Coordination Of Zinc Ion Research Articles

Active Components of Essential Oils as Anti-Obesity Potential Drugs Investigated by in Silico Techniques.

In this study, for the first time, we have considered essential oils (EOs) as possible resources of carbonic anhydrase inhibitors (CAIs), in particular against the mitochondrial isoform VA that, actually, represents an innovative target for the obesity treatment. In silico structure-based virtual screening was performed in order to speed up the identification of promising antiobesity agents. The potential hit compounds were submitted to in vitro assays and experimental results, corroborated by molecular modeling studies, showed EOs components as a new class of CAIs with a competitive mechanism of action due to the zinc ion coordination within the active sites of these metallo-enzymes.

On the Crystal Structure of a Previously Unknown Anhydrous Zinc Hydroxide Sulfate

AbstractAnhydrous zinc hydroxide sulfates are promising precursors for the preparation of pigments and ZnO nanomaterials. The crystal structure of one such compound 5[Zn(OH)2]·2[ZnSO4] was determined from high resolution laboratory X‐ray powder diffraction data by use of a combination of charge flipping,18 simulated annealing,26 and difference Fourier analysis. The material crystallizes in the space group P with the lattice parameters of a = 5.4559(2) Å, b = 8.0528(3) Å, c = 8.9275(3) Å, α = 112.697(2)°, β = 85.219(3)°, γ = 95.441(3)°, and a volume of V = 359.76(2) Å3. The basic crystal structure consists of brucite type Zn(OH)2 layers where every sixth octahedral site is vacant. Tetrahedrally coordinated zinc ions are located above and below these vacancies and consecutive layers are bridged by sulfate molecules. The composition of this layered structure can be written as [Zn5VI□(OH)4·Zn2IV(OH)6·(SO4)2]. Its thermal decomposition was studied by X‐ray powder diffraction and thermal analysis.

Redox-dependent disulfide bond formation in SAP30L corepressor protein: Implications for structure and function.

Sin3A-associated protein 30-like (SAP30L) is one of the key proteins in a multi-subunit protein complex involved in transcriptional regulation via histone deacetylation. SAP30L, together with a highly homologous SAP30 as well as other SAP proteins (i.e., SAP25, SAP45, SAP130, and SAP180), is an essential component of the Sin3A corepressor complex, although its actual role has remained elusive. SAP30L is thought to function as an important stabilizing and bridging molecule in the complex and to mediate its interactions with other corepressors. SAP30L has been previously shown to contain an N-terminal Cys3 His type zinc finger (ZnF) motif, which is responsible for the key protein-protein, protein-DNA, and protein-lipid interactions. By using high-resolution mass spectrometry, we studied a redox-dependent disulfide bond formation in SAP30L ZnF as a regulatory mechanism for its structure and function. We showed that upon oxidative stress SAP30L undergoes the formation of two specific disulfide bonds, a vicinal Cys29-Cys30 and Cys38-Cys74, with a concomitant release of the coordinated zinc ion. The oxidized protein was shown to remain folded in solution and to bind signaling phospholipids. We also determined a solution NMR structure for SAP30L ZnF that showed an overall fold similar to that of SAP30, determined earlier. The NMR titration experiments with lipids and DNA showed that the binding is mediated by the C-terminal tail as well as both α-helices of SAP30L ZnF. The implications of these results for the structure and function of SAP30L are discussed.

The Cysteine-rich Domain of the DHHC3 Palmitoyltransferase Is Palmitoylated and Contains Tightly Bound Zinc

DHHC palmitoyltransferases catalyze the addition of the fatty acid palmitate to proteins on the cytoplasmic leaflet of cell membranes. There are 23 members of the highly diverse mammalian DHHC protein family, all of which contain a conserved catalytic domain called the cysteine-rich domain (CRD). DHHC proteins transfer palmitate via a two-step catalytic mechanism in which the enzyme first modifies itself with palmitate in a process termed autoacylation. The enzyme then transfers palmitate from itself onto substrate proteins. The number and location of palmitoylated cysteines in the autoacylated intermediate is unknown. In this study, we present evidence using mass spectrometry that DHHC3 is palmitoylated at the cysteine in the DHHC motif. Mutation of highly conserved CRD cysteines outside the DHHC motif resulted in activity deficits and a structural perturbation revealed by limited proteolysis. Treatment of DHHC3 with chelating agents in vitro replicated both the specific structural perturbations and activity deficits observed in conserved cysteine mutants, suggesting metal ion-binding in the CRD. Using the fluorescent indicator mag-fura-2, the metal released from DHHC3 was identified as zinc. The stoichiometry of zinc binding was measured as 2 mol of zinc/mol of DHHC3 protein. Taken together, our data demonstrate that coordination of zinc ions by cysteine residues within the CRD is required for the structural integrity of DHHC proteins.

