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Current Opinion in Biotechnology Apr 2022The pressing need for novel bioproduction approaches faces a limitation in the number and type of molecules accessed through synthetic biology. Halogenation is widely... (Review)
Review
The pressing need for novel bioproduction approaches faces a limitation in the number and type of molecules accessed through synthetic biology. Halogenation is widely used for tuning physicochemical properties of molecules and polymers, but traditional halogenation chemistry often lacks specificity and generates harmful by-products. Here, we pose that deploying synthetic metabolism tailored for biohalogenation represents an unique opportunity towards economically attractive and environmentally friendly organohalide production. On this background, we discuss growth-coupled selection of functional metabolic modules that harness the rich repertoire of biosynthetic and biodegradation capabilities of environmental bacteria for in vivo biohalogenation. By rationally combining these approaches, the chemical landscape of living cells can accommodate bioproduction of added-value organohalides which, as of today, are obtained by traditional chemistry.
Topics: Bacteria; Biodegradation, Environmental; Halogenation; Synthetic Biology
PubMed: 34954625
DOI: 10.1016/j.copbio.2021.11.009 -
Neurologia Oct 2022Laboratory studies identified changes in the metabolism of halogens in the serum and cerebrospinal fluid (CSF) of patients with Parkinson's disease, which indicates the... (Review)
Review
Laboratory studies identified changes in the metabolism of halogens in the serum and cerebrospinal fluid (CSF) of patients with Parkinson's disease, which indicates the presence of "accelerated self-halogenation" of CSF and/or an increase in haloperoxidases, specifically serum thyroperoxidase and CSF lactoperoxidase. Furthermore, an excess of some halogenated derivatives, such as advanced oxygenation protein products (AOPP), has been detected in the CSF and serum. "Accelerated self-halogenation" and increased levels of haloperoxidases and AOPP proteins indicate that halogenative stress is present in Parkinson's disease. In addition, 3-iodo-L-tyrosine, a halogenated derivative, shows "parkinsonian" toxicity in experimental models, since it has been observed to induce α-synuclein aggregation and damage to dopaminergic neurons in the mouse brain and intestine. The hypothesis is that patients with Parkinson's disease display halogenative stress related to a haloenzymatic alteration of the synthesis or degradation of oxyacid of halogens and their halogenated derivatives. This halogenative stress would be related to nervous system damage.
Topics: Advanced Oxidation Protein Products; Animals; Halogens; Humans; Lactoperoxidase; Mice; Parkinson Disease; alpha-Synuclein
PubMed: 36195375
DOI: 10.1016/j.nrleng.2018.12.017 -
Neurologia Oct 2022Laboratory studies identified changes in the metabolism of halogens in the serum and cerebrospinal fluid (CSF) of patients with Parkinson's disease, which indicates the... (Review)
Review
Laboratory studies identified changes in the metabolism of halogens in the serum and cerebrospinal fluid (CSF) of patients with Parkinson's disease, which indicates the presence of «accelerated self-halogenation» of CSF and/or an increase in haloperoxidases, specifically serum thyroperoxidase and CSF lactoperoxidase. Furthermore, an excess of some halogenated derivatives, such as advanced oxygenation protein products (AOPP), has been detected in the CSF and serum. «Accelerated self-halogenation» and increased levels of haloperoxidases and AOPP proteins indicate that halogenative stress is present in Parkinson's disease. In addition, 3-iodo-L-tyrosine, a halogenated derivative, shows «parkinsonian» toxicity in experimental models, since it has been observed to induce α-synuclein aggregation and damage to dopaminergic neurons in the mouse brain and intestine. The hypothesis is that patients with Parkinson's disease display halogenative stress related to a haloenzymatic alteration of the synthesis or degradation of oxyacid of halogens and their halogenated derivatives. This halogenative stress would be related to nervous system damage.
