SciCombinator

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Journal: Coordination chemistry reviews

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As an NNN-tridentate ligand, the 2,2':6',2"-terpyridine plays an important role in coordination chemistry. With three coordination sites and low LUMO, terpyridine and its derivatives are one of the typical Pincer ligand and/or non-innocent ligands in transition metal catalysis. Interesting catalytic reactivities have been obtained with these tpy-metal complexes targeting some challenging transformations, such as C-C bond formation and hydrofunctionalization. On the other hand, terpyridine ligands can form “closed-shell” octahedral complexes, which provide a linear and stable linkage in supramolecular chemistry. Numerous supramolecular architectures have been achieved using modified terpyridine ligands including Sierpiński triangles, hexagonal gasket and supramolecular rosettes. This review presents a summary of recent progress regarding transition metal-terpyridine complexes with the focus on their applications in catalysis and supramolecular structure construction. Facile synthesis of terpyridine derivatives is also described. We hope this article can serve to provide some general perspectives of the terpyridine ligand and their applications in coordination chemistry.

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Metalloporphyrins serve key roles in natural biological processes and also have demonstrated utility for biomedical applications. They can be encapsulated or grafted in conventional nanoparticles or can self-assemble themselves at the nanoscale. A wide range of metals can be stably chelated either before or after porphyrin nanoparticle formation, without the necessity of any additional chelator chemistry. The addition of metals can substantially alter a range of behaviors such as modulating phototherapeutic efficacy; conferring responsiveness to biological stimuli; or providing contrast for magnetic resonance, positron emission or surface enhanced Raman imaging. Chelated metals can also provide a convenient handle for bioconjugation with other molecules via axial coordination. This review provides an overview of some recent biomedical, nanoparticulate approaches involving gain-of-function metalloporphyrins and related molecules.

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Several diseases share misfolding of different peptides and proteins as a key feature for their development. This is the case of important neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases and type II diabetes mellitus. Even more, metal ions such as copper and zinc might play an important role upon interaction with amyloidogenic peptides and proteins, which could impact their aggregation and toxicity abilities. In this review, the different coordination modes proposed for copper and zinc with amyloid-β, α-synuclein and IAPP will be reviewed as well as their impact on the aggregation, and ROS production in the case of copper. In addition, a special focus will be given to the mutations that affect metal binding and lead to familial cases of the diseases. Different modifications of the peptides that have been observed in vivo and could be relevant for the coordination of metal ions are also described.

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A new paradigm in metallobiochemistry describes the activation of inactive metalloenzymes by metal ion removal. Protein tyrosine phosphatases (PTPs) do not seem to require a metal ion for enzymatic activity. However, both metal cations and metal anions modulate their enzymatic activity. One binding site is the phosphate binding site at the catalytic cysteine residue. Oxyanions with structural similarity to phosphate, such as vanadate, inhibit the enzyme with nanomolar to micromolar affinities. In addition, zinc ions (Zn(2+)) inhibit with picomolar to nanomolar affinities. We mapped the cation binding site close to the anion binding site and established a specific mechanism of inhibition occurring only in the closed conformation of the enzyme when the catalytic cysteine is phosphorylated and the catalytic aspartate moves into the active site. We discuss this dual inhibition by anions and cations here for PTP1B, the most thoroughly investigated protein tyrosine phosphatase. The significance of the inhibition in phosphorylation signaling is becoming apparent only from the functions of PTP1B in the biological context of metal cations as cellular signaling ions. Zinc ion signals complement redox signals but provide a different type of control and longer lasting inhibition on a biological time scale owing to the specificity and affinity of zinc ions for coordination environments. Inhibitor design for PTP1B and other PTPs is a major area of research activity and interest owing to their prominent roles in metabolic regulation in health and disease, in particular cancer and diabetes. Our results explain the apparent dichotomy of both cations (Zn(2+)) and oxyanions such as vanadate inhibiting PTP1B and having insulin-enhancing (“anti-diabetic”) effects and suggest different approaches, namely targeting PTPs in the cell by affecting their physiological modulators and considering a metallodrug approach that builds on the knowledge of the insulin-enhancing effects of both zinc and vanadium compounds.

