Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Eighteen chemicals were tested for their mutagenic potential in the L5178Y tk+/- mouse lymphoma cell forward mutation assay by the use of procedures based upon those described by Clive and Spector [Mutat Res 44:269-278, 1975] and Clive et al [Mutat Res 59:61-108, 1979]. Cultures were exposed to the chemicals for 4 hr, then cultured for 2 days before plating in soft agar with or without trifluorothymidine (TFT), 3 micrograms/ml. The chemicals were tested at least twice. Significant responses were obtained with benzofuran, benzyl chloride, bromodichloromethane, butylated hydroxytoluene, chlorendic acid, o-chlorobenzalmalonitrile, 1,2,3,4-diepoxybutane, dimethyl formamide, dimethyl hydrogen phosphite, furfural, glutaraldehyde, hydroquinone, 8-hydroxyquinoline, and resorcinol. Apart from bromodichloromethane, butylated hydroxytoluene and dimethyl hydrogen phosphite, rat liver S9 mix was not a requirement for the activity of any of these compounds. Chemicals not identified as mutagens were water, tert-butyl alcohol, pyridine, and witch hazel.
Environ Mol Mutagen 1988
PMID:Responses of the L5178Y tk+/tk- mouse lymphoma cell forward mutation assay. II: 18 coded chemicals. 333 42

The putative serotonin (5-HT) agonist RU 24969 [5-methoxy-3-1,2,3,6-tetrahydropyridin-4-yl)indole; 5-MeO-THPI] has been extensively used in the study and classification of 5-HT receptors. In order to study molecular determinants for recognition of THPIs at central 5-HT recognition sites, about 25 additional THPI derivatives were synthesized, incorporating, among others, 16 different indole-5-substituents and three different pyridine-N substituents in various combinations. Two saturated derivatives (piperidin-4-ylindoles) and two 2-methyl analogs were also included. Binding affinities at 5-HT1A, 5-HT2, and total 5-HT1 sites were obtained and the data were incorporated in quantitative structure-activity relationships (QSARs) using a combined linear free energy/molecular modeling approach. The QSAR analyses suggest distinct differences in the structural features that determine optimal potency at 5-HT1A sites versus those directing optimal potency for 5-HT2 sites. The parameter of the indole-5 substituent that almost exclusively determines potency for 5-HT1A sites is volume, the optimal size being about 24 cubic angstroms (calculated by fitting the activity versus volume data to a bilinear function). This is approximately the size of a carboxamide group. In contrast, at the 5-HT2 site both volume and hydrophobicity play major but opposing roles for the 5-substituent. A balance between the smallest possible volume and the greatest possible hydrophobicity is required for maximal 5-HT2 potency. Benzyl groups on the indole-1 or pyridyl-1 positions also favor potency at the 5-HT2 site (probably largely due to increased hydrophobic binding) while decreasing potency at the 5-HT1A site. A minor electronic contribution to the QSARs involving the charge on the indole 5-carbon is of opposite sign for 5-HT1A versus 5-HT2 sites and thus may also be useful for selective drug design. The data are consistent with the possibility that the indole and pyridyl rings are in a coplanar configuration when binding at both 5-HT1A and 5-HT2 sites, because the indole-2-methyl substituent, which provides a large energy barrier to the coplanar configuration, greatly reduces the potency of THPIs at both binding sites. Similarities in analog selectivity patterns suggest that the indolic portion of these compounds binds similarly to that of other indole derivatives such as tryptamines; thus, it is possible that optimally selective substituents predicted by these QSARs may be extrapolated to tryptamines and other indoles.
Mol Pharmacol 1988 Jul
PMID:Molecular determinants for recognition of RU 24969 analogs at central 5-hydroxytryptamine recognition sites: use of a bilinear function and substituent volumes to describe steric fit. 339 40

