Impairment of the formation or action of hydrogen sulfide (H 2 S), an endogenous gasotransmitter, is associated with various diseases, such as hypertension, diabetes mellitus, septic and hemorrhagic shock, and pancreatitis. Cystathionine -synthase and cystathionine ␥-lyase (CSE) are two pyridoxal-5-phosphate (PLP)-dependent enzymes largely responsible for the production of H 2 S in mammals. Inhibition of CSE by DL-propargylglycine (PAG) has been shown to alleviate disease symptoms. Here we report crystal structures of human CSE (hCSE), in apo form, and in complex with PLP and PLP⅐PAG. Structural characterization, combined with biophysical and biochemical studies, provides new insights into the inhibition mechanism of hCSEmediated production of H 2 S. Transition from the open form of apo-hCSE to the closed PLP-bound form reveals large conformational changes hitherto not reported. In addition, PAG binds hCSE via a unique binding mode, not observed in PAG-enzyme complexes previously. The interaction of PAG-hCSE was not predicted based on existing information from known PAG complexes. The structure of hCSE⅐PLP⅐PAG complex highlights the particular importance of Tyr 114 in hCSE and the mechanism of PAG-dependent inhibition of hCSE. These results provide significant insights, which will facilitate the structure-based design of novel inhibitors of hCSE to aid in the development of therapies for diseases involving disorders of sulfur metabolism.
Since its discovery 22 years ago, the bacterial cell-to-cell communication system, termed quorum sensing (QS), has shown potential as antipathogenic target. Previous studies reported that ajoene from garlic inhibits QS in opportunistic human pathogen Pseudomonas aeruginosa. In this study, screening of an in-house compound library revealed two sulfur-containing compounds which possess structural resemblance with ajoene and inhibit QS in bioreporter assay. Following a quantitative structure-activity relationship (SAR) study, 25 disulfide bond-containing analogues were synthesized and tested for QS inhibition activities. SAR study indicated that the allyl group could be replaced with other substituents, with the most active being benzothiazole derivative (IC = 0.56 μM). The compounds were able to reduce QS-regulated virulence factors (elastase, rhamnolipid, and pyocyanin) and successfully inhibit P. aeruginosa infection in murine model of implant-associated infection. Altogether, the QS inhibition activity of the synthesized compounds is encouraging for further exploration of novel analogues in antimicrobial drug development.
Mitochondrial structure has a central role both in energy conversion and in the regulation of cell death. We have previously shown that IF1 protects cells from necrotic cell death and supports cristae structure by promoting the oligomerisation of the F1Fo-ATPsynthase. As IF1 is upregulated in a large proportion of human cancers, we have here explored its contribution to the progression of apoptosis and report that an increased expression of IF1, relative to the F1Fo-ATPsynthase, protects cells from apoptotic death. We show that IF1 expression serves as a checkpoint for the release of Cytochrome c (Cyt c) and hence the completion of the apoptotic program. We show that the progression of apoptosis engages an amplification pathway mediated by: (i) Cyt c-dependent release of ER Ca2+, (ii) Ca2+-dependent recruitment of the GTPase Dynamin-related protein 1 (Drp1), (iii) Bax insertion into the outer mitochondrial membrane and (iv) further release of Cyt c. This pathway is accelerated by suppression of IF1 and delayed by its overexpression. IF1 overexpression is associated with the preservation of mitochondrial morphology and ultrastructure, consistent with a central role for IF1 as a determinant of the inner membrane architecture and with the role of mitochondrial ultrastructure in the regulation of Cyt c release. These data suggest that IF1 is an antiapoptotic and potentially tumorigenic factor and may be a valuable predictor of responsiveness to chemotherapy.
