Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The metabolic fate of alclometasone dipropionate (ADP or S-3460) has been studied in rats, rabbits, and mice, with consideration of their interspecies differences. Several reference compounds related to ADP were synthesized for the determination and identification of the metabolites. After sc administration of 14C-labeled ADP, the metabolites in plasma, bile, and urine were separated and analyzed using TLC-ARG (autoradiography) and HPLC in comparison with the reference compounds. The metabolites identified, fully or tentatively, by MS and 1H-NMR totaled 11. The metabolic transformations were: hydrolysis of the side chain esters, dehydrochlorination leading to the formation of delta 6-double bond, 6 beta-hydroxylation, 6 beta, 7 beta-epoxides from 6 beta-hydroxylated metabolites, side chain oxidation to 21-oic and 20-oic acids in the 6 beta-hydroxylated metabolites, and conjugation to glucuronides and sulfates. The metabolic pathway, postulated on the basis of the identified and quantitated metabolites, was a rapid hydrolysis of 21-ester of ADP to the corresponding alcohol, M-1, after systemic uptake. This M-1 was a main metabolite in plasma of animals studied, and due to its relatively longer life time in the media, it seemed to allow a variety of metabolism to occur, giving the oxidative and conjugative metabolites mentioned above.
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PMID:Metabolic fate of alclometasone dipropionate in rats, rabbits, and mice. Metabolic products and pathway following subcutaneous administration. 197 61

Cyclobutane-type photodimers of dinucleoside monophosphates dCpdT, dTpdC and dTpdT were prepared by ultraviolet irradiation in the presence of acetophenone as photosensitizer. The cytosine-containing derivatives were found to deaminate forming uracil products. Using one- and two-dimensional NMR, the photoproducts were characterized as cis-syn and trans-syn cyclobutane photodimers. On the basis of NOE data the structures of the cis-syn and trans-syn products of dUpdT were determined using distance-geometry and restrained-energy-minimization methods. The cis-syn structures showed (high-ANTI/SYN)/high-ANTI glycosidic linkages while the trans-syn structures were in the SYN-ANTI region. The backbone conformations of both structures were in fair agreement with the coupling-constant-data. The trans-syn structures were found to be very rigid and similar in all three products. For the three cis-syn structures more conformational freedom and more variation among the three structures was observed.
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PMID:NMR studies of bipyrimidine cyclobutane photodimers. 199 75

One and two dimensional NMR techniques have been used together with molecular modelling to obtain the solution structure for the photoproduct d(TpA)*. The NMR data confirm that the cyclobutane linkage is formed between the bonds thymine C6-C5 and adenine C5-C6. The 2D NOE data are used as constraints in a distance geometry calculation. The structures obtained show a trans-syn cyclobutane linkage and the glycosidic angles are SYN and ANTI for thymidine and deoxyadenosine, respectively. The coupling constant data are used to check the backbone torsion angles of the obtained structures. Typical torsion angles are a gamma+ and beta t for the deoxyadenosine residue. A free molecular dynamics simulation of a trans-syn d(TpA) photoproduct confirmed all these structural characteristics.
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PMID:The solution structure of the intramolecular photoproduct of d(TpA) derived with the use of NMR and a combination of distance geometry and molecular dynamics. 232 64

2D NMR spectroscopy and J coupling constant analysis are applied to resolve the structure of two photoproducts of thymidylyl-(3'----5')-thymidine. These products are cyclobutane type thymine dimers possessing the cis-syn (the predominant one) and trans-syn geometry. The cis-syn is formed in an ANTI-ANTI conformation about the N-glycosyl linkages and resembles the normal base-stacked configuration. The glycosidic conformation in solution of the 5' terminal fragment differs from the crystal in which the less common SYN conformation is observed. In this isomer only the sugar pucker of the 3' terminal fragment is changed substantially with respect to the dinucleotide. The trans-syn isomer is formed in a SYN-ANTI glycosidic conformation. In this isomer the sugar puckers of both deoxyribose rings are affected and a preference for a pure 2'-endo conformation is observed.
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PMID:Two-dimensional 1H NMR study of two cyclobutane type photodimers of thymidylyl-(3'----5')-thymidine. 356 63

