Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Analytical ion microscopy, a method proposed and developed in 1960 by Casting and Slodzian at the Orsay University (France), makes it possible to obtain easily and rapidly analytical images representing the distribution in a tissue section of elements or isotopes (beginning from the three isotopes of hydrogen until to transuranic elements), even when these elements or isotopes are at a trace concentration of 1 ppm or less. This method has been applied to study the subcellular distribution of different varieties of biomolecules. The subcellular location of these molecules can be easily determined when the molecules contain in their structures a specific atom such as fluorine, iodine, bromine or platinum, what is the case of many pharmaceutical drugs. In this situation, the distribution of these specific atoms can be considered as representative of the distribution of the corresponding molecule. In other cases, the molecules must be labelled with an isotope which may be either radioactive or stable. Recent developments in ion microscopy allow the obtention of their chemical images at ultra structural level. In this paper we present the results obtained with the prototype of a new Scanning Ion Microscope used for the study of the intracellular distribution of different varieties of molecules: glucocorticoids, estrogens, pharmaceutical drugs and pyrimidine analogues.
Cell Mol Biol (Noisy-le-grand) 1996 May
PMID:Mapping the subcellular distribution of biomolecules at the ultrastructural level by ion microscopy. 879 87

Tris-hydroxymethyl-amino-methane telomers bearing a fluorinated end have recently been proposed as potential drug carriers. Using ion microscopy, we have investigated the cell uptake and subcellular distribution of a perfluorinated telomere, called F-TAC, in two cell lines, malignant murine B16 melanoma and normal rat skin fibroblasts. Single layer cell cultures on gold plates were incubated with F-TAC at different concentrations. Ion microscopy using mass spectrometry enabled the detection of Fluorine 19 atoms entering into F-TAC constitution. This microanalytical study showed an elective cytoplasmic localization of the molecule, wherein the distribution is relatively homogeneous. Within same culture and incubation conditions, intercellular variations in F-TAC content were very low. In the malignant line, the intracellular concentration remains practically identical when increasing F-TAC concentration in the culture medium above 0.2 mg/ml, indicating that the uptake phenomenon is saturable. In conclusion, the F-TAC telomer easily crosses the plasma membrane, however, it has difficulties in crossing the nuclear membrane. It is likely that intracellular penetration is essentially due to rapid endocytosis of the telomer.
Cell Mol Biol (Noisy-le-grand) 1996 May
PMID:Subcellular distribution of a new fluorinated, biocompatible, non-ionic telomeric carrier: a study in cultured B16 melanoma and rat skin fibroblasts. 879 88

In an attempt to better understand the role of the cyclohexene ring (ring A) in the biochemical and pharmacological properties of anthracyclines related to doxorubicin and daunorubicin, we investigated the effects of introduction of a fluorine atom at position 8 of idarubicin (4-demethoxydaunorubicin) on drug molecular conformation and biochemical and pharmacological activities. The study showed that the stereochemistry of the substituent at position 8 influenced the "half-chair" conformation, so that in the (8R)-fluoroepimer the A ring retained the alpha half-chair conformation, which is the most stable for natural compounds (i.e., daunorubicin and doxorubicin), and the (8S)-fluoroepimers preferred the beta half-chair conformation. The (8R)-fluoroepimer was more effective than the (8S)-fluoroepimer and idarubicin in stimulating topoisomerase II-mediated DNA cleavage. Similarly, the epimer with the alpha conformation was markedly more potent than the (8S)-epimer as a cytotoxic agent in a variety of human tumor cell lines and was more effective as an antitumor agent in the treatment of an ovarian carcinoma xenograft. In addition, 8-fluoro derivatives were able to overcome the resistance to doxorubicin in a number of human tumor cell lines expressing different mechanisms of resistance. In conclusion, these findings provide evidence that drug interactions involving the external (nonintercalating) moiety of the anthracycline chromophore play an important role in determining pharmacological properties, including drug ability to induce DNA cleavage, and therefore their antitumor efficacy.
Mol Pharmacol 1996 Sep
PMID:Biochemical and pharmacological activity of novel 8-fluoroanthracyclines: influence of stereochemistry and conformation. 879

Molecular dynamics simulations of the reactions between gaseous fluorine atoms and (SiFx)n adsorbates on the Si(100) - (2 x 1) surface are performed using the SW potential and compared to simulations with the WWC reparameterization of the SW potential. Theoretical and experimental work has demonstrated that the reactive fluorosilyl layer during silicon-fluorine etching is composed of tower-like adspecies of SiF, SiF2 and SiF3 groups. The objective of the simulations is to determine how the chemical composition, mechanism of formation, and energy distribution of the etched gas-phase products depend on the identity of the reacting adsorbate, the incident kinetic energy, and the parameterization of the potential energy function. Three reactions are simulated: F(g) + SiF3(a), F(g) + SiF2-SiF3(a), and F(g) + SiF2-SiF2-SiF3(a). SiF4 is the major product and Si2F6 and Si3F8 are minor products. In Si2F6 and Si3F8, the silicon-fluorine bond that is formed is stronger than the silicon-silicon bond in the molecule and, therefore, the majority of these products have enough energy to dissociate and will fragment before reaching the detector. An SN2-like mechanism is the primary mechanism responsible for the formation of SiF4, Si2F6, and Si3F8. In addition, at higher energies, the simulations have discovered a previously unknown mechanism for the formation of SiF4, which involves an insertion between a silicon-silicon bond. The results of the simulations with the two potentials differ quite substantially in their prediction of the reactivity of the adsorbates. The SW potential predicts a 2- to 3-eV lower energy threshold for reaction and a much higher reaction cross-section, especially for the SiF4 product. These results are explained in terms of the differences in the potential energy functions used to describe the silicon-fluorine interactions. In addition, the results are compared to experimental data on silicon-fluorine etching.
J Mol Graph 1996 Oct
PMID:Molecular dynamics simulations of silicon-fluorine etching. 909 32

