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981.
Roberto Della Pergola Luigi Garlaschelli Carlo Manassero Donatella Strumolo Emanuela Grigiotti 《Inorganica chimica acta》2009,362(2):331-338
The reaction between [Fe2Ir2(CO)12]2− and diphenylacetylene in refluxing CH3CN yields the substituted cluster [Fe2Ir2(CO)10(PhC2Ph)]2− (1). In the crystals, the four metal atoms define a butterfly arrangement whose Ir-Ir hinge is parallel to the acetylenic C2 unit. The neutral triangular cluster [FeIr2(CO)9(PhC2Ph)] (2) is obtained by the treatment of 1 with acids at room temperature; in this 48 valence electrons species, the C-C and the Ir-Ir bonds are also parallel, in the coordination mode.The cluster [Fe2Rh(CO)10]− reacts with diphenylacetylene in refluxing THF yielding [Fe2Rh(CO)8(PhC2Ph)]− (3). In this 46 C.V.E.’s cluster, the C2 unit is perpendicular to the Fe-Fe edge, exemplifying the bonding mode. According to 13C NMR spectra, the structure of the three clusters is maintained in solution. Electrochemical investigations show that the one-electron oxidation of [Fe2Ir2(CO)10(L)]2− (L = 2CO, PhC2Ph) as well as the one-electron reduction of [Fe2Rh(CO)8(PhC2Ph)]− only generates the respective short lived products. 相似文献
982.
Cossu F Mastrangelo E Milani M Sorrentino G Lecis D Delia D Manzoni L Seneci P Scolastico C Bolognesi M 《Biochemical and biophysical research communications》2009,378(2):162-167
Inhibitor of apoptosis proteins (IAPs) such as XIAP, cIAP1, and cIAP2 are upregulated in many cancer cells. Several compounds targeting IAPs and inducing cell death in cancer cells have been developed. Some of these are synthesized mimicking the N-terminal tetrapeptide sequence of Smac/DIABLO, the natural endogenous IAPs inhibitor. Starting from such conceptual design, we generated a library of 4-substituted azabicyclo[5.3.0]alkane Smac-mimetics. Here we report the crystal structure of the BIR3 domain from XIAP in complex with Smac037, a compound designed according to structural principles emerging from our previously analyzed XIAP BIR3/Smac-mimetic complexes. In parallel, we present an in silico docking analysis of three Smac-mimetics to the BIR3 domain of cIAP1, providing general considerations for the development of high affinity lead compounds targeting three members of the IAP family. 相似文献
983.
The studies and the researches carried out in the last years on the Palaeolithic site of Isernia La Pineta have brought to consider in new way the activities realized by the human group that lived the basin of Isernia during the Middle Pleistocene offering an important key of interpretation of the behavioural strategies of the prehistoric man. The analysis of the exploitation of the raw material has confirmed the presence on the site of two different lithotypes: flint and limestone; the lithological dichotomy is related to the functional dichotomy of the raw material that seems to have conditioned the activities of the human group in different areas of the site. The necessity to deepen the study on the limestone has derived from the evidence brought to light in the last excavation campaigns of a remarkable concentration of the flaked limestone pebbles and the flake scars in some areas of the explored archeosurfaces, particularly on the 3a and on the overlooking layers. The present study has the purpose to explain the characteristics of the limestone finds both in reference to the raw material and to its state of preservation both to the technotypological evidences and its spatial distribution with the purpose to better understand the modalities of the exploitation of the raw material. The information collected until today have permitted to obtain a precise knowledge of the environmental context and the territorial resources exploited by the human group showing an opportunistic capability to find the most advantageous behavioural solution for the necessities of subsistence. 相似文献
984.
Valentina Tremaroli Matthew L. Workentine Aalim M. Weljie Hans J. Vogel Howard Ceri Carlo Viti Enrico Tatti Ping Zhang Alexander P. Hynes Raymond J. Turner Davide Zannoni 《Applied microbiology》2009,75(3):719-728
Pseudomonas pseudoalcaligenes KF707 is naturally resistant to the toxic metalloid tellurite, but the mechanisms of resistance are not known. In this study we report the isolation of a KF707 mutant (T5) with hyperresistance to tellurite. In order to characterize the bacterial response and the pathways leading to tolerance, we utilized Phenotype MicroArray technology (Biolog) and a metabolomic technique based on nuclear magnetic resonance spectroscopy. The physiological states of KF707 wild-type and T5 cells exposed to tellurite were also compared in terms of viability and reduced thiol content. Our analyses showed an extensive change in metabolism upon the addition of tellurite to KF707 cultures as well as different responses when the wild-type and T5 strains were compared. Even in the absence of tellurite, T5 cells displayed a “poised” physiological status, primed for tellurite exposure and characterized by altered intracellular levels of glutathione, branched-chain amino acids, and betaine, along with increased resistance to other toxic metals and metabolic inhibitors. We conclude that hyperresistance to tellurite in P. pseudoalcaligenes KF707 is correlated with the induction of the oxidative stress response, resistance to membrane perturbation, and reconfiguration of cellular metabolism. 相似文献
985.