Sodium cations localized at crystallographically distinct cation sites in dehydrated zeolites were characterized using 23Na double rotation, two-dimensional nutation, and magic-angle-spinning nuclear magnetic resonance spectroscopy. The new DOR NMR technique has been applied at different magnetic field strengths to determine the quadrupole parameters of the overlapping quadrupole patterns. In the NMR spectra of dehydrated NaY and NaEMT two signals of sodium cations were identified, a low-field gaussian line at -12 +/- 1 ppm and a high-field quadrupole pattern, with an isotropic chemical shift of -8 +/- 1 ppm and a quadrupole coupling constant of about 4 MHz. By comparison of the 23Na MAS NMR intensities of these signals with the population of the cation sites determined by XRD and by calculation of the electric field gradients, the former signal was attributed to sodium cations at the sites SI and the latter one to sodium cations at the sites SI' as well as SII in faujasite and zeolite EMT. This assignment has further been confirmed by 23Na MAS NMR studies of dehydrated HNaY and BaNaY zeolites.
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PMID:Characterization of sodium cations in dehydrated faujasites and zeolite EMT by 23Na DOR, 2D nutation, and MAS NMR. 781 49

Wide-band (1 MHz) 27Al magic-angle spinning nuclear magnetic resonance (MAS NMR) spectra were recorded for zeolite Y (Si/Al approximately 2.7) and high-silica (Si/Al approximately 3.8) FAU, EMT and mixed FAU-EMT structure-type zeolites synthesized using 15-crown-5 and/or 18-crown-6 ethers as templating agents. Spinning sidebands (related to first-order quadrupolar effects affecting satellite transitions) are observed in the spectra of the four calcined and fully rehydrated samples, reflecting a high symmetry of the framework aluminium atom surrounded by four oxygens. It is shown that the intensity of the spinning sidebands progressively increases after calcination and rehydration of the samples, indicating that the restoration of the high local order around the 27Al nuclei is rather slow. On the other hand, second-order quadrupolar interactions rapidly decrease upon rehydration of the calcined samples which is achieved within one day, as indicated by thermogravimetry. Some hypotheses are proposed to explain such a difference, and the role of water is also discussed.
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PMID:Observation of spinning sidebands in the 27Al magic-angle spinning nuclear magnetic resonance spectra of FAU and EMT structure-type zeolites. 784 78

19F NMR spectroscopy has been used to study further the metabolism of 5-trifluoromethyl-2'-deoxyuridine (trifluridine; F3TdR). The synthesis and characterization of alpha-trifluoromethyl-beta-alanyl glycine (F3MBAG), a putative new metabolite of F3TdR, are now reported. This study describes ex vivon and in vivo detection of F3MBAG and other previously reported metabolites of trifluridine, using 19F NMR spectroscopy, in male BALB/C mice bearing EMT-6 tumors. A parallel 19F NMR spectroscopic study was also performed on rats dosed with F3TdR, to observe the qualitative pattern of F3TdR metabolism in another species. Unexpectedly, 5-trifluoromethyl-5,6-dihydroxyuracil (DOHF3T), alpha-trifluoromethyl-beta-ureidopropionic acid (F3MUPA) and fluoride, which result from the metabolic degradation of F3TdR and which were detected in various biological samples from mice dosed with F3TdR, could not be identified in rat urine or in homogenized tissue extracts. The presence of these metabolites in intact tissues is uncertain since in this study 19F NMR spectroscopy of these samples always displayed a broad resonance "hump" across the range of chemical shifts that would encompass these metabolites. No clear explanation for the loss of spectroscopic resolution in this region has been rationalized. N-Carboxy-alpha-trifluoromethyl-beta-alanine (F3MBA-CO2), alpha-trifluoromethyl-beta-alanyl alanine (F3MBAA) and N-acetyl-alpha-trifluoromethyl-beta-alanine (Ac-F3MBA) were synthesized and characterized, but were not detected as metabolites in any of the biological specimens examined.
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PMID:alpha-Trifluoromethyl-beta-alanyl glycine (F3MBAG): a novel mammalian metabolite of trifluridine (F3TdR). 809 91