Regioregular Polythiophene–Porphyrin Supramolecular Copolymers for Optoelectronic Applications

Conjugated poly(3‐hexylthiophene) copolymer derivatives containing 10% appended porphyrin moieties are prepared using a supramolecular approach toward applications in organic electro­nics. The self‐assembled polythiophene–porphyrin copolymers are synthesized by coordination of the porphyrinato central zinc ions to the imidazole‐functionalized polythiophene side chains. Evidence for the self‐assembly process is provided by 1H NMR spectroscopy, single crystal X‐ray diffraction, and optical absorption studies on model compounds. The polythiophene–porphyrin copolymers show an extended absorption window in the region of 420–650 nm due to the contribution of the porphyrin. Photoluminescence studies indicate concentration‐dependent energy transfer from P3HT to the porphyrin. Preliminary photovoltaic studies are performed by combining the polythiophene–porphyrin copolymers with PC61BM in the photo­active layer of bulk heterojunction organic solar cells. image

Synthesis of a Neo-Confused Octaphyrin and the Formation of Its Mononuclear Complexes.

Novel neo-confused octaphyrin(1.1.1.1.1.1.1.0) (1) was synthesized by oxidative ring closure of an octapyrrane bearing two terminal "confused" pyrroles. Crystal structures of its Zn(II) and Cu(II) complexes (2 and 3) show a figure-of-eight conformation with unique mononuclear coordination structures. Photophysical data and theoretical calculations suggest that the neo-confused octaphyrin 1 is a 34π electron conjugated species showing nonaromaticity. Coordination of copper and zinc ions results in the further narrowing of the HOMO-LUMO gaps.

Formation of fluorescent supramolecular polymeric assemblies via orthogonal pillar[5]arene-based molecular recognition and metal ion coordination.

A fluorescent supramolecular polymer was efficiently constructed by pillar[5]arene-based host-guest molecular recognition and zinc ion coordination.

XLOS-observed mutations of MID1 Bbox1 domain cause domain unfolding.

MID1 catalyzes the ubiquitination of the protein alpha4 and the catalytic subunit of protein phosphatase 2A. Mutations within the MID1 Bbox1 domain are associated with X-linked Opitz G syndrome (XLOS). Our functional assays have shown that mutations of Ala130 to Val or Thr, Cys142 to Ser and Cys145 to Thr completely disrupt the polyubiquitination of alpha4. Using NMR spectroscopy, we characterize the effect of these mutations on the tertiary structure of the Bbox1 domain by itself and in tandem with the Bbox2 domain. The mutation of either Cys142 or Cys145, each of which is involved in coordinating one of the two zinc ions, results in the collapse of signal dispersion in the HSQC spectrum of the Bbox1 domain indicating that the mutant protein structure is unfolded. Each mutation caused the coordination of both zinc ions, which are ∼13 Å apart, to be lost. Although Ala130 is not involved in the coordination of a zinc ion, the Ala130Thr mutant Bbox1 domain yields a poorly dispersed HSQC spectrum similar to those of the Cys142Ser and Cys145Thr mutants. Interestingly, neither cysteine mutation affects the structure of the adjacent Bbox2 domain when the two Bbox domains are engineered in their native tandem Bbox1-Bbox2 protein construct. Dynamic light scattering measurements suggest that the mutant Bbox1 domain has an increased propensity to form aggregates compared to the wild type Bbox1 domain. These studies provide insight into the mechanism by which mutations observed in XLOS affect the structure and function of the MID1 Bbox1 domain.

Exploring zinc coordination in novel zinc battery electrolytes.