The Fourier transform infrared spectrum of monoisotopic 80SeF6 has been recorded in the 760-792 cm-1 region with an effective resolution of ca. 2.3 x 10(-3) cm-1. The 80SeF6 sample was prepared by burning monoisotopic 80Se powder (99.2%) in an excess of fluorine. The analysis of infrared transitions of the nu3 band enabled the determination of parameters of the Hamiltonian developed up to the third order and the fourth order. The standard deviation obtained is equal to 4 x 10(-4) cm-1 for the third-order development and 3.2 x 10(-4) cm-1 for the fourth-order development. In the two analyses, 2900 lines were assigned and fitted. Copyright 1997 Academic Press. Copyright 1997Academic Press
J Mol Spectrosc 1997 Sep
PMID:Study of the v3 = 1 State of 80SeF6 by Fourier Transform Spectroscopy 934 98

The catalytic mechanism for the enzyme, IMP cyclohydrolase, may involve a reaction intermediate with negative charge in the 2-position of the purine ring (Szabados, E., Hindmarsh, E., Phillips, L., Duggleby, R.G. & Christopherson, R.I. (1994) Biochemistry 33, 14237-14245). Three analogues of IMP have been synthesised where fluorine, chlorine or bromine has been substituted in the 2-position on the purine ring. These analogues with an electronegative substituent may resemble a reaction intermediate for IMP cyclohydrolase; 2-fluoro IMP is a potent inhibitor of the enzyme with a Ki value of 0.19 microM, while 2-chloro IMP has a Ki of 1.9 microM and 2-bromo IMP is not inhibitory. However, IMP cyclohydrolase is not inhibited in human CCRF-CEM leukaemia cells exposed to 2-fluoro inosine although it is toxic to these cells with an IC50 value of 4.9 microM.
Biochem Mol Biol Int 1998 Mar
PMID:Inosine-5'-monophosphate analogues as inhibitors of human IMP cyclohydrolase and cellular growth. 955 23

4-Fluoro-3-nitrobenzoic acid attached to a solid support was shown to react under mild conditions with a wide range of functionalized phenols to yield, after cleavage, the corresponding biaryl ethers in excellent purity. In a similar fashion, biaryl thioethers could be obtained. Further elaboration of immobilized biaryl ethers demonstrates the potential for combinatorial library generation.
Mol Divers
PMID:Solid phase synthesis of functionalized biaryl ethers: versatile scaffolds for combinatorial chemistry. 959 81

The structure of the tetradeca-(3-fluorotyrosyl) M1-1 GSH transferase (3-FTyr GSH transferase), a protein in which tyrosine residues are globally substituted by 3-fluorotyrosines has been determined at 2.2 A resolution. This variant was produced to study the effect on the enzymatic mechanism and the structure was undertaken to assess how the presence of the 3-fluorotyrosyl residue influences the protein conformation and hence its function. Although fluorinated amino acid residues have frequently been used in biochemical and NMR investigations of proteins, no structure of a protein that has been globally substituted with a fluorinated amino acid has previously been reported. Thus, this structure represents the first crystal structure of such a protein containing a library of 14 (28 crystallographically distinct) microenvironments from which the nature of the interactions of fluorine atoms with the rest of the protein can be evaluated. Numerous conformational changes are observed in the protein structure as a result of substitution of 3-fluorotyrosine for tyrosine. The results of the comparison of the crystal structure of the fluorinated protein with the native enzyme reveal that conformational changes are observed for most of the 3-fluorotyrosines. The largest differences are seen for residues where the fluorine, the OH, or both are directly involved in interactions with other regions of the protein or with a symmetry-related molecule. The fluorine atoms of the 3-fluorotyrosine interact primarily through hydrogen bonds with other residues and water molecules. In several cases, the conformation of a 3-fluorotyrosine is different in one of the monomers of the enzyme from that observed in the other, including different hydrogen-bonding patterns. Altered conformations can be related to differences in the crystal packing interactions of the two monomers in the asymmetric unit. The fluorine atom on the active-site Tyr6 is located near the S atom of the thioether product (9R,10R)-9-(S-glutathionyl)-10-hydroxy-9,10-dihydrophenanthrene and creates a different pattern of interactions between 3-fluorotyrosine 6 and the S atom. Studies of these interactions help explain why 3-FTyr GSH transferase exhibits spectral and kinetic properties distinct from the native GSH transferase.
J Mol Biol 1998 Aug 14
PMID:Conformational changes in the crystal structure of rat glutathione transferase M1-1 with global substitution of 3-fluorotyrosine for tyrosine. 969 51