Pleckstrin homology (PH) domains may act as membrane localization modules through specific interactions with phosphoinositide phospholipids. These interactions could represent responses to second messengers, with scope for regulation by soluble inositol polyphosphates. A biosensor-based assay was used here to probe interactions between PH domains and unilamellar liposomes containing different phospholipids and to demonstrate specificity for distinct phosphoinositides. The dynamin PH domain specifically interacted with liposomes containing phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] and, more weakly, with liposomes containing phosphatidylinositol-4-phosphate [PI(4)P]. This correlates with phosphoinositide activation of the dynamin GTPase. The functional GTPase of a dynamin mutant lacking the PH domain, however, cannot be activated by PI(4,5)P2. The phosphoinositide-PH domain interaction can be abolished selectively by point mutations in the putative binding pocket predicted by molecular modelling and NMR spectroscopy. In contrast, the Bruton's tyrosine kinase (Btk)PH domain specifically bound liposomes containing phosphatidylinositol-3,4,5-trisphosphate [PI(3,4,5)P3]: an interaction requiring Arg28, a residue found to be mutated in some X-linked agammaglobulinaemia patients. A rational explanation for these different specificities is proposed through modelling of candidate binding pockets and is supported by NMR spectroscopy.
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PMID:Distinct specificity in the recognition of phosphoinositides by the pleckstrin homology domains of dynamin and Bruton's tyrosine kinase. 894 47

SH3 domains are protein binding domains that occur widely among signal transduction proteins. Here, we present the NMR-determined solution structure of the SH3 domain from the cytoplasmic protein tyrosine kinase, Hck. Hck is involved in a number of cell signal transduction pathways, frequently in pathways associated with immune response. SH3 domains bind proteins via a left-handed polyproline type II helix on the target protein. We have assessed the structural impact of binding to a ligand through addition of a peptide corresponding to a proline-rich region of a Hck target, the GTPase activating protein of the Ras pathway. Ligand binding effects small structural changes and stabilizes the SH3 domain structure. Also, we have compared the solution structure of the Hck SH3 domain to the crystal structure of Hck, in which the SH3 domain exhibits an intramolecular binding to an interdomain linker region. These structures are interpreted as the apo- and holo- forms of the Hck SH3 domain.
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PMID:Solution structure of the human Hck SH3 domain and identification of its ligand binding site. 957 Oct 48

In the present communication we present the results of surgical treatment of tumours of the adrenal glands, basing on the material from our clinical department. During 1983-1997 at the Department of Clinical Urology Central Clinical Hospital of the Military University School of Medicine (CSK WAM) 27 patients (15 men, 12 women) with tumors of the adrenal glands were treated. Among the operated patients 3 were diagnosed with Cushing's syndrome, 3 with pheochromocytoma, 1 with Cohn's syndrome, while in the remaining 20 the tumours were hormonally inactive. Surgical treatment included 15 right, 10 left and 2 bilateral adrenalectomies. There was no intraoperational mortality. In all patients with hypersecretion, the symptoms disappeared after adrenalectomy. The size of tumours ranged 4-20 cm. In 3 patients there appeared a need for broadening of the size of surgical intervention--2 splenectomies and 2 nephrectomies and 1 resection of pancreatic tail--all due to regional infiltrations with tumorous tissues. During surgery there occurred 2 cases of iatrogenic pleuric injury. Postoperative complications included 1 case of pneumonia and 1 case of wound infection. In case of unilateral tumours of the adrenal glands the best method for surgery appears to be the lateral (lumbal) resection and in case of large tumours and/or bilateral tumours the most convenient appears to be the anterior (transperitoneal) resection. The most applicable method for diagnosis of tumours of the adrenal glands appears to be CT and NMR.
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PMID:[Results of surgical treatment of adrenal gland tumors: own 15-year long experience]. 1048 42


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