Comparative studies on the reactivity of the heterocyclic nitrogen were carried out for pyridine and its three monosubstituted derivatives 2-aminopyridine (2-AP), 3-aminopyridine (3-AP), and 4-aminopyridine (4-AP) to reveal the structural basis for the differences in their susceptibility to N-oxidation. Molecular orbital calculations were performed to obtain the wave functions for the calculation of the molecular electrostatic potentials (MEP) generated by the molecules. The comparison of the reactivity of the cyclic nitrogen, evaluated from the depth and accessibility of the minimum in the MEP, indicates that the nitrogen in 4-AP will be most susceptible to protonation and will be the most protected from N-oxidation at physiological pH values. The MEP map for 2-AP reveals the smallest minimum in the series of compounds and a considerable reduction in the accessibility of the region near the cyclic nitrogen caused by the proximal substitution. On this basis, 3-AP becomes the most likely derivative to form the ring N-oxide. Comparison of the conclusions from the MEP analysis with available data from bioassays suggests that the mechanism responsible for the genotoxic effects of the chemicals, where only 3-AP is active, is very different from the mechanism for systemic toxicity where 3-AP is the least active, and 4-AP is most active probably due to its channel blocking properties. As the mechanisms for the biological activities of the N-oxide metabolites become clear, reliable predictions of the toxicity of the pyridines should become possible based on such reactivity characteristics.
Mol Toxicol
PMID:Analysis of the molecular electrostatic potential for the prediction of N-oxidation and biological activity of substituted pyridines. 344 54

The glutathione reductase from E. coli was rapidly inactivated following aerobic incubation of the pure and cell-free extract enzymes with NADPH, NADH and other reductants. The inactivation of the pure enzyme depended on the time and temperature of incubation (t 1/2 = 2 min at 37 degrees C), and was proportional to the [NADPH]/[enzyme] ratio, reaching 50% in the presence of 0.3 microM NADPH and 45 microM NADH respectively, at a subunit concentration of 20 nM. Higher pyridine nucleotide concentrations were required to inactivate the enzyme from cell-free extracts. Two apparent pKa, corresponding to pH 5.8 and 7.3, were determined for the redox inactivation. The enzyme remained inactive even after eliminating the excess NADPH by gel chromatography. E. coli glutathione reductase was protected by oxidized and reduced glutathione against redox inactivation with both pure and cell-free extract enzymes. Ferricyanide and dithiothreitol protected only the pure enzyme, while NADP+ exclusively protected the cell-free extract enzyme. The inactive glutathione reductase was reactivated by treatment with oxidized and reduced glutathione, ferricyanide, and dithiothreitol in a time-and temperature-dependent process. The oxidized form of glutathione was more efficient and specific than the reduced form in the protection and reactivation of the pure enzyme. The molecular weight of the redox-inactivated E. coli glutathione reductase was similar to that of the dimeric native enzyme, ruling out aggregation as a possible cause of inactivation. A tentative model is discussed for the redox inactivation, involving the formation of an 'erroneous' disulfide bridge at the glutathione-binding site.
Mol Cell Biochem 1985 May
PMID:Redox interconversion of glutathione reductase from Escherichia coli. A study with pure enzyme and cell-free extracts. 389 32

The pncB locus of the pyridine nucleotide cycle of NAD biosynthesis in Salmonella typhimurium was examined in terms of genetic structure and regulation. The gene appears to be regulated at the level of transcription in response to the end product of the pathway, NAD. Insertions into promotor proximal regions of the gene relinquish it from regulation, while insertions into more distal regions allow retention of regulation. Regulation cannot be restored in trans to strains containing promotor proximal insertions implicating the existence of a cis acting regulatory region.
Mol Gen Genet 1985
PMID:Identification of a cis-acting regulatory region in the pncB locus of Salmonella typhimurium. 389 85

1,4-bis-[2-(3,5-Dichloropyridyloxy)]-benzene (TCPOBOP) was previously shown to be an extremely potent phenobarbital-like inducer of hepatic microsomal monooxygenase activity in the mouse. To examine the structure-activity relationship, 31 congeners of TCPOBOP were synthesized and tested for their potency to induce hepatic aminopyrine N-demethylase activity in B6D2F1/J mice. For biological activity, the minimum requirement is a) a central 1,4-dioxygenated benzene ring, b) lateral pyridine rings linked to the central ring by ether bonds, but with other lateral heteroaromatic rings, e.g., quinoline or pyrimidine, also active, c) 5,5'-substituents of Cl, Br, or NO2 on the pyridine rings. For a series of 5,5'-substituted and 3,3'-dichloro,5,5'-substituted bispyridyloxybenzenes, no correlation was observed for Hansch pi and sigma p values. To account for this lack of correlation and conformational variability produced by the two ether bonds, we performed x-ray structure determinations on three compounds: a) TCPOBOP, b) the 5,5'-dichloro analogue, and c) the biologically inactive, 3,3'-dichloro analogue. In the two biologically active congeners the positioning of the pyridine rings is anti to the plane of the central benzene ring, and the dihedral angle between the central ring and the pyridines is approximately 60 degrees. In the inactive analogue the pyridine rings are syn and the dihedral angle is 84 degrees. The x-ray crystallographic data are consistent with the ether oxygen having an sp2-bonding conjugating with the heterodipolar bond of the pyridine C(2)--N(1), which strongly restricts rotation about the ether bonds. The potency of TCPOBOP and other bispyridyloxybenzene analogues to induce a phenobarbital-like pleiotropic response and the sharply defined structure-activity relationship among these congeners support the hypothesis that they act by binding to a specific recognition site.
Mol Pharmacol 1985 Nov
PMID:Structure-activity relationship of bispyridyloxybenzene for induction of mouse hepatic aminopyrine N-demethylase activity. Chemical, biological, and X-ray crystallographic studies. 405 24

