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Molecules (Basel, Switzerland) Mar 2020Iodothyronine deiodinases (Dios) are involved in the regioselective removal of iodine from thyroid hormones (THs). Deiodination is essential to maintain TH homeostasis,... (Review)
Review
Iodothyronine deiodinases (Dios) are involved in the regioselective removal of iodine from thyroid hormones (THs). Deiodination is essential to maintain TH homeostasis, and disruption can have detrimental effects. Halogen bonding (XB) to the selenium of the selenocysteine (Sec) residue in the Dio active site has been proposed to contribute to the mechanism for iodine removal. Polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) are known disruptors of various pathways of the endocrine system. Experimental evidence shows PBDEs and their hydroxylated metabolites (OH-BDEs) can inhibit Dio, while data regarding PCB inhibition are limited. These xenobiotics could inhibit Dio activity by competitively binding to the active site Sec through XB to prevent deiodination. XB interactions calculated using density functional theory (DFT) of THs, PBDEs, and PCBs to a methyl selenolate (MeSe) arrange XB strengths in the order THs > PBDEs > PCBs in agreement with known XB trends. THs have the lowest energy C-X*-type unoccupied orbitals and overlap with the Se lp donor leads to high donor-acceptor energies and the greatest activation of the C-X bond. The higher energy C-Br* and C-Cl* orbitals similarly result in weaker donor-acceptor complexes and less activation of the C-X bond. Comparison of the I···Se interactions for the TH group suggest that a threshold XB strength may be required for dehalogenation. Only highly brominated PBDEs have binding energies in the same range as THs, suggesting that these compounds may inhibit Dio and undergo debromination. While these small models provide insight on the I···Se XB interaction itself, interactions with other active site residues are governed by regioselective preferences observed in Dios.
Topics: Animals; Halogenated Diphenyl Ethers; Halogens; Humans; Iodide Peroxidase; Polychlorinated Biphenyls; Thyroid Hormones
PubMed: 32183289
DOI: 10.3390/molecules25061328 -
Nature Communications Dec 2022Halogen bonding (XB), a non-covalent interaction between an electron-deficient halogen atom and a Lewis base, is widely adopted in organic synthesis and supramolecular...
Halogen bonding (XB), a non-covalent interaction between an electron-deficient halogen atom and a Lewis base, is widely adopted in organic synthesis and supramolecular crystal engineering. However, the roadmap towards materials applications is hindered by the challenges in harnessing this relatively weak intermolecular interaction to devise human-commanded stimuli-responsive soft materials. Here, we report a liquid crystalline network comprising permanent covalent crosslinks and dynamic halogen bond crosslinks, which possess reversible thermo-responsive shape memory behaviour. Our findings suggest that I···N halogen bond, a paradigmatic motif in crystal engineering studies, enables temporary shape fixation at room temperature and subsequent shape recovery in response to human body temperature. We demonstrate versatile shape programming of the halogen-bonded polymer networks through human-hand operation and propose a micro-robotic injection model for complex 1D to 3D shape morphing in aqueous media at 37 °C. Through systematic structure-property-performance studies, we show the necessity of the I···N crosslinks in driving the shape memory effect. The halogen-bonded shape memory polymers expand the toolbox for the preparation of smart supramolecular constructs with tailored mechanical properties and thermoresponsive behaviour, for the needs of, e.g., future medical devices.
Topics: Humans; Smart Materials; Halogens; Polymers; Temperature
PubMed: 36470884
DOI: 10.1038/s41467-022-34962-7 -
Chemical Reviews Feb 2016The halogen bond occurs when there is evidence of a net attractive interaction between an electrophilic region associated with a halogen atom in a molecular entity and a... (Review)
Review
The halogen bond occurs when there is evidence of a net attractive interaction between an electrophilic region associated with a halogen atom in a molecular entity and a nucleophilic region in another, or the same, molecular entity. In this fairly extensive review, after a brief history of the interaction, we will provide the reader with a snapshot of where the research on the halogen bond is now, and, perhaps, where it is going. The specific advantages brought up by a design based on the use of the halogen bond will be demonstrated in quite different fields spanning from material sciences to biomolecular recognition and drug design.
