Reductive Elimination Leading to C-C Bond Formation in Gold(III) Complexes: A Mechanistic and Computational Study

The factors affecting the rates of reductive C-C cross-coupling reactions in gold(III) aryls were studied using complexes that allow easy access to a series of electronically modified aryl ligands, as well as to gold methyl and vinyl complexes, using the pincer compounds (C^N^C)AuR (R = C6F5, CH=CMe2, Me and p-C6H4X, where X = OMe, F, H, But, Cl, CF3, or NO2) as starting materials (C^N^C = 2,6-(4′-ButC6H3)2pyridine dianion). Protodeauration followed by addition of 1 equiv. SMe2 leads to the quantitative generation of the thioether complexes [(C^N-CH)AuR(SMe2)]+. Upon addition of a second SMe2 pyridine is displaced, which triggers reductive aryl-R elimination. The rates for these cross-couplings increase in the sequence k(vinyl) > k(aryl) >> k(C6F5) > k(Me). Vinyl-aryl coupling is particularly fast, 1.15 × 10–3 L mol–1 s–1 at 221 K, while both C6F5 and Me couplings encountered higher barriers for the C-C bond forming step. Using P(p-tol)3 in place of SMe2 greatly accelerates C–C couplings. Computational modelling shows that in the C^N bonded compounds displacement of N by a donor L is required before the aryl ligands can adopt a conformation suitable for C-C bond formation, so that elimination takes place from a four-coordinate intermediate. C-C bond formation is rate limiting. In the non-chelating case, reductive C(sp2)-C(sp2) elimination from three-coordinate cations [(Ar1)(Ar2)AuL]+ is almost barrierless, particularly if L = phosphine

Phosphoinositide Signaling and Polarized Membrane Growth: A Perspective from Sec14-Like PITPs

Sec14-like phosphatidylinositol/phosphatidylcholine (PtdIns/PtdCho) transfer proteins (PITPs) represent important regulatory components that integrate phospholipid metabolism and membrane trafficking in eukaryotes. Data derived from yeast studies suggest that this regulation results from a Sec14-mediated PtdIns/PtdCho exchange reaction that stimulates PtdIns kinase activity, thus facilitating the generation of phosphoinositides (PIPs) such as PtdIns(4)P and PtdIns(4,5)P2. The present work reports recent findings on the roles and functional mechanisms of yeast and plant Sec14-like PITPs. The Arabidopsis Sec14-nodulin AtSFH1, an important regulator of root hair formation, was used as a model to show that the nodulin domain represents a plasma membrane association module with high binding specificity towards PtdIns(4,5)P2. A Lys-rich C-terminal motif is necessary for PIP binding activity, which is amplified by homo-oligomerization of the nodulin domain. Both PIP association and homooligomerization are essential properties of AtSFH1 and mutants defective in PtdIns(4,5)P2 binding can be rescued by a translational fusion with a bona fide PtdIns(4,5)P2 binding domain. A model for the mode of action of AtSFH1 is proposed herein, and suggests that the physical linkage of the N-terminal Sec14 and the nodulin domains couples PIP synthesis and organization, so as to promote defined landmarks for PIP effectors that modulate developmental control of polarized membrane growth. A second approach used to gain further insights on AtSFH1 functions is also discussed. EMS-mutagenized plants that suppress the atsfh1-1-dependent short root hair henotype were isolated. By employing nextgeneration sequencing combined with deep candidate resequencing (dCARE), a mutation in the AtSTR1 sulfurtranferase encoding gene was identified. The preliminary results presented here suggest that cyanide detoxifying enzymes could represent additional cellular components that regulate root hair development, possibly in a pathway that is independent of AtSFH1. Finally, a directed evolution screen was performed in order to identify mutations that confer Sec14-like activities to the functionally inactive yeast Sec14 homolog Sfh1. Biochemical, biophysical and computational approaches helped to discover a network of transient interactions that propagates conformational energy from the lipid binding pocket to the ‘helical gating module’ that controls lipid access, thus enhancing the rates of phospholipid exchange and presentation in the mutant proteins. Taken together, the discoveries presented herein provide important details into the mechanisms regulating phospholipid exchange and PIP organization by Sec14-like PITPs, as well as comprehensive clues of how these fascinating proteins ultimately promote phosphoinositide homeostasis in eukaryotes

Relações hídricas, trocas gasosas e atividade de enzimas antioxidantes em plantas transgenicas de citrumelo "Swingle"com alto acúmulo de prolina subemtidas ao déficit hídrico

Orientador: João Carlos Bespalhok FilhoCo-orientador: Luiz Gonzaga Esteves VieiraDissertação (mestrado) - Universidade Federal do Paraná, Setor de Ciências Agrárias, Programa de Pós-Graduação em Agronomia. Defesa: Curitiba, 27/02/2009Inclui bibliografiaÁrea de concentração: Produção vegeta