Aspartate aminotransferase is a pyridoxal phosphate-dependent enzyme that catalyses the transamination reaction: L-aspartate + 2-oxoglutarate----oxaloacetate + L-glutamate. The enzyme shuttles between its pyridoxal and pyridoxamine forms in a double-displacement process. This paper proposes a mechanism of action that delineates the dynamic role of the protein moiety of this enzyme. It is based on crystallographically determined spatial structures (at 2.8 A resolution) of the mitochondrial isoenzyme in its unliganded forms and in complexes with substrate analogues, as well as on model building studies. The enzyme is composed of two identical subunits, which consist of two domains. The coenzyme is bound to the larger domain and is situated in a pocket near the subunit interface. The proximal and distal carboxylate group of dicarboxylic substrates are bound to Arg386 and Arg292 , respectively, the latter residue belonging to the adjacent subunit. These interactions largely determine the substrate specificity of the enzyme. They not only position the substrate efficient catalysis but also bring about a bulk movement of the small domain that closes the active site crevice and moves Arg386 about 3 A closer to the coenzyme. The replacement of the epsilon-amino group of Lys258 by the alpha-amino group of the substrate in the aldimine bond to pyridoxal phosphate is accompanied by a tilting of the coenzyme by approximately 30 degrees. The released epsilon-amino group of Lys258 serves as a proton acceptor/donor in the 1,3- prototropic shift producing the ketimine intermediate. At this stage, or after hydrolysis of the ketimine bond, the coenzyme rotates back to an orientation between that in the "external" aldimine intermediate and that in the pyridoxal form. Throughout this process, the protonated pyridine nitrogen atom maintains a hydrogen bond to the beta-carboxylate group of Asp222 . Upon formation of the pyridoxamine form, the small domain moves back to its original position. The proposed mechanism is compatible with the known kinetic and stereochemical features of enzymic transamination.
J Mol Biol 1984 Apr 15
PMID:Mechanism of action of aspartate aminotransferase proposed on the basis of its spatial structure. 614 29

Niridazole, an antischistosomal nitrothiazole derivative, is metabolized by adult Schistosoma mansoni to one or more reactive intermediates, as evidenced by extensive covalent binding of [14C]niridazole to parasite macromolecules. When worm pairs were incubated for 16 hr in culture medium containing 70 microM [14C]niridazole, 26-34% of the total parasite-associated radioactivity was irreversibly bound to trichloroacetic acid-precipitable material. Drug binding was both time- and [14C]niridazole concentration-dependent. Of the bound drug fraction, 85-90% was associated with parasite proteins, 3-5% with RNA and 4-7% with DNA. When schistosomes were recovered from infected mice, treated with periodic doses of [14C]niridazole, over 40% of the total parasite-associated radioactivity was bound to macromolecules. Niridazole caused up to a 40% decrease in the concentration of total nonprotein thiols in intact schistosomes incubated with the drug over an 8-hr period. Under strictly anaerobic conditions, cell-free schistosome preparations catalyzed a reduced pyridine nucleotide-dependent reduction of niridazole's essential nitro group, as evidenced by disappearance of absorption at 400 nm. Net nitroreduction did not occur under aerobic conditions, although the drug did stimulate oxidation of the pyridine nucleotide cofactor. Covalent binding of [14C]niridazole also took place in this cell-free system, with requirements identical with those needed for enzymatic nitroreduction. Covalent drug binding, but not nitroreduction, was inhibited up to 80-85% by 2 mM L-cysteine, N-acetyl-L-cysteine, or glutathione; S-carboxymethyl-L-cysteine, which has no free sulfhydryl group, was not inhibitory. [14C]4'-Methylniridazole, a nonschistosomicidal analogue of niridazole, was taken up by intact schistosomes in vitro, but was not metabolized and did not bind covalently to parasite macromolecules. Furthermore, 4'-methylniridazole did not affect the concentration of nonprotein thiols in intact parasites and did not serve as a substrate for schistosomal nitroreductase in vitro. These results indicate a positive correlation between proximal metabolic activation of niridazole within these facultative anaerobic organisms and its antiparasitic activity.
Mol Pharmacol 1983 Sep
PMID:Reductive metabolism of niridazole by adult Schistosoma mansoni. Correlation with covalent drug binding to parasite macromolecules. 619 6