Topics: Halogens; Hydrocarbons, Halogenated; Molecular Structure
PubMed: 26812185
DOI: 10.1021/acs.chemrev.5b00484 -
Molecules (Basel, Switzerland) May 2018The variety of halogenated substances and their derivatives widely used as pesticides, herbicides and other industrial products is of great concern due to the hazardous... (Review)
Review
The variety of halogenated substances and their derivatives widely used as pesticides, herbicides and other industrial products is of great concern due to the hazardous nature of these compounds owing to their toxicity, and persistent environmental pollution. Therefore, from the viewpoint of environmental technology, the need for environmentally relevant enzymes involved in biodegradation of these pollutants has received a great boost. One result of this great deal of attention has been the identification of environmentally relevant bacteria that produce hydrolytic dehalogenases—key enzymes which are considered cost-effective and eco-friendly in the removal and detoxification of these pollutants. These group of enzymes catalyzing the cleavage of the carbon-halogen bond of organohalogen compounds have potential applications in the chemical industry and bioremediation. The dehalogenases make use of fundamentally different strategies with a common mechanism to cleave carbon-halogen bonds whereby, an active-site carboxylate group attacks the substrate C atom bound to the halogen atom to form an ester intermediate and a halide ion with subsequent hydrolysis of the intermediate. Structurally, these dehalogenases have been characterized and shown to use substitution mechanisms that proceed via a covalent aspartyl intermediate. More so, the widest dehalogenation spectrum of electron acceptors tested with bacterial strains which could dehalogenate recalcitrant organohalides has further proven the versatility of bacterial dehalogenators to be considered when determining the fate of halogenated organics at contaminated sites. In this review, the general features of most widely studied bacterial dehalogenases, their structural properties, basis of the degradation of organohalides and their derivatives and how they have been improved for various applications is discussed.
Topics: Bacteria; Bacterial Proteins; Biodegradation, Environmental; Catalytic Domain; Chemical Industry; Environmental Pollutants; Esters; Halogens; Humans; Hydrocarbons, Halogenated; Hydrolases; Hydrolysis; Isoenzymes; Pesticides
PubMed: 29735886
DOI: 10.3390/molecules23051100 -
Annual Review of Biochemistry Jun 2018Flavin-dependent halogenases (FDHs) catalyze the halogenation of organic substrates by coordinating reactions of reduced flavin, molecular oxygen, and chloride. Targeted... (Review)
Review
Flavin-dependent halogenases (FDHs) catalyze the halogenation of organic substrates by coordinating reactions of reduced flavin, molecular oxygen, and chloride. Targeted and random mutagenesis of these enzymes have been used to both understand and alter their reactivity. These studies have led to insights into residues essential for catalysis and FDH variants with improved stability, expanded substrate scope, and altered site selectivity. Mutations throughout FDH structures have contributed to all of these advances. More recent studies have sought to rationalize the impact of these mutations on FDH function and to identify new FDHs to deepen our understanding of this enzyme class and to expand their utility for biocatalytic applications.
Topics: Biocatalysis; Catalytic Domain; Directed Molecular Evolution; Drug Design; Enzyme Stability; Flavins; Halogenation; Hydrocarbons, Halogenated; Metabolic Networks and Pathways; Models, Molecular; Mutagenesis; Oxidoreductases; Substrate Specificity
PubMed: 29589959
DOI: 10.1146/annurev-biochem-062917-012042 -
International Journal of Molecular... Aug 20232,3,5,6-Tetramethyl-1,4-diisocyanobenzene (), 1,4-diisocyanobenzene (), and 1,4-dicyanobenzene () were co-crystallized with 1,3,5-triiodotrifluorobenzene (1,3,5-FIB) to...