Concepts: Cell, Metabolism, Enzyme, Hydrogen, Ion, Solid, Silver, Protein tyrosine phosphatase

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The coordination chemistry of metal nitrosyls has expanded rapidly in the past decades due to major advances of nitric oxide and its metal compounds in biology. This review article highlights advances made in the area of multinuclear metal nitrosyl complexes, including Roussin’s salts and their ester derivatives from 2003 to present. The review article focuses on isolated multinuclear metal nitrosyl complexes and is organized into different sections by the number of metal centers and bridging ligands.

Concepts: Ammonia, Chemistry, Ligand, Nitric oxide, Chemical compound, Hydroxide, Nitric acid, Metal nitrosyl

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Small redox active molecules such as reactive nitrogen and oxygen species and hydrogen sulfide have emerged as important biological mediators that are involved in various physiological and pathophysiological processes. Advancement in understanding of cellular mechanisms that tightly regulate both generation and reactivity of these molecules is central to improved management of various disease states including cancer and cardiovascular dysfunction. Imbalance in the production of redox active molecules can lead to damage of critical cellular components such as cell membranes, proteins and DNA and thus may trigger the onset of disease. These small inorganic molecules react independently as well as in a concerted manner to mediate physiological responses. This review provides a general overview of the redox biology of these key molecules, their diverse chemistry relevant to physiological processes and their interrelated nature in cellular signaling.

Concepts: DNA, Protein, Oxygen, Gene, Bacteria, Biology, Physiology, Nitrogen

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Polyoxometalates (POMs) are discrete polynuclear metal-oxo anions with a fascinating variety of structures and unique chemical and physical properties. Their application in various fields is well covered in the literature, however little information about their usage in protein crystallization is available. This review summarizes the impact of the vast class of POMs on the formation of protein crystals, a well-known (frustrating) bottleneck in macromolecular crystallography, with the associated structure elucidation and a particular emphasis focused on POM’s potential as a powerful crystallization additive for future research. The Protein Data Bank (PDB) was scanned for protein structures with incorporated POMs which were assigned a PDB ligand ID resulting in 30 PDB entries. These structures have been analyzed with regard to (i) the structure of POM itself in the immediate protein environment, (ii) the kind of interaction and position of the POM within the protein structure and (iii) the beneficial effects of POM on protein crystallography apparent so far.

Concepts: Protein, Protein structure, Crystal, Crystallography, Receptor, X-ray crystallography, Crystallization, Protein Data Bank

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Much emphasis has been given to vanadium compounds as potential therapeutic reagents for the treatment of diabetes mellitus. Thus far, no vanadium compound has proven efficacious for long-term treatment of this disease in humans. Therefore, in review of the research literature, our goal has been to identify properties of vanadium compounds that are likely to favor physiological and biochemical compatibility for further development as therapeutic reagents. We have, therefore, limited our review to those vanadium compounds that have been used in both in vivo experiments with small, laboratory animals and in in vitro studies with primary or cultured cell systems and for which pharmacokinetic and pharmacodynamics results have been reported, including vanadium tissue content, vanadium and ligand lifetime in the bloodstream, structure in solution, and interaction with serum transport proteins. Only vanadyl (VO(2+)) chelates fulfill these requirements despite the large variety of vanadium compounds of different oxidation states, ligand structure, and coordination geometry synthesized as potential therapeutic agents. Extensive review of research results obtained with use of organic VO(2+)-chelates shows that the vanadyl chelate bis(acetylacetonato)oxidovanadium(IV) [hereafter abbreviated as VO(acac)2], exhibits the greatest capacity to enhance insulin receptor kinase activity in cells compared to other organic VO(2+)-chelates, is associated with a dose-dependent capacity to lower plasma glucose in diabetic laboratory animals, and exhibits a sufficiently long lifetime in the blood stream to allow correlation of its dose-dependent action with blood vanadium content. The properties underlying this behavior appear to be its high stability and capacity to remain intact upon binding to serum albumin. We relate the capacity to remain intact upon binding to serum albumin to the requirement to undergo transcytosis through the vascular endothelium to gain access to target tissues in the extravascular space. Serum albumin, as the most abundant transport protein in the blood stream, serves commonly as the carrier protein for small molecules, and transcytosis of albumin through capillary endothelium is regulated by a Src protein tyrosine kinase system. In this respect it is of interest to note that inorganic VO(2+) has the capacity to enhance insulin receptor kinase activity of intact 3T3-L1 adipocytes in the presence of albumin, albeit weak; however, in the presence of transferrin no activation is observed. In addition to facilitating glucose uptake, the capacity of VO(2+)- chelates for insulin-like, antilipolytic action in primary adipocytes has also been reviewed. We conclude that measurement of inhibition of release of only free fatty acids from adipocytes stimulated by epinephrine is not a sufficient basis to ascribe the observations to purely insulin-mimetic, antilipolytic action. Adipocytes are known to contain both phosphodiesterase-3 and phosphodiesterase-4 (PDE3 and PDE4) isozymes, of which insulin antagonizes lipolysis only through PDE3B. It is not known whether the other isozyme in adipocytes is influenced directly by VO(2+)- chelates. In efforts to promote improved development of VO(2+)- chelates for therapeutic purposes, we propose synergism of a reagent with insulin as a criterion for evaluating physiological and biochemical specificity of action. We highlight two organic compounds that exhibit synergism with insulin in cellular assays. Interestingly, the only VO(2+)- chelate for which this property has been demonstrated, thus far, is VO(acac)2.

