Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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The linear dichroism (LD) spectra of the C-phycocyanin (C-PC) trimer disks oriented in poly(vinyl alcohol) films (PVA) at room temperature and at 95 K were determined. Utilizing the known atomic coordinates of the chromophores (Schirmer, T., Bode, W. and Huber, R. (1987) J. Mol. Biol. 196, 677-695) and theoretical estimates of the orientations of the transition dipole moments relative to the molecular framework, the LD spectra were simulated using the pairwise exciton interaction model of Sauer and Scheer (Biochim. Biophys. Acta 936 (1988) 157-170); in this model, the alpha 84 and beta 84 transition moments are coupled by an exciton mechanism, while the beta 155 chromophore remains uncoupled. Linear dichroism spectra calculated using this exciton model, as well as an uncoupled chromophore (molecular) model, were compared with experimental LD spectra. Satisfactory qualitative agreement can be obtained in both the exciton and molecular models using somewhat different relative values of the theoretically estimated magnitudes of the beta 155 oscillator strength. Because the relative contributions of each of the chromophores (and thus exciton components) to the overall absorption of the C-PC trimer are not known exactly, it is difficult to differentiate successfully between the molecular and exciton models at this time. The linear dichroism spectra of PC dodecamers derived from phycobilisomes of Nostoc sp. oriented in stretched PVA films closely resemble those of the C-PC trimers from Mastigocladus laminosus, suggesting that the phycocyanin chromophores are oriented in a similar manner in both cases, and that neither linker polypeptides nor the state of aggregation have a significant influence on these orientations and linear dichroism spectra. The LD spectra of oriented phycocyanins in stretched PVA films at low temperatures (95 K) appear to be of similar quality and magnitude as the LD spectra of single C-PC crystals (Schirmer, T. and Vincent, M.G. (1987) Biochim. Biophys. Acta 893, 379-385).
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PMID:Orientation and linear dichroism of Mastigocladus laminosus phycocyanin trimer and Nostoc sp. phycocyanin dodecamer in stretched poly(vinyl alcohol) films. 190 56

As part of an ongoing program to develop high affinity estrogenic ligands we have synthesized the 11 beta-vinyl, 11 beta-ethyl- and 1,11 beta-ethanoestradiols. Because the 1,11 beta-ethano-estradiol had not been previously reported in the literature, the investigation of its receptor binding characteristics would provide valuable insight into the effect of 1/11 beta-substitution. The data obtained in this study indicate that although significant estrogen receptor affinity is present for the 1,11 beta-ethano derivative, the RBA values, 5-22.4%, were far less than those observed (5-300-fold less) for the corresponding 11 beta-ethyl and 11 beta-vinyl estradiols and less than those for the 1-methyl and 11 beta-methyl estradiols. These results suggest that the orientation that the 11 beta-substituent must occupy is directed away from the A-ring and that substituents in the 1-11 pocket produce a detrimental effect on receptor interactions.
J Steroid Biochem Mol Biol 1990 Oct
PMID:Estrogen receptor binding characteristics of 1,11 beta-ethanoestradiol: effect of a 1,11 beta-bridge on steroidal estrogen. 226 62

Structural features of the heme and the heme cavity of the monomeric hemoglobin (Hb) from the platyhelminth Dicrocoelium dendriticum were investigated by optical and proton nuclear magnetic resonance spectroscopy. Using nuclear Overhauser effects (NOEs) from resonances assigned previously through isotope labeling, most hyperfine-shifted resonances could be attributed to individual heme and protein protons in the cyano-metHb complex. It was observed that the heme 2-vinyl group is held in the trans orientation by nearby residues, whereas the 4-vinyl group exhibits an equilibrium between cis and trans orientations. NOE experiments in 1H2O allowed the identification of exchangeable protons belonging to the proximal histidine residue (F8) and to a distal residue. Detailed analysis of the NOE patterns obtained from the distal labile proton to non-labile protons and among these latter protons leads to the conclusion that a tyrosine side-chain occupies the distal site E7. Optical spectra of the alkaline-metHb also lead to this view, in that they are not typical of a hydroxy-metHb complex but instead resemble that of a hemin-phenolate or human mutant (M-type) Hb with a tyrosine residue linked to the iron atom. Further evidence for a distal tyrosine residue stems from the occurrence of an unusually stable transient ferrous Hb-cyanide complex, formed upon reduction of cyano-metHb to deoxy-Hb with dithionite. We suggest that the stability of this intermediate is due to a slow re-orientation of a large distal side-chain prior to cyanide dissociation. The sequence of the E-helix, known from the partially determined primary structure, was realigned to accommodate these findings. A frame-shift by one residue now positions a tyrosine at the distal site E7 instead of the originally proposed glycine residue.
J Mol Biol 1989 Sep 20
PMID:Structural and electronic properties of the liver fluke heme cavity by nuclear magnetic resonance and optical spectroscopy. Evidence for a distal tyrosine residue in a normally functioning hemoglobin. 255 18