Schiffmann S Sandner J Schmidt R Birod K Wobst I Schmidt H Angioni C Geisslinger G Grösch S 《Journal of lipid research》2009,50(1):32-40
Sphingolipids such as ceramides (Cers) play important roles in cell proliferation, apoptosis, and cell cycle regulation. An increased Cer level is linked to the cytotoxic effects of several chemotherapeutics. Various selective cyclooxygenase-2 (COX-2) inhibitors induce anti-proliferative effects in tumor cells. We addressed the possible interaction of the selective COX-2 inhibitors, coxibs, with the sphingolipid pathway as an explanation of their anti-proliferative effects. Sphingolipids were measured using liquid chromatography tandem mass spectrometry. Treatment of various cancer cell lines with celecoxib significantly increased sphinganine, C(16:0)-, C(24:0)-, C(24:1)-dihydroceramide (dhCer) and led to a depletion of C(24:0)-, C(24:1)-Cer in a time- and concentration-dependent manner, whereas other coxibs had no effect. Using (13)C,(15)N-labeled l-serine, we demonstrated that the augmented dhCers after celecoxib treatment originate from de novo synthesis. Celecoxib inhibited the dihydroceramide desaturase (DEGS) in vivo with an IC(50) of 78.9 +/- 1.5 muM and increased total Cer level about 2-fold, indicating an activation of sphingolipid biosynthesis. Interestingly, inhibition of the sphingolipid biosynthesis by specific inhibitors of l-serine palmitoyltransferase diminished the anti-proliferative potency of celecoxib. In conclusion, induction of de novo synthesis of sphingolipids and inhibition of DEGS contribute to the anti-proliferative effects of celecoxib. 相似文献
986.
Flavia Pichiorri Hiroshi Okumura Tatsuya Nakamura Preston N. Garrison Pierluigi Gasparini Sung-Suk Suh Teresa Druck Kelly A. McCorkell Larry D. Barnes Carlo M. Croce Kay Huebner 《The Journal of biological chemistry》2009,284(2):1040-1049
We have previously shown that Fhit tumor suppressor protein interacts with
Hsp60 chaperone machinery and ferredoxin reductase (Fdxr) protein.
Fhit-effector interactions are associated with a Fhit-dependent increase in
Fdxr stability, followed by generation of reactive oxygen species and
apoptosis induction under conditions of oxidative stress. To define Fhit
structural features that affect interactions, downstream signaling, and
biological outcomes, we used cancer cells expressing Fhit mutants with amino
acid substitutions that alter enzymatic activity, enzyme substrate binding, or
phosphorylation at tyrosine 114. Gastric cancer cell clones stably expressing
mutants that do not bind substrate or cannot be phosphorylated showed
decreased binding to Hsp60 and Fdxr and reduced mitochondrial localization.
Expression of Fhit or mutants that bind interactor proteins results in
oxidative damage and accumulation of cells in G2/M or
sub-G1 fractions after peroxide treatment; noninteracting mutants
are defective in these biological effects. Gastric cancer clones expressing
noncomplexing Fhit mutants show reduction of Fhit tumor suppressor activity,
confirming that substrate binding, interaction with heat shock proteins,
mitochondrial localization, and interaction with Fdxr are important for Fhit
tumor suppressor function.Fhit protein is a powerful tumor suppressor that is frequently lost or
reduced in cancer cells because of rearrangement of the exquisitely DNA
damage-sensitive fragile FHIT gene. Restoration of Fhit expression
suppresses tumorigenicity of cancer cells of various types, and the ability to
induce apoptosis in cancer cells in vitro is reduced by specific Fhit
mutations (1,
2).Through studies of signal pathways affected by Fhit expression, by searches
for Fhit protein effectors, and by in vitro analyses of Fhit
activity, we and others have defined Fhit enzymatic activity in vitro
(3), apoptotic activity in
cells and tumors
(4–6),
and most recently identification of a Fhit protein complex that affects Fhit
stability, mitochondrial localization, and interaction with ferredoxin
reductase (Fdxr)5
(7). The complex includes Hsp60
and Hsp10 that mediate Fhit stability and may affect import into mitochondria,