The coordination of zinc ions by tetraglyme has been investigated here to support the development of novel electrolytes for rechargeable zinc batteries. Zn(2+) reduction is electrochemically reversible from tetraglyme. The spectroscopic data, molar conductivity and thermal behavior as a function of zinc composition, between mole ratios [80 : 20] and [50 : 50] [tetraglyme : zinc chloride], all suggest that strong interactions take place between chloro-zinc complexes and tetraglyme. Varying the concentration of zinc chloride produces a range of zinc-chloro species (ZnClx)(2-x) in solution, which hinder full interaction between the zinc ion and tetraglyme. Both the [70 : 30] and [50 : 50] mixtures are promising electrolyte candidates for reversible zinc batteries, such as the zinc-air device.

Crystal structures of 26 kDa Clonorchis sinensis glutathione S-transferase reveal zinc binding and putative metal binding

The crystal structures of CsGST in two different space groups revealed that Asp26 and His79 coordinate a zinc ion. In one space group, His46 of an adjacent molecule participates in the coordination within 2.0Å. In the other space group, Asp26, His79 and a water molecule coordinate a zinc ion. The CsGST–D26H structure showed that four histidine residues – His26 and His79 from one molecule and the same residues from a symmetry-related neighboring molecule – coordinate a zinc ion. The coordinated zinc ions are located between two molecules and mediate molecular contacts within the crystal.

The cancer‐testis antigen BORIS phenocopies the tumor suppressor CTCF in normal and neoplastic cells

BORIS and CTCF are paralogous, multivalent 11-zinc finger transcription factors that play important roles in organizing higher-order chromatin architecture. BORIS is a cancer-testis antigen with a poorly defined function in cancer, although it has been hypothesized to exhibit oncogenic properties. CTCF, however, has been postulated as a candidate tumor suppressor. We collated the genetic lesions in BORIS and CTCF from multiple cancers identified using high-throughput genomics. In BORIS, nonsense and missense mutations are evenly distributed. In CTCF, recurrent mutations are mostly clustered in the conserved zinc finger domain and at residues critical for contacting DNA and zinc ion co-ordination. Three missense mutations are common to both proteins. We used an inducible lentivector to express wildtype BORIS or CTCF in primary cells and cancer cell lines in order to define their functional differences. Both BORIS and CTCF caused a significant decrease in cell proliferation and clonogenic capacity, without alteration of specific cell cycle phases. Both BORIS and CTCF conferred protective effects in primary cells and some cancer cells during UV damage-induced apoptosis. Using a bioluminescent MCF-7 orthotopic breast cancer model in vivo, we demonstrated that CTCF and BORIS suppressed breast cancer growth. These findings provide further evidence that CTCF behaves as a tumor suppressor, and show BORIS has a similar growth inhibitory effect in vitro and in vivo. Hence, acquired zinc finger mutations may disrupt these functions, thereby contributing to tumor growth and development.

Redox state of p63 and p73 core domains regulates sequence-specific DNA binding

Cysteine oxidation and covalent modification of redox sensitive transcription factors including p53 are known, among others, as important events in cell response to oxidative stress. All p53 family proteins p53, p63 and p73 act as stress-responsive transcription factors. Oxidation of p53 central DNA binding domain destroys its structure and abolishes its sequence-specific binding by affecting zinc ion coordination at the protein-DNA interface. Proteins p63 and p73 can bind the same response elements as p53 but exhibit distinct functions. Moreover, all three proteins contain highly conserved cysteines in central DNA binding domain suitable for possible redox modulation.In this work we report for the first time the redox sensitivity of p63 and p73 core domains to a thiol oxidizing agent azodicarboxylic acid bis[dimethylamide] (diamide). Oxidation of both p63 and p73 abolished sequence-specific binding to p53 consensus sequence, depending on the agent concentration. In the presence of specific DNA all p53 family core domains were partially protected against loss of DNA binding activity due to diamide treatment. Furthermore, we detected conditional reversibility of core domain oxidation for all p53 family members and a role of zinc ions in this process. We showed that p63 and p73 proteins had greater ability to resist the diamide oxidation in comparison with p53. Our results show p63 and p73 as redox sensitive proteins with possible functionality in response of p53 family proteins to oxidative stress.

