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Natural Product Reports Oct 2021Covering: Up to December 2020Enzymatic halogenation reactions are essential for the production of thousands of halogenated natural products. However, in recent years,... (Review)
Review
Covering: Up to December 2020Enzymatic halogenation reactions are essential for the production of thousands of halogenated natural products. However, in recent years, scientists discovered several halogenases that transiently incorporate halogen atoms in intermediate biosynthetic molecules to activate them for further chemical reactions such as cyclopropanation, terminal alkyne formation, C-/O-alkylation, biaryl coupling, and C-C rearrangements. In each case, the halogen atom is lost in the course of biosynthesis to the final product and is hence termed "cryptic". In this review, we provide an overview of our current knowledge of cryptic halogenation reactions in natural product biosynthesis.
Topics: Biological Products; Halogenation
PubMed: 34676862
DOI: 10.1039/d1np00010a -
Chembiochem : a European Journal of... Jan 2023The late-stage site-selective derivatisation of peptides has many potential applications in structure-activity relationship studies and postsynthetic modification or...
The late-stage site-selective derivatisation of peptides has many potential applications in structure-activity relationship studies and postsynthetic modification or conjugation of bioactive compounds. The development of orthogonal methods for C-H functionalisation is crucial for such peptide derivatisation. Among them, biocatalytic methods are increasingly attracting attention. Tryptophan halogenases emerged as valuable catalysts to functionalise tryptophan (Trp), while direct enzyme-catalysed halogenation of synthetic peptides is yet unprecedented. Here, it is reported that the Trp 6-halogenase Thal accepts a wide range of amides and peptides containing a Trp moiety. Increasing the sequence length and reaction optimisation made bromination of pentapeptides feasible with good turnovers and a broad sequence scope, while regioselectivity turned out to be sequence dependent. Comparison of X-ray single crystal structures of Thal in complex with d-Trp and a dipeptide revealed a significantly altered binding mode for the peptide. The viability of this bioorthogonal approach was exemplified by halogenation of a cyclic RGD peptide.
Topics: Halogenation; Tryptophan; Peptides; Structure-Activity Relationship; Catalysis
PubMed: 36259362
DOI: 10.1002/cbic.202200569 -
Scientific Reports Mar 2020Fish muscle may constitute one of the main sources of iodine (I) for the indigenous peoples of the Russian Arctic, although limited information is available about its...
Fish muscle may constitute one of the main sources of iodine (I) for the indigenous peoples of the Russian Arctic, although limited information is available about its content in commonly consumed fish species. In the current study, bromine (Br), I, the essential elements (copper, selenium and zinc) and other non-essential elements - specifically mercury, arsenic (As), cadmium, lead and nickel - have been quantified in 10 fish species consumed by people living in the Nenets and Chukotka Regions. Fish muscle was analysed by ICP-MS after nitric acid or tetramethylammonium hydroxide digestion. Certified reference materials were employed and concentrations are reported as geometric means (GMs). Atlantic cod (6.32 mg/kg) and navaga (0.934 mg/kg) contained substantially higher amounts of I than all other fish species, while broad whitefish had the lowest (0.033 mg/kg). By comparison, navaga contained more Br (14.5 mg/kg) than the other fish species, ranging 7.45 mg/kg in Atlantic cod to 2.39 mg/kg in northern pike. A significant inter-fish association between As and I in freshwater and marine fish was observed, suggesting common sources and perhaps parallel absorption patterns. Only Atlantic cod and, to lesser extent, navaga constituted significant dietary sources of I.
Topics: Animals; Arctic Regions; Arsenic; Bromine; Cadmium; Copper; Fish Products; Fishes; Fresh Water; Humans; Indigenous Peoples; Iodine; Mercury; Russia; Seawater; Selenium; Zinc
PubMed: 32214169
DOI: 10.1038/s41598-020-62242-1 -
Journal of Lipid Research Apr 2018α-Chlorofatty aldehydes (α-ClFALDs) and α-bromofatty aldehydes (α-BrFALDs) are produced in activated neutrophils and eosinophils. This study investigated the ability...
α-Chlorofatty aldehydes (α-ClFALDs) and α-bromofatty aldehydes (α-BrFALDs) are produced in activated neutrophils and eosinophils. This study investigated the ability of α-BrFALD and α-ClFALD to react with the thiols of GSH and protein cysteinyl residues. Initial studies showed that 2-bromohexadecanal (2-BrHDA) and 2-chlorohexadecanal (2-ClHDA) react with GSH producing the same fatty aldehyde-GSH adduct (FALD-GSH). In both synthetic and cellular reactions, FALD-GSH production was more robust with 2-BrHDA compared with 2-ClHDA as precursor. NaBr-supplemented phorbol myristate acetate (PMA)-activated neutrophils formed more α-BrFALD and FALD-GSH compared with non-NaBr-supplemented neutrophils. Primary human eosinophils, which preferentially produce hypobromous acid and α-BrFALD, accumulated FALD-GSH following PMA stimulation. Mice exposed to Br gas had increased levels of both α-BrFALD and FALD-GSH in the lungs, as well as elevated systemic plasma levels of FALD-GSH in comparison to mice exposed to air. Similar relative reactivity of α-ClFALD and α-BrFALD with protein thiols was shown using click analogs of these aldehydes. Collectively, these data demonstrate that GSH and protein adduct formation are much greater as a result of nucleophilic attack of cysteinyl residues on α-BrFALD compared with α-ClFALD, which was observed in both primary leukocytes and in mice exposed to bromine gas.