2,3,5,6-Tetramethyl-1,4-diisocyanobenzene (), 1,4-diisocyanobenzene (), and 1,4-dicyanobenzene () were co-crystallized with 1,3,5-triiodotrifluorobenzene (1,3,5-FIB) to give three cocrystals, ·1,3,5-FIB, ·2(1,3,5-FIB), and ·2(1,3,5-FIB), which were studied by X-ray diffraction. A common feature of the three structures is the presence of I···C or I···N halogen bonds (HaBs), which occurs between an iodine σ-hole and the isocyanide C-(or the nitrile N-) atom. The diisocyanide and dinitrile cocrystals ·2(1,3,5-FIB) and ·2(1,3,5-FIB) are isostructural, thus providing a basis for accurate comparison of the two types of noncovalent linkages of C≡N/N≡C groups in the composition of structurally similar entities and in one crystal environment. The bonding situation was studied by a set of theoretical methods. Diisocyanides are more nucleophilic than the dinitrile and they exhibit stronger binding to 1,3,5-FIB. In all structures, the HaBs are mostly determined by the electrostatic interactions, but the dispersion and induction components also provide a noticeable contribution and make the HaBs attractive. Charge transfer has a small contribution (<5%) to the HaB and it is higher for the diisocyanide than for the dinitrile systems. At the same time, diisocyanide and dinitrile structures exhibit typical electron-donor and π-acceptor properties in relation to the HaB donor.
Topics: Cyanides; Halogens; Nitriles; Iodine
PubMed: 37686131
DOI: 10.3390/ijms241713324 -
Chemistry (Weinheim An Der Bergstrasse,... Jan 2022Oxidation of the iron(II) precursor [(L )Fe Cl ], where L is a tetradentate bispidine, with soluble iodosylbenzene ( PhIO) leads to the extremely reactive ferryl oxidant...
Oxidation of the iron(II) precursor [(L )Fe Cl ], where L is a tetradentate bispidine, with soluble iodosylbenzene ( PhIO) leads to the extremely reactive ferryl oxidant [(L )(Cl)Fe =O] with a cis disposition of the chlorido and oxido coligands, as observed in non-heme halogenase enzymes. Experimental data indicate that, with cyclohexane as substrate, there is selective formation of chlorocyclohexane, the halogenation being initiated by C-H abstraction and the result of a rebound of the ensuing radical to an iron-bound Cl . The time-resolved formation of the halogenation product indicates that this primarily results from PhIO oxidation of an initially formed oxido-bridged diiron(III) resting state. The high yield of up to >70 % (stoichiometric reaction) as well as the differing reactivities of free Fe and Fe in comparison with [(L )Fe Cl ] indicate a high complex stability of the bispidine-iron complexes. DFT analysis shows that, due to a large driving force and small triplet-quintet gap, [(L )(Cl)Fe =O] is the most reactive small-molecule halogenase model, that the Fe /radical rebound intermediate has a relatively long lifetime (as supported by experimentally observed cage escape), and that this intermediate has, as observed experimentally, a lower energy barrier to the halogenation than the hydroxylation product; this is shown to primarily be due to steric effects.
Topics: Carbon; Ferric Compounds; Halogenation; Hydrogen Bonding; Iron
PubMed: 34792224
DOI: 10.1002/chem.202103452 -
Aging May 2018Non-enzymatic protein modifications occur inevitably in all living systems. Products of such modifications accumulate during aging of cells and organisms and may... (Review)
Review
Non-enzymatic protein modifications occur inevitably in all living systems. Products of such modifications accumulate during aging of cells and organisms and may contribute to their age-related functional deterioration. This review presents the formation of irreversible protein modifications such as carbonylation, nitration and chlorination, modifications by 4-hydroxynonenal, removal of modified proteins and accumulation of these protein modifications during aging of humans and model organisms, and their enhanced accumulation in age-related brain diseases.
Topics: Aging; Animals; Brain Diseases; Halogenation; Humans; Oxidative Stress; Protein Carbonylation; Protein Processing, Post-Translational
PubMed: 29779015
DOI: 10.18632/aging.101450 -
Environmental Science and Pollution... Dec 2022Chlorinated disinfectants are widely used in hospitals, COVID-19 quarantine facilities, households, institutes, and public areas to combat the spread of the novel... (Review)
Review
Chlorinated disinfectants are widely used in hospitals, COVID-19 quarantine facilities, households, institutes, and public areas to combat the spread of the novel coronavirus as they are effective against viruses on various surfaces. Medical facilities have enhanced their routine disinfection of indoors, premises, and in-house sewage. Besides questioning the efficiency of these compounds in combating coronavirus, the impacts of these excessive disinfection efforts have not been discussed anywhere. The impacts of chlorine-based disinfectants on both environment and human health are reviewed in this paper. Chlorine in molecular and in compound forms is known to pose many health hazards. Hypochlorite addition to soil can increase chlorine/chloride concentration, which can be fatal to plant species if exposed. When chlorine compounds reach the sewer/drainage system and are exposed to aqueous media such as wastewater, many disinfection by-products (DBPs) can be formed depending on the concentrations of natural organic matter, inorganics, and anthropogenic pollutants present. Chlorination of hospital wastewater can also produce toxic drug-derived disinfection by-products. Many DBPs are carcinogenic to humans, and some of them are cytotoxic, genotoxic, and mutagenic. DBPs can be harmful to the flora and fauna of the receiving water body and may have adverse effects on microorganisms and plankton present in these ecosystems.