Electrophilic Organoiridiunn(III) Pincer Complexes on Sulfated Zirconia for Hydrocarbon Activation and Functionalization

Single-site supported organometallic catalysts bring together the favorable aspects of homogeneous and heterogeneous catalysis while offering opportunities to investigate the impact of metal–support interactions on reactivity. We report a (dmPhebox)Ir(III) (dmPhebox = 2,6-bis(4,4-dimethyloxazolinyl)-3,5-dimethylphenyl) complex chemisorbed on sulfated zirconia, the molecular precursor for which was previously applied to hydrocarbon functionalization. Spectroscopic methods such as diffuse reflectance infrared Fourier transformation spectroscopy (DRIFTS), dynamic nuclear polarization (DNP)-enhanced solid-state nuclear magnetic resonance (SSNMR) spectroscopy, and X-ray absorption spectroscopy (XAS) were used to characterize the supported species. Tetrabutylammonium acetate was found to remove the organometallic species from the surface, enabling solution-phase analytical techniques in conjunction with traditional surface methods. Cationic character was imparted to the iridium center by its grafting onto sulfated zirconia, imbuing high levels of activity in electrophilic C–H bond functionalization reactions such as the stoichiometric dehydrogenation of alkanes, with density functional theory (DFT) calculations showing a lower barrier for β-H elimination. Catalytic hydrogenation of olefins was also facilitated by the sulfated zirconia-supported (dmPhebox)Ir(III) complex, while the homologous complex on silica was inactive under comparable conditions

Non-covalent allosteric regulation of capsule catalysis

Allosteric regulation is an essential biological process that allows enzymes to modulate their active site properties by binding a control molecule at the protein exterior. Here we show the first example of capsule catalysis in which activity is changed by exotopic binding. This study utilizes a simple Pd(2)L(4) capsule that can partition substrates and external effectors with high fidelity. We also present a detailed, quantitative understanding of how effector interactions alter both substrate and transition state binding. Unlike other allosteric host systems, perturbations are not a consequence of large mechanical changes, rather subtle electronic effects resulting from weak, non-covalent binding to the exterior surface. This investigation paves the way to more sophisticated allosteric systems

The Frequencies of Different Inborn Errors of Metabolism in Adult Metabolic Centres:10 Years Later, Another Report From the SSIEM Adult Metabolic Physicians Group

There are still few centres, which specialise in the care of adults with inborn errors of metabolism (IEM). All physicians who participated in the SSIEM adult metabolic physicians group paper in 2014 were contacted to provide updated data on their IEM patients. Fifteen adult centres responded to our survey with information on their patients. Nine thousand, six hundred fifty-one patients were included in the final cohort, compared with 6 182 in the previous analysis. There were 394 separate diagnoses. The most common diseases were phenylketonuria (19.6%), mitochondrial disorders (12.3%) and lysosomal storage disorders such as Fabry disease (20.1% of LSD's), Pompe disease (3.1%), and Gaucher disease (2.8%). Among the disorders that can present with acute metabolic decompensation, the urea cycle disorders (4.0%), were most common (ornithine transcarbamylase deficiency 2.6%), followed by maple syrup urine disease (1.1%) and glycogen storage disease type I (0.7%). Patients were frequently diagnosed as adults, particularly those with mitochondrial disease and lysosomal storage disorders. Many patients are only diagnosed in adulthood (&gt; 40%) and the cohort is increasing substantially with 9 651 patients included in the final analysis (34% increase compared to our original paper). Thus reinforcing the need for adult specialists to be trained in this area.</p

Signal transduction in a covalent post-assembly modification cascade

Natural reaction cascades control the movement of biomolecules between cellular compartments. Inspired by these systems, we report a synthetic reaction cascade employing post-assembly modification reactions to direct the partitioning of supramolecular complexes between phases. The system is composed of a self-assembled tetrazine-edged FeII8L12 cube and a maleimide-functionalized FeII4L6 tetrahedron. Norbornadiene (NBD) functions as the stimulus that triggers the cascade, beginning with the inverse-electron-demand Diels–Alder reaction of NBD with the tetrazine moieties of the cube. This reaction generates cyclopentadiene as a transient by-product, acting as a relay signal that subsequently undergoes a Diels–Alder reaction with the maleimide-functionalized tetrahedron. Cyclooctyne can selectively inhibit the cascade by outcompeting NBD as the initial trigger. Initiating the cascade with 2-octadecyl NBD leads to selective alkylation of the tetrahedron upon cascade completion. The increased lipophilicity of the C18-tagged tetrahedron drives this complex into a non-polar phase, allowing its isolation from the initially inseparable mixture of complexes

PD-1 blockade and allogeneic hematopoietic stem cell transplantation in Hodgkin lymphoma, a matter of time: a national study on behalf of the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire

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