The coelomic cells of the common marine bloodworm Glycera dibranchiata contain several hemoglobin monomers and polydisperse polymers. We present the refined structure of one of the Glycera monomers at 1.5 A resolution. The molecular model for protein and ordered solvent for the deoxy form of the Glycera monomer has been refined to a crystallographic R-factor of 12.7% against an X-ray diffraction dataset at 1.5 A resolution. The positions of 1095 protein atoms have been determined with a maximum root-mean-square (r.m.s.) error of 0.13 A, and the r.m.s. deviation from ideal bond lengths is 0.015 A and from ideal bond angles is 1.0 degree. The r.m.s. deviation of planar groups from their least-squares planes is 0.007 A, and the r.m.s. deviation for torsion angles is 1.2 degrees for peptide groups and 16.8 degrees for side-chains. A total of 153 water molecules has been located, and they have been refined to a final average occupancy of 0.80. Multiple conformations have been found for five side-chains, and a change has been suggested for the sequence at five residues. The heme group is present in the "reverse" orientation that differs only in the positions of the vinyl beta-carbons from the "normal" orientation. The doming of the heme towards the proximal side, and the bond distances and angles of the heme and proximal histidine are typical of most deoxy globin structures. The substitution of leucine for the distal histidine residue (E7) creates an unusually hydrophobic heme pocket.
J Mol Biol 1989 Nov 05
PMID:Glycera dibranchiata hemoglobin. Structure and refinement at 1.5 A resolution. 258 15

The selective inactivation by 17 beta-substituted steroids of rabbit and rat liver cytochromes P-450 involved in the 21-hydroxylation of progesterone has been investigated. Five derivatives each of pregnenolone and progesterone were prepared, in which the methylketo substituent of the 17 beta-position was replaced by a dichloromethylketo, chlorofluoromethylketo, difluoromethylketo, vinyl, or ethynyl group. The ability of the compounds to cause time-dependent (inactivation) and time-independent (inhibition) decreases in progesterone hydroxylase activity was assessed in vitro using intact liver microsomes as well as reconstituted systems containing the major forms of hepatic cytochrome P-450 responsible for progesterone 21-hydroxylation, P-450 1 in the rabbit and PB-C in the rat. In each species, one compound was identified that specifically inactivated the 21-hydroxylase, namely 21-chloro-21-fluoropregnenolone in the rabbit and pregn-4,20-diene-3-one in the rat, although both compounds inhibited several other hydroxylases as well. Moreover, the most effective and specific 21-hydroxylase inactivators were not necessarily the most effective or specific inhibitors. These results suggest that conversion of the enzyme-inhibitor complex to metabolites that inactivate the enzyme, rather than complex formation, is the crucial factor in determining the specificity of the compounds as cytochrome P-450 inactivators. The results indicate the feasibility of designing specific inactivators of hepatic cytochromes P-450 by utilizing the normal regioselectivity of the target enzyme towards steroids.
Mol Pharmacol 1989 Jan
PMID:Specific inactivation by 17 beta-substituted steroids of rabbit and rat liver cytochromes P-450 responsible for progesterone 21-hydroxylation. 278 20