Topics: Mice; Animals; Humans; Parkinson Disease; Advanced Oxidation Protein Products; Dopaminergic Neurons; Halogens
PubMed: 30952477
DOI: 10.1016/j.nrl.2018.12.008 -
Chemical Reviews Apr 2017Naturally produced halogenated compounds are ubiquitous across all domains of life where they perform a multitude of biological functions and adopt a diversity of... (Review)
Review
Naturally produced halogenated compounds are ubiquitous across all domains of life where they perform a multitude of biological functions and adopt a diversity of chemical structures. Accordingly, a diverse collection of enzyme catalysts to install and remove halogens from organic scaffolds has evolved in nature. Accounting for the different chemical properties of the four halogen atoms (fluorine, chlorine, bromine, and iodine) and the diversity and chemical reactivity of their organic substrates, enzymes performing biosynthetic and degradative halogenation chemistry utilize numerous mechanistic strategies involving oxidation, reduction, and substitution. Biosynthetic halogenation reactions range from simple aromatic substitutions to stereoselective C-H functionalizations on remote carbon centers and can initiate the formation of simple to complex ring structures. Dehalogenating enzymes, on the other hand, are best known for removing halogen atoms from man-made organohalogens, yet also function naturally, albeit rarely, in metabolic pathways. This review details the scope and mechanism of nature's halogenation and dehalogenation enzymatic strategies, highlights gaps in our understanding, and posits where new advances in the field might arise in the near future.
Topics: Enzymes; Flavins; Halogens; Vanadium
PubMed: 28106994
DOI: 10.1021/acs.chemrev.6b00571 -
Biomolecules Dec 2022Halogenation of bioactive peptides via incorporation of non-natural amino acid derivatives during chemical synthesis is a common strategy to enhance functionality....
Halogenation of bioactive peptides via incorporation of non-natural amino acid derivatives during chemical synthesis is a common strategy to enhance functionality. Bacterial tyrptophan halogenases efficiently catalyze regiospecific halogenation of the free amino acid tryptophan, both in vitro and in vivo. Expansion of their substrate scope to peptides and proteins would facilitate highly-regulated post-synthesis/expression halogenation. Here, we demonstrate novel in vitro halogenation (chlorination and bromination) of peptides by select halogenase enzymes and identify the C-terminal (G/S)GW motif as a preferred substrate. In a first proof-of-principle experiment, we also demonstrate chemo-catalyzed derivatization of an enzymatically chlorinated peptide, albeit with low efficiency. We further rationally derive PyrH halogenase mutants showing improved halogenation of the (G/S)GW motif, both as a free peptide and when genetically fused to model proteins with efficiencies up to 90%.
Topics: Halogenation; Oxidoreductases; Bacterial Proteins; Peptides; Amino Acids
PubMed: 36551269
DOI: 10.3390/biom12121841 -
Chemistry (Weinheim An Der Bergstrasse,... Apr 2020Pd-mediated reactions have emerged as a powerful tool for the site-selective and bioorthogonal late-stage diversification of amino acids, peptides and related compounds.... (Review)
Review
Pd-mediated reactions have emerged as a powerful tool for the site-selective and bioorthogonal late-stage diversification of amino acids, peptides and related compounds. Indole moieties of tryptophan derivatives are susceptible to C H-activation, whereas halogenated aromatic amino acids such as halophenylalanines or halotryptophans provide a broad spectrum of different functionalisations. The compatibility of transition-metal-catalysed cross-couplings with functional groups in peptides, other biologically active compounds and even proteins has been demonstrated. This Review primarily compiles the application of different cross-coupling reactions to modify halotryptophans, halotryptophan containing peptides or halogenated, biologically active compounds derived from tryptophan. Modern approaches use regio- and stereoselective biocatalytic strategies to generate halotryptophans and derivatives on a preparative scale. The combination of bio- and chemocatalysis in cascade reactions is given by the biocompatibility and bioorthogonality of Pd-mediated reactions.
Topics: Amino Acids; Catalysis; Halogenation; Peptides; Tryptophan
PubMed: 31544296
DOI: 10.1002/chem.201903756 -
Chemosphere May 2020Brominated organic compounds (BOCs), abundant in Nature, originate from its own sources or anthropogenic activity. Many of these compounds are harmful and constitute a... (Review)
Review
Brominated organic compounds (BOCs), abundant in Nature, originate from its own sources or anthropogenic activity. Many of these compounds are harmful and constitute a serious threat, therefore it is important to study and understand their behavior and fate. In situ, BOCs undergo various chemical and biochemical reactions through distinctive mechanistic pathways. However, breaking C-Br specific bond is a crucial step in the transformation of brominated organic compounds. Understanding the mechanisms of debromination can be substantially enhanced by studying Br isotope effects. In this Mini-review we provide overlook of existing experimental techniques for Br isotope analysis, discuss Br kinetic isotope effects measured for selected chemical and biochemical reactions in the light of underlying reaction mechanisms, and review the outcome from computational study of performed to provide more insightful interpretation of observed findings.