A β-cyclodextrin-containing polymeric salicylidene Schiff base: synthesis, zinc ion coordination and fluorescence resonance energy transfer with protein

Living/controlled polymerization of a salicylaldehyde-functionalized vinyl monomer, 2-hydrox-5-vinylbenzaldehyde (HVB), was achieved by reversible addition–fragmentation chain transfer (RAFT) polymerization with S-1-dodecyl-S′-(α,α′-dimethyl-α′′-acetic acid)trithiocarbonate as the RAFT agent in THF at 65 °C. The resulting well-defined polymer with pendant salicylaldehyde groups could react directly with mono-6-deoxy-6-aminoethyl-β-CD to yield a new β-CD-containing polymeric salicylidene Schiff base PHVB-graft-β-CD with precise structure and high solubility. PHVB-graft-β-CD was then coordinated with zinc ions to give the luminescent PHVB-graft-β-CD/Zn2+ complex which displayed intense blue fluorescence with a maximum emission peak around 452 nm in DMF. The obtained PHVB-graft-β-CD/Zn2+ tended to self-aggregate in aqueous media because of the hydrophobic nature of PHVB-graft-β-CD backbone, and therefore its fluorescence emission in water was weak as a result of the aggregation-induced fluorescence quenching. An obvious decrease of the aggregate size from 290 nm to 40 nm in aqueous media was observed after adding 1.0 equiv. (relative to β-CD moieties) of the guest molecule, sodium adamantanecarboxylate (Ad-COONa), and concomitantly a remarkable fluorescence enhancement (4.5-fold) was obtained due to a better water-dispersibility of PHVB-graft-β-CD/Zn2+. The incorporation of carboxylic groups on the PHVB-graft-β-CD/Zn2+ complex via the inclusion with Ad-COONa also endowed the resulting fluorescent nanoparticles with a further protein-binding function. Upon gradual addition of the fluorescent nanoparticle aqueous dispersion to the BSA buffer solution, the fluorescence intensity at ∼349 nm corresponding to BSA decreased, while the fluorescence intensity of the nanoparticle at ∼429 nm increased through an isoemissive point at 388 nm, indicating the occurrence of efficient fluorescence resonance energy transfer (FRET) between the fluorescent nanoparticles and protein. This novel protein sensing capability would give the fluorescent nanoparticles great potential in biotechnology.

Fabrication of a shape memory hydrogel based on imidazole–zinc ion coordination for potential cell-encapsulating tubular scaffold application

A dipole–dipole reinforced copolymer hydrogel was synthesized by the one-step photopolymerization of vinylimidazole (VI) and acrylonitrile (AN) comonomer in the presence of a polyethylene glycol-based crosslinker. The mechanical properties of PVI–AN gels were tremendously increased by only chelating several mmol L−1 zinc ions, which was shown to firmly lock the temporary shape of the gel. Extraction of zinc ions by a complexing agent could facilitate the recovery of a permanent shape, and the memory behavior was reversible. The PVI–AN hydrogels supported the growth of L929 cells. The cell-seeded flat hydrogel sheet was folded into a temporary tubular scaffold and fixed in a culture medium containing 5 mmol L−1 zinc ions. After unfolding the tube, the exposed L929 cells were shown to adhere well on the surface of the gel. It is anticipated that this cell-loaded SM hydrogel could be fixed to a desired shape in vitro by small numbers of zinc ions for a potential implantable tissue engineering scaffold.

Zinc ion coordination as a modulating factor of the ZnuA histidine-rich loop flexibility: A molecular modeling and fluorescence spectroscopy study

ZnuA is the soluble component of the high-affinity ZnuABC zinc transporter belonging to the ATP-binding cassette-type periplasmic Zn-binding proteins. The zinc transporter ZnuABC is composed by three proteins: ZnuB, the membrane permease, ZnuC, the ATPase component and ZnuA, the soluble periplasmic metal-binding protein which captures Zn and delivers it to ZnuB.The ZnuA protein contains a charged flexible loop, rich in histidines and acidic residues, showing significant species-specific differences. Various studies have established that this loop contributes to the formation of a secondary zinc binding site, which has been proposed to be important in the acquisition of periplasmic Zn for its delivery to ZnuB or for regulation of zinc uptake. Due to its high mobility the structure of the histidine-rich loop has never been solved by X-ray diffraction studies. In this paper, through a combined use of molecular modeling, mutagenesis and fluorescence spectroscopy, we confirm the presence of two zinc binding sites characterized by different affinities for the metal ion and show that the flexibility of the loop is modulated by the binding of the zinc ions to the protein. The data obtained by fluorescence spectroscopy have then be used to validate a 3D model including the unsolved histidine-rich loop.

