coenzyme molecules are useful in affinity chromatography which are on the surface of the gel grains; it is supposed that this may be due to the slow diffusion of an enzyme into the inner parts of an affinity gel.

Binding Sites↗
PubMed1977

Intramolecularly-quenched fluorescent peptides as fluorogenic substrates ofleucine aminopeptidase and inhibitors of clostridial aminopeptidase.

Fluorogenic oligopeptide derivatives of the type Lys(ABz)-ONBzl, where ABz iso-aminobenzoyl (anthraniloyl), X stands for Ala Phe, or Ala-Ala, and ONBzlis p-nitrobenzyloxy, were synthesized and shown to be hydrolyzed by leucine aminopeptidase. The hydrolysis is accompanied by an increase in fluorescence due to disruptionof the intramolecular quenching of the fluorescent anthraniloyl moiety by the nitrobenzyester group. The spectral characteristics of the compounds are not consistent withan energy transfer mechanism according to Förster, therefore the quenching isassumed to be caused by a direct encouter between the quenching and the fluorecentgroups. The change in fluorescence that accompanies the enzymic hydrolysis ofthe first peptide bound was used for quantitative measurement of the activity ofthe activity of leucine aminopeptidase and for the determination of some of itskinetic parameters. A bacterial aminopeptidase from Clostrdium histolyticumthat is very similar to leucine aminopeptidase in its substrate specificity inits substrate specificity did not hydrolyze the above peptidederivatives. Thehydrolysis of leucine p-nitroanilide by this enzyme was found to be inhibitedby the three peptides and the corresponding inhibition constants were determined.

Aminopeptidases↗
PubMed1975

Characterization of bleomycin action on DNA.

Cleavage of SV40 DNA by bleomycin was assayed quantitatively in vitro in the presence of various ppolynucleotides. SV40 DNA was protected from bleomycin- duced cleavage by native or denatured DNA of other origins, oly dG-C.poly dG-C, poly dA-T.poly dA-T and poly dA-T (denatured) but not by tRNA of E. coli, apurinic acid, poly dA, poly dT and various deoxyribooligonucleotides. Various bleomycins and their derivatives and various fragments of bleomycin were tested for possible activity in cleaving SV40 DNA and from the results some structure-activity relationships for the action of bleomycin to act on DNA were outlined. Actinomycin D stimulated bleomycin action while ethidium bromide inhibited it.

Animals↗
PubMedDate not supplied

[Quantitative comparison of ribosome binding sites of twelve nucleotide sequences from Escherichia coli (RNA- and DNA phages) based on triplet patterns (author's transl)].

The molecular structure of ribosome binding sites of ten phage genes and two messengers of Escherichia coli were compared concerning the signation parts which are presumably used by ribosomes for recognition and binding. With a simple calculation based on triplet patterns sofar unknown agreements between all of these sequences were found. In several cases it was shown that agreements between old sequences are easier recognizable if the purine- and pyrimidine bases are put into the triplets instead of the four A, G, C, and U (T) bases. In such cases "homologous" parts of sequences were recognized with more distinctness. This is true in our case for the double triplet (hexaplet) py-pu-pu-pu-pu-(pu) and the binding site triplet py-pu-pu, which are preceding the initiator. These triplets are in specific positions in all twelve sequences which were compared. The different course of the quaternary and the binary conformity curves (diagram 1) may show for the investigated area that the RNA phage gene-part is organized according to the well known quaternary triplet code. On the contrary the phage phi-gene-part seems to be organized according to a more simple, binary triplet sequence of purine and pyrimidine bases. The binary sequence seems to be the more original, the quaternary the derived one.

Base Sequence↗
PubMed1979

[Hansch analysis of the inhibitory action of 3- and 4-substituted benzamidines on thrombin, plasmin and trypsin (author's transl)].

Using Hansch formalism, the suthors studied quantitatively the relationship between the structure and the inhibitory action of 3- and 4-substituted amidinophenyl derivatives on thrombin, plasmin and trypsin. It was found that the inhibitory action on all three enzymes depends in the same way from the hydrophobic and electronic properties of the substituents and from an additional term in case of substituents with X-CO-Y structure. The predictive value of the equations is satisfactory.

Amidines↗
PubMed1975

Synthesis and study of the estrogenic activity of 2,4-bis(bromomethyl)estradiol-17 beta 3-methyl ether.

Synthesis of 2,4-bis(bromomethyl)estradiol-17 beta 3-methyl ether (BBE2M) was accomplished by reducing a methanolic solution of 2,4-bis(bromomethyl)estrone methyl ether with sodium borohydride. In 0.5 M phosphate buffer, pH 7.0, 25 degrees, BBE2M readily reacts with Ellman's anion and alkylates cysteine to form a steroid-amino acid conjugate. Stoichiometry of the reaction indicates that the bromosteroid is divalent with cysteine. Tryptophan and histidine react more slowly with the bromosteroid. Estrogenic activity of BBE2M was evaluated in ovariectomized rats by uterine intraluminal administration and quantitation of glucose-6-phosphate dehydrogenase (D-glucose-6-P:NADP+ oxidoreductase, EC 1.1.1.49) activity in the uterus. BBE2M induced glucose-6-phosphate dehydrogenase activity as did estradiol-17 beta or estradiol-17 beta 3-methyl ether (E2M). BBE2M was more persistent in activity than E2M. Histological examination of uterus following BBE2M treatment shows classic estrogenic morphology. BBE2M covalently binds to the cytoplasmic estrogen receptor of calf uterus. Such binding is prevented by pretreatment of the receptor protein with estradiol-17 beta. The covalently bound steroid-receptor complex appears to stimulate RNA synthesis in isolated nuclei from calf endometrium.

