Williams, Shoshana C. C.Luongo, DahliaOrman, MarinaVizcarra, Christina L. L....
4页
查看更多>>摘要：Alkane monooxygenase (AlkB) is a non-heme diiron enzyme that catalyzes the hydroxylation of alkanes. It is commonly found in alkanotrophic organisms that can live on alkanes as their sole source of carbon and energy. Activation of AlkB occurs via two-electron reduction of its diferric active site, which facilitates the binding, activation, and cleavage of molecular oxygen for insertion into an inert C-H bond. Electrons are typically supplied by NADH via a rubredoxin reductase (AlkT) to a rubredoxin (AlkG) to AlkB, although alternative electron transfer partners have been observed. Here we report a family of AlkBs in which both electron transfer partners (a ferredoxin and a ferredoxin reductase) appear as an N-terminal gene fusion to the hydroxylase (ferr_ferrR_AlkB). This enzyme catalyzes the hydroxylation of medium chain alkanes (C6-C14), with a preference for C10-C12. It requires only NADH for activity. It is present in a number of bacteria that are known to be human pathogens. A survey of the genome neighborhoods in which is it found suggest it may be involved in alkane metabolism, perhaps facilitating growth of pathogens in non-host environments.
查看更多>>摘要：Two amide group containing pyridine derivatives, N-(pyridin-2-ylmethyl)picolinamide (PMPA) and N-(pyridin-2-ylmethyl)-2-((pyridin-2-ylmethyl)amino)acetamide (DPMGA), have been investigated as potential metallophores in the therapy of Alzheimer's disease. Their complex formation with Cu(II) and Zn(II) were characterized in details. Unexpectedly not only the Cu(II) but also the Zn(II) was able to induce deprotonation of the amide-NH, however, it occurred only at higher pH or at higher metal ion concentrations than the biological conditions. At mu M concentration level mono complexes (MLH-1) dominate with both ligands. Direct fluorescence and reactive oxygen species (ROS) producing measurements prove that both ligands are able to remove Cu(II) from its amyloid-beta complexes (CuA beta). Correlation was also established between the conditional stability constant of the Cu(II) complexes with different ligands and their ability of inhibition of ROS production by CuA beta.
Oakley, Kady M.Lehane, Ryan L.Zhao, ZiyiKim, Eunsuk...
5页
查看更多>>摘要：Fumarate and nitrate reductase (FNR) is a gene regulatory protein that controls anaerobic to aerobic respiration in Escherichia coli, for which O-2 serves as a control switch to induce a protein structural change by converting [4Fe-4S] cofactors to [2Fe-2S] clusters. Although biomimetic models can aid in understanding the complex functions of their protein counterparts, the inherent sensitivity of discrete [Fe-S] molecules to aerobic conditions poses a unique challenge to mimic the O-2-sensing capability of FNR. Herein, we report unprecedented biomimetic O-2 reactivity of a discrete [4Fe-4S] complex, [Fe4S4(SPhF)(4)](2-)(1) where SPhF is 4-fluorothiophenolate, in which the reaction of 1 with O-2(g) in the presence of thiolate produces its [2Fe-2S] analogue, [Fe2S2(SPhF)(4)](2-)(2), at room temperature. The cluster conversion of 1 to 2 can also be achieved by employing disulfide as an oxidant under the same reaction conditions. The [4Fe-4S] to [2Fe-2S] cluster conversion by O-2 was found to be significantly faster than that by disulfide, while the reaction with disulfide produced higher yields of 2.
查看更多>>摘要：In this report, a new ligand TFBIP (TFBIP = 2-(4'-trifluoromethyl)-[1,1'-biphenyl]-4-yl)-1H-imidazo[4,5-f][1,10] phenanthroline) and its three iridium (III) complexes [Ir(ppy)2(TFBIP)](PF6) (Ir1, ppy = 2-phenylpyridine), [Ir (bzq)2(TFBIP)](PF6) (Ir2, bzq = benzo[h]quinolone) and [Ir(piq)2(TFBIP)](PF6) (Ir3, piq = 1-phenylisoquinoline) were synthesized and characterized. The cytotoxicity in vitro of the complexes toward several cancer cells was evaluated by 3-(4,5-dimethylthiazole-2-yl)-2,5-biphenyl tetrazolium bromide (MTT) methods. The complexes show no cytotoxicity (IC50 > 100 mu M) against these cancer cells. To enhance anticancer activity, these complexes were trapped in liposomes to form Ir1Lipo, Ir2Lipo and Ir3Lipo. The liposomes Ir1Lipo, Ir2Lipo and Ir3Lipo exhibit high or moderate cytotoxic activity. In particular, Ir1Lipo can effectively inhibit the cell growth with a low IC50 value (< 10 mu M) toward A549, HepG2, BEL-7402, B16, HeLa and SGC-7901 cells. Surprisingly, Ir1Lipo has no cytotoxic activity against the normal cell LO2 (IC50 > 100 mu M). The apoptosis and pyroptosis were investigated. Ir3Lipo induces apoptosis with a high early apoptotic number of 37%. The reactive oxygen species (ROS) levels, mitochondrial permeability transition pore open and mitochondrial membrane potential were detected. The intracellular Ca2+ concentration and release of cytochrome c were investigated. The expression of Bcl-2 (B-cell lymphoma-2) family proteins was explored by western blot. The antitumor activity in vivo of Ir1Lipo was evaluated with an inhibitory rate of 53%.