where Fhit interacts with Fdxr, which is responsible for transferring
electrons from NADPH to cytochrome P450 via ferredoxin. Virally mediated Fhit
restoration in Fhit-deficient cancer cells increases production of
intracellular reactive oxygen species (ROS), followed by increased apoptosis
of cancer cells under oxidative stress conditions; conversely, Fhit-negative
cells escape apoptosis, likely carrying oxidative DNA damage that contributes
to accumulation of mutations.The Fhit protein sequence, showing high homology to the histidine triad
(HIT) family of proteins, suggested that the protein product would hydrolyze
diadenosine tetraphosphate or diadenosine triphosphate (Ap3A)
(8), and in vitro
studies showed that Ap3A was cleaved into ADP and AMP by Fhit. The
catalytic histidine triad within Fhit was essential for catalytic activity
(3), and a Fhit mutant that
substituted Asn for His at the central histidine (H96N mutant) was
catalytically inactive, although it bound substrate well
(3). Early tumor suppression
studies showed that cancer cells stably transfected with wild type (WT) or
H96N mutant Fhit were suppressed for tumor growth in nude mice. This suggested
the hypothesis that the Fhit-substrate complex sends the tumor suppression
signal (9,
10). To test this hypothesis,
a series of FHIT alleles was designed to reduce substrate-binding
and/or hydrolytic rates and was characterized by quantitative cell-death
assays on cancer cells virally infected with each allele. The allele series
covered defects as great as 100,000-fold in kcat and
increases as large as 30-fold in Km. Mutants with
2–7-fold increases in Km had significantly reduced
apoptotic indices and the mutant with a 30-fold increase in
Km retained little apoptotic function. Thus, the
proapoptotic function of Fhit, which is likely associated with tumor
suppressor function, is limited by substrate binding and is unrelated to
substrate hydrolysis (11).Fhit, a homodimeric protein of 147 amino acids, is a target of tyrosine
phosphorylation by the Src family protein kinases, which can phosphorylate
Tyr-114 of Fhit in vitro and in vivo
(12). After co-expression of
Fhit with the Elk tyrosine kinase in Escherichia coli to generate
phosphorylated forms of Fhit, unphosphorylated, mono-, and diphosphorylated
Fhit were purified, and enzyme kinetics studies showed that monophosphorylated
Fhit exhibited monophasic kinetics with Km and
kcat values ∼2- and ∼7-fold lower, respectively,
than for unphosphorylated Fhit. Diphosphorylated Fhit exhibited biphasic
kinetics; one site had Km and kcat
values ∼2- and ∼140-fold lower, respectively, than for
unphosphorylated Fhit; the second site had a Km
∼60-fold higher and a kcat ∼6-fold lower than for
unphosphorylated Fhit (13).
Thus, it was possible that the alterations in Km and
kcat values for phosphorylated forms of Fhit might favor
formation and lifetime of the Fhit-Ap3A complex and enhance tumor
suppressor activity (see Fhit forms
Kinetic parameters
% Sub-G1
Direct binding
Subcellular location
Co-IP in vivo
8-OHdG
Apoptosis
Tumor suppressor
Km (mm) kcat (s–1) A549 MKN74 Hsp60 Fdxr Hsp60 Fdxr
Fhit WT
1.6 +/– 0.19
2.7 +/– 0.95
43
24
Yes
Yes
Cyt & mito
Yes
Yes
Yes
Yes
Yes
Catalyt mutants H96D
Up 2-fold
Down >2 × 104 29
NT
NT
NT
Cyt & mito
Yes
Yes
NT
Yes
NT
H96N
Up 2-fold
Down >5 × 105
31
14.4
NT
NT
Cyt & mito
Yes
Yes
Yes
Yes
Yes
Loop mutants Y114A
Up 23-fold
Down 2-fold
3.7
NT
NT
NT
Cyt
+/–
+/–
+/–
No
No
Y114D
NT
NT
2.9
6
NT
NT
Cyt
+/–
+/–
–
No
–/+
Y114E
NT
NT
NT
NT
NT
NT
Cyt & mito
–/+
–/+
–
No
NT
Y114F
Up 5-fold
Up 1.1-fold
11.5
3
NT
NT
Cyt & mito
–/+
–/+
–
No
No
Y114W
Up 5-fold
Up 1.4-fold
NT
NT
NT
NT
Cyt & mito
–/+
–
–
NT
NT
del113–117
Up 10-fold
Down 38-fold
5
NT
NT
NT
NT
NT
NT
–
No
NT
Other mutants L25W
Up 7-fold
Down 4-fold
15
NT
NT
NT
Cyt
–
–
–
NT
–/+
I10W,L25W
Up 32-fold
Down 6-fold
11
NT
NT
NT
NT
NT
NT
NT
NT
NT
F5W
Up 3.3 fold
NT
NT
5
NT
NT
NT
NT
NT
+/–
No
NT
Purified pFhit pFhit
Down 0.4-fold
Down 7-fold
NA
NA
–/+
Yes
NA
NA
NA
NA
NA
NA
ppFhit
Down 0.4-fold
Down > 100-fold
NA
NA
–/+
Yes
NA
NA
NA
NA
NA
NA
Up 60-fold
Down 6-fold