Topics: Aldehydes; Animals; Bromine; Click Chemistry; Eosinophil Peroxidase; Glutathione Transferase; Healthy Volunteers; Humans; Mice; Peroxidase; RAW 264.7 Cells
PubMed: 29444934
DOI: 10.1194/jlr.M083279 -
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 -
Andrology Jul 2020Environmental chemicals that interfere with the production and/or action of hormones may have adverse effects on male reproduction. This review focuses on the possible... (Review)
Review
BACKGROUND
Environmental chemicals that interfere with the production and/or action of hormones may have adverse effects on male reproduction. This review focuses on the possible impact of exposure to flame retardant chemicals on male reproduction. Flame retardants are added to a wide variety of combustible materials to prevent fires from starting, slow their spread, and provide time to escape. However, these chemicals are often additive so they leach out into the environment. Governments have restricted the use of polybrominated diphenyl ether flame retardants based on evidence that they are persistent and bioaccumulate and have adverse effects on health. The phasing out of these "legacy" flame retardants has resulted in their replacement with alternatives, such as tetrabromobisphenol A and the organophosphate esters.
OBJECTIVE
To review the literature on the effects of brominated and organophosphate ester flame retardant chemicals on male reproduction.
METHODS
PubMed database was searched for studies reporting the effects of brominated and organophosphate ester flame retardants on male reproduction.
RESULTS
Cell-based, animal model, and human studies provide evidence that the polybrominated diphenyl ethers act as endocrine-disrupting chemicals; further, exposure during critical windows of development may be associated with a permanent impact on male reproduction. In vitro and animal model data are accumulating with respect to the effects of tetrabromobisphenol A and organophosphate esters, but few studies have evaluated their impact on human health.
CONCLUSIONS
More research on human exposure to replacement flame retardants and the possibility that they may be associated with adverse reproductive health outcomes is a high priority.
Topics: Animals; Bromine; Endocrine Disruptors; Environmental Pollutants; Flame Retardants; Genitalia, Male; Halogenated Diphenyl Ethers; Humans; Male; Organophosphates; Polybrominated Biphenyls
PubMed: 32216051
DOI: 10.1111/andr.12789 -
The Journal of Organic Chemistry Dec 2017We developed an atom-economical and metal-free method for the regio- and stereo-selective hydrohalogenation of ynones and ynamides using easy to handle DMPU/HX (X = Br...
We developed an atom-economical and metal-free method for the regio- and stereo-selective hydrohalogenation of ynones and ynamides using easy to handle DMPU/HX (X = Br or Cl) reagents. The reaction operates under mild conditions and a range of functional groups is well tolerated. We propose that the hydrohalogenation of ynones gives the anti-addition products via a concerted multimolecular Ad3 mechanism and that the hydrohalogenation of ynamides produces the syn-addition products via a cationic keteniminium intermediate.
Topics: Amides; Halogenation; Ketones; Metals; Stereoisomerism
PubMed: 29166765
DOI: 10.1021/acs.joc.7b02257 -
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 -
Journal of Clinical Pathology May 1993To examine the possible consequences of high plasma concentrations of bromine on thyroid hormone. (Comparative Study)
Comparative Study
AIMS
To examine the possible consequences of high plasma concentrations of bromine on thyroid hormone.
METHODS
Bromine was measured by inductively coupled plasma mass spectrometry in the plasma of 799 patients consulting for thyroid disorders. Because the mean (SD) bromine concentration in the plasma of healthy subjects is 4 (1) mg/l, concentrations above 6 mg/l were regarded as outside the normal range. Bromine, free thyroxine (FT4), and thyroid stimulating hormone (TSH) values were compared.
RESULTS
The percentage of patients with normal, low, and high FT4 and TSH plasma activities, measured separately, did not differ between patients with low and high bromine concentrations. The percentage of patients with high TSH but normal FT4 values was significantly higher in the group with bromine values of more than 6 mg/l than in the group with bromine concentrations below this (p < 0.02).
CONCLUSION
An increase in plasma bromine could potentiate an increase in plasma TSH concentration, probably as a consequence of a minor inhibitory effect on thyroid activity.
Topics: Bromine; Humans; Thyroid Diseases; Thyroid Gland; Thyroid Hormones; Thyrotropin; Thyroxine
PubMed: 8320326
DOI: 10.1136/jcp.46.5.456 -
Journal of the American Chemical Society Aug 2023The biosynthetic installation of halogen atoms is largely performed by oxidative halogenases that target a wide array of electron-rich substrates, including aromatic...
The biosynthetic installation of halogen atoms is largely performed by oxidative halogenases that target a wide array of electron-rich substrates, including aromatic compounds and conjugated systems. Halogenated alkyne-containing molecules are known to occur in Nature; however, halogen atom installation on the terminus of an alkyne has not been demonstrated in enzyme catalysis. Herein, we report the discovery and characterization of an alkynyl halogenase in natural product biosynthesis. We show that the flavin-dependent halogenase from the jamaicamide biosynthetic pathway, JamD, is not only capable of terminal alkyne halogenation on a late-stage intermediate en route to the final natural product but also has broad substrate tolerance for simple to complex alkynes. Furthermore, JamD is specific for terminal alkynes over other electron-rich aromatic substrates and belongs to a newly identified family of halogenases from marine cyanobacteria, indicating its potential as a chemoselective biocatalyst for the formation of haloalkynes.
Topics: Halogenation; Halogens; Alkynes; Biological Products; Catalysis
PubMed: 37594919
DOI: 10.1021/jacs.3c05750