Nucleus accumbens neurons are the targets of glutamatergic inputs. By coupling in situ hybridization for glutamate receptor mRNAs with retrograde transport of Fluoro-Gold, the present study examined the relationship between the distribution patterns of glutamate receptor subtypes/subunits and the output pathways of the nucleus accumbens to the ventral pallidum and ventral tegmental area. Following iontophoretic deposits of Fluoro-Gold into the ventral pallidum, neurons in both the nucleus accumbens shell and core were retrogradely labeled. A high percentage of accumbens neurons retrogradely labeled from the ventral pallidum were double-labeled for mRNAs encoding for mGluR5 (82+/-4.1%), NMDAR1 (71+/-3.5%), GluR1 (70+/-6.1%) and GluR2 (76+/-3.6%). No significant difference in the proportion of double-labeled neurons between the core and shell was observed. Following the deposit of Fluoro-Gold into the ventral tegmental area, only the accumbens shell neurons were retrogradely labeled. The proportion of neurons expressing NMDAR1, GluR1 and GluR2 were somewhat less in the projection to the ventral tegmental area compared to the ventral pallidum since approximately 60% of the neurons retrogradely-labeled from the ventral tegmental area expressed these transcripts. In contrast to the high proportion of mGluR5-containing neurons in the nucleus accumbens innervating the ventral pallidum, only half of the neurons projecting to the ventral tegmental area expressed mGluR5. These data show that accumbens neurons innervating the ventral pallidum and ventral tegmental area differ in the relative proportion of expressed mRNA encoding mGluR5, implying differential postsynaptic impact by glutamate transmission on neurons contributing to the two major efferent pathways of the nucleus accumbens.
Brain Res Mol Brain Res 1999 Jan 08
PMID:Expression of glutamate receptor subunit/subtype messenger RNAS for NMDAR1, GLuR1, GLuR2 and mGLuR5 by accumbal projection neurons. 987 92

Fluoride is an acknowledged bone anabolic agent. Nevertheless, a narrow therapeutic window and the adverse effects at higher therapeutic doses prevent broad clinical application of fluoride for treatment of diseases of bone loss, such as osteoporosis. The cellular and molecular mechanisms of fluoride action are poorly understood. recent advances in the elucidation of signal transduction pathways induced by fluoride in osteoblastic cells are reviewed. Fluoride and traces of aluminum form a complex, fluoroaluminate, which stimulates cellular heterotrimeric G proteins. Such complex can form in food, drinking water and in the organism after administration of sodium fluoride. Fluoroaluminate crosses the cell membrane and directly binds to the membrane-associated inactive G alpha protein subunits. Within the G alpha subunit, fluoroaluminate occupies the position next to GDP. The resulting G alpha-GDP-AlF4- complex assumes an active state conformation, which resembles that of G alpha-GTP complex. Under physiological conditions, G alpha-GTP complex is formed upon activation of seven transmembrane receptors that couple to heterotrimeric G proteins. Both fluoroaluminate-activated and receptor-activated G alpha subunits are capable of transmitting intracellular signals that lead to cellular responses. In bone-forming cells osteoblasts, fluoroaluminate stimulates pertussis toxin-sensitive G alpha i proteins. G alpha i activation leads to the reduction in cAMP (cyclic adenosine monophosphate) levels and to the activation of mitogen activated protein kinases, Erks (extracellular signal-regulated kinases) and p70 S6 kinase. These kinases are involved in the regulation of gene transcription and protein syntheses. Fluoroaluminate also stimulates pertussis toxin-insensitive proteins. Pertussis toxin-insensitive G proteins, most likely from G alpha 12 class, cause the activation of several cytoplasmic protein tyrosine kinases [Src, Pyk2 (proline-rich tyrosine kinase 2), and Fak (focal adhesion kinase)]. Activation of Erks can lead to osteoblast proliferation and differentiation, while activation of Src, Pyk2 and Fak can modulate the adhesion properties of osteoblasts. Osteoblast adhesion may, in turn, influence differentiation, migration, and apoptosis of these cells. The susceptibility of osteoblasts to fluoroaluminate can be achieved by their specific cellular context and by the rigidity of the surrounding bone tissue. In particular, higher levels of G alpha i proteins and of certain focal adhesion proteins are expressed by osteoblastic rather than by fibroblastic cells. The rigidity of adhesion substratum of osteoblasts may signal on its own and potentiate the signaling by fluoroaluminate. The information on mechanisms of intracellular signaling by fluoroaluminate can be utilized to identify a fluoroaluminate mimic, a drug that exhibits anabolic action on bone with a broader therapeutic range and less adverse effects than fluoride.
Int J Mol Med 1999 Feb
PMID:Heterotrimeric G proteins as fluoride targets in bone (review). 991 18


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