3,5-Diethoxycarbonyl-1,4-dihydro-2,6-dimethyl-4-ethylpyridine and its 4-propyl analogue were administered to phenobarbital-pretreated rats. The N-alkylprotoporphyrins (N-alkylPPs) that were isolated from rat livers, viz., N-ethylPP and N-propylPP, were found to have greater ferrochelatase-inhibitory potency than the corresponding synthetic N-alkylPPs. The N-ethylPP that was isolated from rat liver was found to contain 72% of the NB plus NA regioisomers, whereas synthetic N-ethylPP contained 40% of the NB plus NA regioisomers. In contrast, the N-propylPP that was isolated from rat liver contained the same amount of the NB/A regioisomer(s) as synthetic N-propylPP (33%). The NB plus NA regioisomers of N-ethylPP and the NB/A regioisomer(s) of N-propylPP that were isolated from rat liver were found to be significantly more potent than the corresponding synthetic regioisomers. We conclude that 1) the ferrochelatase-inhibitory potency of N-ethylPP that is isolated from rat liver is greater than that of synthetic N-ethylPP, due to differences in both regioisomer composition and the inhibitory potency of the NB plus NA regioisomers and stereoisomers, and 2) the ferrochelatase-inhibitory potency of N-propylPP that is isolated from rat liver is greater than that of synthetic N-propylPP, due solely to the difference in the ferrochelatase-inhibitory potency of the NB/A regioisomer(s) and stereoisomers. From the enhanced ferrochelatase-inhibitory potency of the NB plus NA regioisomers of N-ethylPP and the NB/A regioisomer(s) of N-propylPP that were isolated from rat liver, relative to the corresponding synthetic N-alkyllPP regioisomers, it was inferred that 2- and 4-vinyl substituents located on pyrrole rings A and B contribute to the optimal binding of N-alkylPPs to the ferrochelatase active site.
Mol Pharmacol 1989 Oct
PMID:Evidence for the stereoselective inhibition of chick embryo hepatic ferrochelatase by N-alkylated porphyrins. 281 58

A dynamic flow-through exposure system was designed for mutagenicity studies of gaseous compounds in Salmonella. Salmonella typhimurium strain TA100 was the primary tester strain. The dose ranges were 0.5-20% of vinyl chloride, ethene, propene, and 1,3-butadiene, 1-200 ppm of ethylene oxide, 0.5-20 ppm of nitrogen dioxide, and 0.1-3.5 ppm of ozone. The gas flow rate was 250, 500, or 1,000 ml/min, and the exposure time was 6 or 7 hours. Of the tested gases, vinyl chloride, ethylene oxide, and nitrogen dioxide were mutagenic. Ethene, propene, and 1,3-butadiene were not mutagenic in this system. Ozone is bacteriotoxic, and no mutagenic effect could be demonstrated in the nontoxic dose range. The exposure system was considered suitable for studies on gaseous chemicals.
Environ Mol Mutagen 1988
PMID:A method for studying the mutagenicity of some gaseous compounds in Salmonella typhimurium. 327 8

In order to investigate the possible formation of mutagenic compounds from alkenes emitted in ambient air, laboratory experiments were performed with Salmonella typhimurium strain TA100 in a small-scale flow-through exposure system. The reaction time for mixtures of alkenes with ozone or nitrogen dioxide was 40 minutes, and the exposure time for bacteria was 6 hours. Ozone gave rise to a small mutagenic effect in combination with 1,3-butadiene or vinyl chloride, with and without ultraviolet (UV) irradiation, but not in combination with ethene or propene. Nitrogen dioxide gave rise to a mutagenic effect in combination with propene, 1,3-butadiene, or vinyl chloride, but only after UV irradiation. The mutagenic activity was highest with butadiene and seemed to be dose-related to the concentration of nitrogen dioxide. Nitrogen dioxide with ethene did not produce a mutagenic effect. A mixture of ethene, propene, and butadiene, tested with ozone or nitrogen dioxide with UV irradiation, did not potentiate each other's mutagenic effect.
Environ Mol Mutagen 1988
PMID:Photochemical formation of mutagenic compounds from alkenes and ozone or nitrogen dioxide. 327 9