Animals↗
PubMed1975

[Antiviral thiosemicarbazone and related compounds. III. Quantitative relationships between structure and antiviral activity of isantin-beta-isothio-semicarbazone against mengo virus].

The virostatic activity of isatin-beta-isothiosemicarbazones can be described quantitatively by hydrophobic, electronic, and steric substituent constants using multivariate regression analysis. A preceding Free-Wilson analysis allows data smoothening, and thus improved adaptation. Predictions made on the basis of the quantitative structure-action relationships obtained could be confirmed experimentally by synthesizing and testing the corresponding compounds.

Antiviral Agents↗
PubMed1976

Mechanism of salt-mediated inhibition of lipoprotein lipase.

The activity of lipoprotein lipase isolated from rat postheparin plasma has been determined with synthetic lipids, in the presence and absence of apoprotein of the natural substrate very low density lipoprotein, as a function of medium ion-pair concentration of a number of different inorganic salts. The several kinetic effects of lipoprotein protein on lipase activity were specifically and quantitatively reversed in the presence of molar sodium chloride or solutions of equivalent effective ion concentrations of other salts. Salt-mediated inhibition was fully reversible by silution and was independent of substrate concentration. Inhibition was a function of the identity of the salt anion within a Hofmeister (lyotropic) series: I- greater than SCN- greater than NO3- greater than Cl- greater than F-, and, in these terms, was not significantly different for a series of inorganic chlorides (Li+, Na+, K+, Cs+). The effects of salts on the natural lipoprotein substrates, chylomicrons, and very low density lipoproteins were similar to those obtained with a synthetic lipid-protein substrate complex. These findings are discussed in the light of recent ideas on the activation of lipoprotein lipase.

Animals↗
PubMed1975

Use of 5-deazaFAD to study hydrogen transfer in the D-amino acid oxidase reaction.

The apoprotein of hog kidney D-amino acid oxidase was reconstituted with 5-deazaflavin adenine dinucleotide (5-deazaFAD) to yield a protein which contains 1.5 mol of 5-deazaFAD/mol of enzyme. The deazaFAD-containing enzyme forms complexes with benzoate, 2-amino benzoate, and 4-aminobenzoate which are both qualitatively and quantitatively similar to those observed with native enzyme. The complex with 2-aminobenzoate exhibits a new long wavelength absorption band characteristic of a flavin charge-transfer complex. The reconstituted enzyme exhibits no activity when assayed by D-alanine oxidation. However, the bound chromophore can be reduced by alanine, phenylalanine, proline, methionine, and valine, but not by glutamate or aspartate, indicating the deazaFAD enzyme retains the substrate specificity of the native enzyme. Reduction of the enzyme by D-alanine exhibits a 1.6-fold deuterium isotope effect. Reoxidation of the reduced enzyme occurred in the presence of pyruvate plus ammonia, but not with pyruvate alone or ammonia alone. beta-Phenylpyruvate and alpha-ketobutyrate, but not alpha-ketoglutarate could replace pyruvate. Reduced enzyme isolated following reaction with [alpha-3H]alanine was found to contain 0.5 mol of tritium/mol of deazaFADH2. After denaturation of the tritium-labeled enzyme, the radioactivity was identified as deazaFADH2. Reaction of the reduced tritium-labeled enzyme with pyruvate plus ammonia prior to denaturation yields [alpha-3H]alanine and unlabeled deazaFAD. These results suggest that reduction and reoxidation of enzyme-bound deazaFAD involves the stereo-specific transfer of alpha-hydrogen from substrate to deazaFAD.

Aminobenzoates↗
PubMed1979

Nonlinear dependence of biological activity on hydrophobic character: the bilinear model.

In homologous series of compounds biological activity is linearly dependent on hydrophobic character until a cut-off point is reached where this linear relationship changes to a nonlinear relationship: biological activity increases with increase of hydrophobic character, reaches a maximum and then decreases with further increase of hydrophobic character. Drug transport in biological systems is determined by the rate constants of transfer of the drug through aqueous and organic compartments. In simple in vitro systems the rate constant k1 of transport of a drug from an aqueous phase into an organic phase and the rate constant k2 of the reverse process can be described as functions of the partition coefficient P: log k1 = log P - log (beta P + 1) + c and log k2 = - log (beta P + 1) + c. Observed and calculated k1 and k2 values are used to simulate drug transport in different multicompartment systems. Based on the McFarland probability model a new model for the quantitative description of the dependence of biological activity on hydrophobic character, called bilinear model, log 1/C = a log P - b log (beta P + 1) + C, has been derived recently: unsymmetrical curves with linear ascending and descending sides and a parabolic part within the range of optimal lipophilicity result from this model. The bilinear model is applied to experimental data of drug absorption, drug distribution and drug activity in biological systems. A comparison of the parabolic model and the bilinear model shows that in nearly all cases a better fit of the data results from the bilinear model.

Acids↗