Topics: Humans; Disinfectants; Chlorine; COVID-19; Wastewater; Water Purification; Chlorides; Ecosystem; Pandemics; Water Pollutants, Chemical; Disinfection; Halogenation; Halogens
PubMed: 35091954
DOI: 10.1007/s11356-021-18316-2 -
Accounts of Chemical Research Jan 2009Simple halogen substituents frequently afford key structural features that account for the potency and selectivity of natural products, including antibiotics and... (Review)
Review
Simple halogen substituents frequently afford key structural features that account for the potency and selectivity of natural products, including antibiotics and hormones. For example, when a single chlorine atom on the antibiotic vancomycin is replaced by hydrogen, the resulting antibacterial activity decreases by up to 70% ( Harris , C. M. ; Kannan , R. ; Kopecka , H. ; Harris , T. M. J. Am. Chem. Soc. 1985 , 107 , 6652 - 6658 ). This Account analyzes how structure underlies mechanism in halogenases, the molecular machines designed by nature to incorporate halogens into diverse substrates. Traditional synthetic methods of integrating halogens into complex molecules are often complicated by a lack of specificity and regioselectivity. Nature, however, has developed a variety of elegant mechanisms for halogenating specific substrates with both regio- and stereoselectivity. An improved understanding of the biological routes toward halogenation could lead to the development of novel synthetic methods for the creation of new compounds with enhanced functions. Already, researchers have co-opted a fluorinase from the microorganism Streptomyces cattleya to produce (18)F-labeled molecules for use in positron emission tomography (PET) ( Deng , H. ; Cobb , S. L. ; Gee , A. D. ; Lockhart , A. ; Martarello , L. ; McGlinchey , R. P. ; O'Hagan , D. ; Onega , M. Chem. Commun. 2006 , 652 - 654 ). Therefore, the discovery and characterization of naturally occurring enzymatic halogenation mechanisms has become an active area of research. The catalogue of known halogenating enzymes has expanded from the familiar haloperoxidases to include oxygen-dependent enzymes and fluorinases. Recently, the discovery of a nucleophilic halogenase that catalyzes chlorinations has expanded the repertoire of biological halogenation chemistry ( Dong , C. ; Huang , F. ; Deng , H. ; Schaffrath , C. ; Spencer , J. B. ; O'Hagan , D. ; Naismith , J. H. Nature 2004 , 427 , 561 - 565 ). Structural characterization has provided a basis toward a mechanistic understanding of the specificity and chemistry of these enzymes. In particular, the latest crystallographic snapshots of active site architecture and halide binding sites have provided key insights into enzyme catalysis. Herein is a summary of the five classes of halogenases, focusing on the three most recently discovered: flavin-dependent halogenases, non-heme iron-dependent halogenases, and nucleophilic halogenases. Further, the potential roles of halide-binding sites in determining halide selectivity are discussed, as well as whether or not binding-site composition is always a seminal factor for selectivity. Expanding our understanding of the basic chemical principles that dictate the activity of the halogenases will advance both biology and chemistry. A thorough mechanistic analysis will elucidate the biological principles that dictate specificity, and the application of those principles to new synthetic techniques will expand the utility of halogenations in small-molecule development.
Topics: Animals; Binding Sites; Enzymes; Flavin-Adenine Dinucleotide; Halogenation; Halogens; Humans; Iron; Molecular Structure; Oxygen; Protein Conformation; Substrate Specificity; Vanadium
PubMed: 18774824
DOI: 10.1021/ar800088r