查看更多>>摘要：A nitrosyl complex of cobalt(II) porphyrinate, [Co(F20TPP2-)(NO)], (F20TPPH2 = 5,10,15,20-tetrakis(pentafluorophenyl)porphyrin) having {Co(NO)}(8) configuration was synthesized and characterized by means of spectroscopic and structural analyses. Single crystal X-ray structure of the complex revealed the square pyramidal geometry around the cobalt center with a bent nitrosyl group. It reacts with superoxide (O-2(center dot-)) ion in CH2Cl2 at -40 degrees C to result in the corresponding nitrite (NO2-) complex. Involvement of a cobalt(II)-peroxynitrite intermediate is proposed in the course of the reaction. Moreover, spectroscopic studies suggested the formation of a transient six-coordinated [Co-II(NO)(O-2(center dot-))] species.
Nagendraraj, ThavasilingamKumaran, S. SenthilMayilmurugan, Ramasamy
8页
查看更多>>摘要：The Mn(II) complexes are emerging as alternative T1-MRI contrast agents (CAs) to the currently available Gdbased CAs. The complexes [Mn(L1)] 1 and [Mn(L2)] 2 of o-phenylenediamine based macrocyclic ligands are reported as T1-CAs for MRI applications. The high spin state of the Mn(II) complexes (S = 5/2) is confirmed by EPR spectra. The complexes showed an irreversible Mn(II)/Mn(III) redox potential at pH 7.28, which became more and less positive at the acidic and alkaline pHs, respectively. The species [MnL], [Mn(LH-1), and [Mn (LH-2) are persisted in solution. Complex 1 is inert towards Ca(II), Mg(II), and Zn(II), whereas complex 2 is inert for Ca(II) and Mg(II) and labile under Zn(II) and Cu(II) ions. Complex 1 showed an r(1)-relaxivity of 3.27 and 2.32 mM(-1) s(-1) at 1.41 T, 25, and 37 & nbsp;C respectively via inner-sphere water relaxation, which is lower than that of 2 (r(1), 5.56, and 4.19 mM(-1) s(-1)) at pH 7.28 and 1.41 T. The Mn(II) complexes showed a 2-8% enhancement of r(1)- relaxivity while lowering the pH to acidic, which corresponds to the release of free Mn(II) ions. In contrast, the r(1)-relaxivity is dropped to 52% and 20% for 1 and 2 respectively under alkaline pH due to the deprotonation of inner-sphere water. Phantom images obtained on Bruker 'BIOSPEC' 47/40 animal research MRI/MRS scanner showed concentration-dependent brightness. The interaction of human serum albumin (HSA) with 1 and 2 exhibited five times higher r1-relaxivities (11.3 and 22.0 mM(-1) s(-1) at 1.41 T, respectively).
查看更多>>摘要：Fur (ferric uptake regulator) is a transcription factor that regulates expression of downstream genes containing a specific Fe2+-binding sequence called the Fur box. In Vibrio cholerae, a Fur box is located upstream of the nik operon, which is responsible for nickel uptake, suggesting that its expression is regulated by Fur. However, there are no reports that Ni2+ induces expression of Fur box genes. Accordingly, we here investigated whether Ni2+ or Fe2+ binds to Fur to regulate expression of the nik operon. We found that Fur binds to the Fur box in the presence of Fe2+ with a dissociation constant (K-d) of 1.2 mu M, whereas only non-specific binding was observed in the presence of Ni2+. Thus, Fur-mediated expression of the nik operon is dependent on Fe2+, but not Ni2+. Since most iron in cells exists as heme, we examined the effect of heme on the Fur box binding activity of V. cholerae Fur (VcFur). Addition of heme to the VcFur-Fur box complex induced dissociation of VcFur from the Fur box, indicating that expression of the V. cholerae nik operon is regulated by both iron and heme. Furthermore, VCA1098, a nik operon-encoded protein, bound heme with a K-d of 1.3 mu M. Collectively, our results suggest that the V. cholerae nik operon is involved not only in nickel uptake but also in heme uptake, and depends on iron and heme concentrations within bacteria.