Catalysts accelerate biological processes and organic reactions in a controlled and selective fashion. There are continuing efforts in asymmetric catalysis to develop efficient catalysts with broad reaction scope and industrial practicability. Among the various modes of asymmetric catalysis, phase-transfer catalysis has attracted intense interest due to its facile scale up and low catalyst loading. Chiral quaternary ammonium and phosphonium salts are well-studied classes of chiral phase-transfer catalysts, and they are typically composed of sp-hybridized quaternary onium salts. In this Account, we describe our recent attempts to develop N-sp-hybridized guanidinium-type salts as efficient phase-transfer catalysts as well as ion-pair catalysis based on N-sp hybridized bisguanidinium-type salts. The sp-quaternized ammonium salts, pentanidiums, which contain five nitrogen atoms in conjugation, displayed remarkable phase-transfer catalytic efficiency. We have shown that pentanidium can catalyze Michael additions of tert-butyl glycinate-benzophenone Schiff bases with various α,β-unsaturated acceptors, such as vinyl ketones, acrylates, and chalcones, in high enantioselectivities. The structurally amendable pentanidium phase-transfer catalysts supply diverse reactivity and selectivity to various other organic transformations, such as α-hydroxylation of 3-substituted-2-oxindoles, Michael addition of 3-alkyloxindoles with vinyl sulfone, and alkylation reactions of sulfenate anions and dihydrocoumarins. Pentanidium salts are applicable to enantioselective transformations on a preparative scale at low catalyst loading, allowing for the synthesis of a broad range of enantiopure compounds. From computational and experimental results, we also proposed that the halogenated pentanidium catalysts participated in halogen bonding and that this contributed to the excellent stereocontrol in alkylation reactions. Subsequently, we determined that chiral cations can direct functional anions besides basic anions in traditional Brønsted basic phase-transfer reactions, including metal-centered anions. We identified dicationic bisguanidinium as an excellent ion-pairing catalyst, first demonstrating that bisguanidinium formed an ion pair with permanganate and directed the anion in enantioselective dihydroxylation and oxohydroxylation of a,β-unsaturated esters. This initial success led us to explore chiral cationic ion-pairing catalysis as a general mode of catalysis. This mode of catalysis is at the interphase between organocatalysis, phase-transfer catalysis and organometallic catalysis. We then identified bisguanidinium diphosphatobisperoxotungstate and bisguanidinium dinuclear oxodiperoxomolybdosulfate ion pairs as the active catalysts in enantioselective sulfoxidations using aqueous HO as the oxidant. The structure of the bisguanidinium dinuclear oxodiperoxomolybdosulfate ion pair was elucidated using single-crystal X-ray analysis. Bisguanidinium-catalyzed sulfoxidations emerged as a practical methodology for the synthesis of enantioenric...
The extractive membrane bioreactor (EMBR) system combining a membrane process and a biological process has been developed to extract and biodegrade recalcitrant organic pollutants in wastewater. Removal of the organics such as phenol by EMBR requires an effective membrane to selectively extract the organic compounds while rejecting water and other harsh inorganic components. In this work, novel composite membranes consisting of a highly porous substrate, made by tiered polyvinylidene fluoride (PVDF) nanofibers with ultrafine nanofibers on top (61 ± 12 nm in diameter), and a dense polydimethylsiloxane (PDMS) selective layer have been fabricated. We have investigated (1) the effect of the pore size of PVDF nanofibrous substrates, (2) the effect of PDMS preparation method, and (3) the effect of prewetting agent on the resultant composite membranes’ morphologies, mechanical properties, and phenol removal performance. Compared with the symmetric substrate with a nanofiber diameter of 129 ± 13 nm, the tiered substrate can effectively support a uniform and defect-free PDMS coating. This is attributed to the smaller surface pore size of the tiered substrate as a result of its top ultrafine nanofibers. Besides, the use of partially precross-linked PDMS coating solution with increased viscosity and 50 wt % glycerol aqueous solution as the prewetting agent to fill the substrate pores is preferred in order to mitigate PDMS intrusion. On the basis of the resistance model, the overall membrane resistance decreases with the decrease of the PDMS intrusion level, giving rise to a higher overall mass transfer coefficient, k 0, for phenol removal. With the above-mentioned factors being taken into account, the first PDMS-coated PVDF nanofibrous composite membrane has been developed to remove phenol with a high k 0 (over 4 times higher than the existing commercial PDMS tubular membrane) for EMBR. This study provides insights and guidelines for fabricating highly efficient membranes for organic removal in the EMBR process.
Sulfur can form diverse S(IV) and S(VI) stereogenic centers, of which some have gained significant attention recently due to their increasing use as pharmacophores in drug discovery programs. The preparation of these sulfur stereogenic centers in their enantiopure form has been challenging, and progress made will be discussed in this Perspective. This Perspective summarizes different strategies, with selected works, for asymmetric synthesis of these moieties, including diastereoselective transformations using chiral auxiliaries, enantiospecific transformations of enantiopure sulfur compounds, and catalytic enantioselective synthesis. We will discuss the advantages and limitations of these strategies and will provide our views on how this field will develop.
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