Conversion of carbohydrates into 5-hydroxymethylfurfural catalyzed by ZnCl2 in water

The incompletely coordinated zinc ions in the concentrated aqueous ZnCl(2) solution catalyze the direct conversion of carbohydrates into 5-hydroxymethylfurfural, and a moderate HMF yield up to 50% can be achieved.

One- and two-photon absorption properties of two metalloporphyrin complexes

The linear and nonlinear optical properties of two metalloporphyrin complexes formed by the complementary coordination of central zinc or magnesium ions to the ligand 5, 10, 15-tri-(p-tolyl)-20-phenylethynylporphyrin are theoretically investigated by using the analytic response theory at the density functional theory level. The results indicate that the studied complexes present more symmetric geometry structures than the ligand. The charge-transfer states of the two complexes in the lower energy region are all almost degenerate but those of the ligand are well separated. The ratio of the two-photon absorption cross sections of the ligand, zinc-porphyrin and magnesium-porphyrin complexes is 1.0:1.5:1.8, demonstrating that the two-photon absorption capability can be greatly increased when the ligand is coordinated with a metal ion. Moreover, several physical micro-mechanisms including electron transitions and intramolecular charge-transfer processes are discussed to explore the differences in optical property between the ligand and two complexes.

Design and synthesis of potent Gram-negative specific LpxC inhibitors

Antibiotic resistant hospital acquired infections are on the rise, creating an urgent need for novel bactericidal drugs. Enzymes involved in lipopolysaccharide (LPS) biosynthesis are attractive antibacterial targets since LPS is the major structural component of the outer membrane of Gram-negative bacteria. Lipid A is an essential hydrophobic anchor of LPS and the first committed step in lipid A biosynthesis is catalyzed by a unique zinc dependent metalloamidase, UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC). LpxC is an attractive Gram-negative only target that has been chemically validated by potent bactericidal hydroxamate inhibitors that work by coordination of the enzyme's catalytic zinc ion. An exploratory chemistry effort focused on expanding the SAR around hydroxamic acid zinc-binding 'warheads' lead to the identification of novel compounds with enzyme potency and antibacterial activity similar to CHIR-090.

Synthesis of trans-1,4-cyclohexanedisulfonic acid and its zinc salt – A belt-like metal–organic coordination polymer with tetrahedrally and octahedrally coordinated zinc ions

Diastereomerically pure trans-1,4-cyclohexanedisulfonic acid H 2CDS was prepared in three steps from 1,4-cyclohexanediol ( cis/ trans-mixture) as a new linker molecule for metal–organic coordination polymers. The crystalline zinc salt contained two molecules DMF per formular unit. Infinite polymeric belts were observed in the solid state structure of [Zn(CDS)(dmf) 2]. These flat belts were formed by connecting two chains of Zn(dmf)-CDS-polymers bearing tetrahedrally coordinated Zn 2+ ions in one chain and octahedrally coordinated Zn 2+ centers in the second. Thermal analysis of this polymer revealed its stability up to 400 °C, above which it decomposed cleanly under formation of crystalline ZnO.

Diamondoid and square-grid networks based on bent wheel-and-axle diols

New coordination compounds of general formula Zn(ligand)2X2 (ligand = 2,6-diphenylphenol 4-pyridyl aldimine; X = Cl, Br, and I) have been synthesised and structurally characterized. They are analogous of palladium wheel-and-axle diols (waads), that have high propensity to include small guest molecules into their lattice, but the tetrahedral coordination of zinc ion bends their molecular axle. Here we demonstrate that the tuning of the molecular shape by axle bending enables to achieve a good self-packing efficiency, with loss of the clathrating properties of the material. In particular, Zn(ligand)2X2waads self assemble to form a fourfold interpenetrated superdiamondoid network with a close-packed structure.