查看更多>>摘要：The cellular prion protein (PrPC) is a membrane-anchored copper binding protein that undergoes proteolytic processing. beta-cleavage of PrPC is associated with a pathogenic condition and it yields two fragments: N2 with residues 23-89, and C2 including residues 90-231. The membrane-bound C2 fragment retains the Cu binding sites at His96 and His111, but it also has a free N-terminal NH2 group. In this study, the impact of beta-cleavage of PrPC in its Cu(II) binding properties was evaluated, using the peptide of the human prion protein hPrP(90-115) as a model for the C2 fragment. The Cu(II) coordination properties of hPrP(90-115) were studied using circular dichroism (CD) and electron paramagnetic resonance (EPR); while the H96A and H111A substitutions and its acetylated variants were also studied. Cu binding to hPrP(90-115) is dependent on metal ion concentration: At low copper concentrations the participation of His96 and free NH2-terminus is evident, while at high copper concentrations the His111 site is populated without participation of the N-terminal NH2 group. The presence of a free NH2-terminal group in the C2 fragment significantly impacts the Cu(II) coordination properties of the His96 site, where the NH2 group also anchors the metal ion. This study provides further insights into the impact of proteolytic processing of PrPC in the Cu binding properties of this important neuronal protein.
查看更多>>摘要：In this study, four hybrid organic-inorganic compounds (8-H(2)Q)(2)[PdCl4] (1), (H(2)ClQ)(2)[PdCl4] (2), (H(2)NQ)(2)[PdCl4] (3) and (H(2)MeQ)(2)[PdCl4].2H(2)O (4) (where 8-H(2)Q = 8-hydroxyquinolinium, H(2)ClQ = 5-chloro-8-hydroxyquinolinium, H(2)NQ = 5-nitro-8-hydroxyquinolinium and H(2)MeQ = 2-methyl-8-hydroxyquinolinium) were synthesized through organic cation modulation. Single-crystal X-ray structure analysis of compounds 1 and 3 indicates that their structures are planar and consist of [PdCl4](2-& nbsp;)anions and 8-H(2)Q or H(2)NQ cations, respectively. Both ionic components are held together through ionic interactions and hydrogen bonds forming infinite chains linked through pi-pi interactions to form 2D structures. Furthermore, NMR spectroscopy, UV-Vis spectroscopy, elemental analysis, and FT-IR spectroscopy were used to explore the synthesized compounds. The DNA interaction, antimicrobial activity, antiproliferative activity, and radical scavenging effect of the com-pounds were evaluated. The hybrid compounds and their free ligands can interact with the calf thymus DNA via an intercalation mode involving the insertion of the aromatic chromophore between the base pairs of DNA; compound 1 has the highest binding affinity. Moreover, they have high antimicrobial efficacy against the tested 14 strains of microorganisms with minimum inhibitory concentration values ranging from < 1.95 to 250 mu g/mL. The antiproliferative activity of the compounds was investigated against three different cancer cell lines, and their selectivity was verified on mesenchymal stem cells. Compounds 1 and 2 displayed selective and high cytotoxicity against human lung and breast cancer cells and showed moderate cytotoxicity against colon cancer cells. Accordingly, they might be auspicious candidates for future pharmacological investigations in lung and breast cancer research.
de Sousa, Eduardo Henrique SilvaMartins, Alice Maria CostaMarinho, Aline DiogoJorge, Roberta Jeane Bezerra...
11页
查看更多>>摘要：This study aimed to investigate the synthesis and potential vasodilator effect of a novel ruthenium complex, cis-[Ru(bpy)(2)(2-MIM)(NO2)]PF6 (bpy = 2,2'-bipyridine and 2-MIM = 2-methylimidazole) (FOR711A), containing an imidazole derivative via an in silico molecular docking model using beta 1 H-NOX (Heme-nitric oxide/oxygen binding) domain proteins of reduced and oxidized soluble guanylate cyclase (sGC). In addition, pharmacokinetic properties in the human organism were predicted through computational simulations and the potential for acute irritation of FOR711A was also investigated in vitro using the hen's egg chorioallantoic membrane (HET-CAM). FOR711A interacted with sites of the beta 1 H-NOX domain of reduced and oxidized sGC, demonstrating shorter bond distances to several residues and negative values of total energy. The predictive study revealed molar refractivity (RM): 127.65; Log Po/w = 1.29; topological polar surface area (TPSA): 86.26 angstrom(2); molar mass (MM) = 541.55 g/mol; low solubility, high unsaturation index, high gastrointestinal absorption; toxicity class 4; failure to cross the blood-brain barrier and to react with cytochrome P450 (CYP) enzymes CYP1A2, CYP2C19, CYP2C9, CYP2D6 and CYP3A4. After the HET-CAM assay, the FOR711A complex was classified as non-irritant (N.I.) and its vasodilator effect was confirmed through greater evidence of blood vessels after the administration and ending of the observation period of 5 min. These results suggest that FOR711A presented a potential stimulator/activator effect of sGC via NO/sGC/cGMP. However, results indicate it needs a vehicle for oral administration.
NSTL
Elsevier