Concepts: Protein, Signal transduction, Blood, Insulin, Diabetes mellitus, Glucose, Protein kinase, Tyrosine kinase

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Metalloenzymes efficiently catalyze some of the most important and difficult reactions in nature. For many years, coordination chemists have effectively used small molecule models to understand these systems. More recently, protein design has been shown to be an effective approach for mimicking metal coordination environments. Since the first designed proteins were reported, much success has been seen for incorporating metal sites into proteins and attaining the desired coordination environment but until recently, this has been with a lack of significant catalytic activity. Now there are examples of designed metalloproteins that, although not yet reaching the activity of native enzymes, are considerably closer. In this review, we highlight work leading up to the design of a small metalloprotein containing two metal sites, one for structural stability (HgS3) and the other a separate catalytic zinc site to mimic carbonic anhydrase activity (ZnN3O). The first section will describe previous studies that allowed for a high affinity thiolate site that binds heavy metals in a way that stabilizes three-stranded coiled coils. The second section will examine ways of preparing histidine rich environments that lead to metal based hydrolytic catalysts. We will also discuss other recent examples of the design of structural metal sites and functional metalloenzymes. Our work demonstrates that attaining the proper first coordination geometry of a metal site can lead to a significant fraction of catalytic activity, apparently independent of the type of secondary structure of the surrounding protein environment. We are now in a position to begin to meet the challenge of building a metalloenzyme systematically from the bottom-up by engineering and analyzing interactions directly around the metal site and beyond.

Concepts: Protein, Metabolism, Enzyme, Hydrogen, Catalysis, Histidine, Carbonic anhydrase, Metalloprotein

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The interplay between redox-active transition metal ions and redox-active ligands in metalloenzyme sites is an area of considerable research interest. Galactose oxidase (GO) is the archetypical example, catalyzing the aerobic oxidation of primary alcohols to aldehydes via two one-electron cofactors: a copper atom and a cysteine-modified tyrosine residue. The electronic structure of the oxidized form of the enzyme (GO(ox)) has been investigated extensively through small molecule analogues including metal-salen phenoxyl radical complexes. Similar to GO(ox), one-electron oxidized metal-salen complexes are mixed-valent species, in which molecular orbitals (MOs) with predominantly phenolate and phenoxyl π-character act as redox-active centers bridged by mixing with metal d-orbitals. A detailed evaluation of the electronic distribution in these odd electron species using a variety of spectroscopic, electrochemical, and theoretical techniques has led to keen insights into the electronic structure of GO(ox).

Concepts: Electron, Alcohol, Iron, Redox, Molecule, Atom, Transition metal, Electron configuration