Pharmacological studies have provided considerable information about the molecular structure of ion channels in the membranes of excitable cells. Two classes of drugs, the local anesthetics and the biotoxins, have been used to study sodium channels in nerve, skeletal muscle, and cardiac cells, and tetraethylammonium ion and many of its derivatives have provided structural information about potassium channels in nerve. More recently, organic compounds that block calcium channels (calcium channel antagonists) have begun to be used to probe calcium channels in cardiac and smooth muscle cells (see). One group of calcium channel blockers, the dihydropyridines, has provided considerable information on the structure and function of these channels on the basis of electrophysiological and binding studies. Slight modification of the structure of one of these dihydropyridines, nifedipine, has led to the discovery of a group of compounds that are presumed to act by increasing the influx of Ca2+ into cardiac and smooth muscle cells. One of these novel compounds, Bay K 8644 (methyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)-pyridine-5 carboxylate) has been reported to act at the same receptor site as the calcium channel antagonist nifedipine, but enhances contractile activity of the perfused heart and aortic strips. Because activation of contraction in cardiac muscle is closely linked to calcium entry via voltage-dependent calcium channels (see for review) these results suggested that Bay K 8644 might act on these channels.
J Mol Cell Cardiol 1984 Jul
PMID:Regulation of cardiac calcium channel current and contractile activity by the dihydropyridine Bay K 8644 is voltage-dependent. 620 31

The structure of oxidized flavodoxin from the cyanobacterium Anacystis nidulans has been determined at 2.5 A resolution with phases calculated from ethylmercury phosphate and dimercuriacetate derivatives. The determination of partial sequences, including a total of 85 residues, has assisted in the interpretation of the electron density. Preliminary refinement of a partial model (1072 atoms) has reduced R to 0.349 for the 10.997 reflections between 2.0 and 5.0 A with 1 greater than 2 sigma. The polypeptide backbone, which comprises 167 residues in the current model, adopts the familiar beta-alpha-beta conformation found in other flavodoxins and in the nucleotide-binding domains of the pyridine-nucleotide dehydrogenases, with five parallel strands in the central sheet. Comparison with flavodoxin from Clostridium MP (138 residues) shows that extra residues of A. nidulans flavodoxin are accommodated in a major insertion about 20 residues in length, which forms a lobe adjacent to the fifth strand of parallel sheet, and in additions to several external segments. Residues added between the fourth sheet strand and the start of the third helix alter the environment of the pyrimidine end of the flavin mononucleotide ring. The flavin mononucleotide phosphate binds to the start of helix 1, interacting with hydroxyamino acids and with main-chain amide groups. Two hydrophobic residues, both tentatively identified as Trp, enclose the isoalloxazine ring; the solvent-exposed Trp is nearly parallel to the flavin ring. The hydrophobic environment provided by these residues must be partly responsible for the pronounced vibrational resolution of the flavin spectrum near 450 nm. The flavin ring is tilted relative to its orientation in Clostridium MP flavodoxin. In addition, atoms N-3 and O-2 alpha of the isoalloxazine appear to form hydrogen bonds to the backbone at CO97 and NH99 in a conformation entirely different from that found in Clostridium MP flavodoxin but structurally analogous to Desulfovibrio vulgaris flavodoxin.
J Mol Biol 1983 Apr 25
PMID:Structure of oxidized flavodoxin from Anacystis nidulans. 640 74


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