Seventy-two chemicals were tested for their mutagenic potential in the L5178Y tk+/- mouse lymphoma cell forward mutation assay, using 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 allyl isothiocyanate, p-benzoquinone dioxime, benzyl acetate, 2-biphenylamine HCl, bis(2-chloro-1-methylethyl)ether, cadmium chloride, chlordane, chlorobenzene, chlorobenzilate, 2-chloroethanol, chlorothalonil, cytarabine.HCl, p,p'-DDE, diazinon, 2,6-dichloro-p-phenylenediamine, N,N-diethylthiourea, diglycidylresorcinol ether, 2,4-dimethoxy aniline.HCl, disperse yellow 3, endosulfan, 1,2-epoxyhexadecane, ethyl acrylate, ethyl benzene, ethylene thiourea, F D and C yellow Number 6, furan, heptachlor, isophorone, mercuric chloride, 4,4'-methylenedianiline.2 HCl, methyl viologen, nickel sulfate.6H2O, 4,4'-oxydianiline, pentachloroethane, piperonyl butoxide, propyl gallate, quinoline, rotenone, 2,4,5,6-tetrachloro-4-nitro-anisole, 1,1,1,2-tetrachloroethane, trichlorfon, 2,4,6-trichlorophenol, 2,4,5-trimethoxybenzaldehyde, 1,1,3-trimethyl-2-thiourea, 1-vinyl-3-cyclopetene dioxide, vinyl toluene, and ziram. Apart from 2-biphenylamine.HCl, 2-chloroethanol, disperse yellow 3, ethylene thiourea, FD and C yellow number 6, phenol, and 1,1,2-tetrachloroethane, rat liver S9 mix was not a requirement for these compounds. Chemicals not identified as mutagens were acid red, 11-aminoudecanoic acid, boric acid, 5-chloro-o-toluidine, coumaphos, cyclohexanone, decabromodiphenyl oxide, di(2-ethylhexyl)adipate, ferric chloride, fluometuron, melamine, monuron, phenesterin, phthalimide, reserpine, sodium dodecyl sulfate, 4,4-sulfonyldianiline, tetrachloroethylene, and zearalenone. The assay was incapable of providing a clear indication of whether some chemicals were mutagens; these were benzyl alcohol, 1,4-dichlorobenzene, phenol, succinic acid-2,2-dimethyl hydrazide, and toluene.
Environ Mol Mutagen 1988
PMID:Responses of the L5178Y tk+/tk- mouse lymphoma cell forward mutation assay: III. 72 coded chemicals. 338 42

The haem-rotational disorder (insertion of haem into globin rotated about the alpha, gamma-meso axis by 180 degrees) has been investigated in the cyano-Met form of the monomeric allosteric insect haemoglobins, CTT III and CTT IV, by resonance Raman spectroscopy. The effect of haem disorder on the resonance Raman spectra has been observed in proto-IX, deutero-IX, and meso-IX CTTs. Most importantly, in the absence of overlapping vinyl vibrations, we have identified two Fe-C-N bending vibrations at 401 cm-1 and 422 cm-1 (pH 9.5) for 57Fe deutero-IX CTT IV ligated with 13C15N-, which are attributed to the two haem-rotational components. One Fe-C-N bending mode at 422 cm-1 shows a pH-induced shift to 424 cm-1 (pH 5.5) indicating the t----r conformational transition, whereas the other bending mode is pH-insensitive, representing a non-allosteric component. By replacing the unsymmetrical porphyrins with the "symmetrical" protoporphyrin-III we eliminate the haem disorder. Then, sharpening of the Fe-N epsilon(His) (at 313 cm-1) and Fe-CN (at 453 cm-1) stretching modes is observed and a single Fe-C-N bending mode (at 412 cm-1) appears. In cyano-Met proto-IX CTT III two vinyl bending vibrations at 412 cm-1 and 591 cm-1 assigned by deuteration of the vinyl groups also reflect the haem disorder. The 412 cm-1 vinyl vibration is intensity-enhanced via through-space coupling with one of the Fe-C-N bending modes (at 412 cm-1). In the cyano-Met form of proto-III CTT III this vinyl vibration is shifted to 430 cm-1 resulting in a dramatic drop in intensity. It is most likely that the specific vinyl-protein interaction at position 4 in one of the haem-rotational components is the origin of the coupling between the Fe-C-N and vinyl bending modes. The Fe-N epsilon(proximal His) and the Fe-CN stretching vibrations as well as the Fe-C-N bending vibration have been identified by 54Fe/57Fe and 13C15N/12C15N/13C14N/12C14N isotope exchange.
J Mol Biol 1987 Apr 05
PMID:Haem-rotational disorder in monomeric allosteric cyano-Met insect haemoglobins monitored by resonance Raman spectroscopy. 362 73


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