Topics: Bromine; Halogenation; Isotopes; Kinetics
PubMed: 31918087
DOI: 10.1016/j.chemosphere.2019.125746 -
Applied Microbiology and Biotechnology Nov 2021Fluorinated compounds are widely used in the fields of molecular imaging, pharmaceuticals, and materials. Fluorinated natural products in nature are rare, and the... (Review)
Review
Fluorinated compounds are widely used in the fields of molecular imaging, pharmaceuticals, and materials. Fluorinated natural products in nature are rare, and the introduction of fluorine atoms into organic compound molecules can give these compounds new functions and make them have better performance. Therefore, the synthesis of fluorides has attracted more and more attention from biologists and chemists. Even so, achieving selective fluorination is still a huge challenge under mild conditions. In this review, the research progress of enzymatic synthesis of fluorinated compounds is summarized since 2015, including cytochrome P450 enzymes, aldolases, fluoroacetyl coenzyme A thioesterases, lipases, transaminases, reductive aminases, purine nucleoside phosphorylases, polyketide synthases, fluoroacetate dehalogenases, tyrosine phenol-lyases, glycosidases, fluorinases, and multienzyme system. Of all enzyme-catalyzed synthesis methods, the direct formation of the C-F bond by fluorinase is the most effective and promising method. The structure and catalytic mechanism of fluorinase are introduced to understand fluorobiochemistry. Furthermore, the distribution, applications, and future development trends of fluorinated compounds are also outlined. Hopefully, this review will help researchers to understand the significance of enzymatic methods for the synthesis of fluorinated compounds and find or create excellent fluoride synthase in future research.Key points• Fluorinated compounds are distributed in plants and microorganisms, and are used in imaging, medicine, materials science.• Enzyme catalysis is essential for the synthesis of fluorinated compounds.• The loop structure of fluorinase is the key to forming the C-F bond.
Topics: Aldehyde-Lyases; Catalysis; Fluorine; Halogenation; Transaminases
PubMed: 34625820
DOI: 10.1007/s00253-021-11608-0 -
Marine Drugs Nov 2016While alkyl halides are valuable intermediates in synthetic organic chemistry, their use as bioactive motifs in drug discovery and medicinal chemistry is rare in... (Review)
Review
While alkyl halides are valuable intermediates in synthetic organic chemistry, their use as bioactive motifs in drug discovery and medicinal chemistry is rare in comparison. This is likely attributable to the common misconception that these compounds are merely non-specific alkylators in biological systems. A number of chlorinated compounds in the pharmaceutical and food industries, as well as a growing number of halogenated marine natural products showing unique bioactivity, illustrate the role that chiral alkyl halides can play in drug discovery. Through a series of case studies, we demonstrate in this review that these motifs can indeed be stable under physiological conditions, and that halogenation can enhance bioactivity through both steric and electronic effects. Our hope is that, by placing such compounds in the minds of the chemical community, they may gain more traction in drug discovery and inspire more synthetic chemists to develop methods for selective halogenation.
Topics: Animals; Biological Products; Halogenation; Humans; Hydrocarbons, Halogenated; Molecular Conformation; Molecular Structure; Stereoisomerism
PubMed: 27827902
DOI: 10.3390/md14110206 -
Molecules (Basel, Switzerland) May 2022In nature, living organisms produce a wide variety of specialized metabolites to perform many biological functions. Among these specialized metabolites, some carry... (Review)
Review
In nature, living organisms produce a wide variety of specialized metabolites to perform many biological functions. Among these specialized metabolites, some carry halogen atoms on their structure, which can modify their chemical characteristics. Research into this type of molecule has focused on how organisms incorporate these atoms into specialized metabolites. Several families of enzymes have been described gathering metalloenzymes, flavoproteins, or S-adenosyl-L-methionine (SAM) enzymes that can incorporate these atoms into different types of chemical structures. However, even though the first halogenation enzyme was discovered in a fungus, this clade is still lagging behind other clades such as bacteria, where many enzymes have been discovered. This review will therefore focus on all halogenation enzymes that have been described in fungi and their associated metabolites by searching for proteins available in databases, but also by using all the available fungal genomes. In the second part of the review, the chemical diversity of halogenated molecules found in fungi will be discussed. This will allow the highlighting of halogenation mechanisms that are still unknown today, therefore, highlighting potentially new unknown halogenation enzymes.
Topics: Bacteria; Fungi; Genome, Fungal; Halogenation; Halogens
PubMed: 35630634
DOI: 10.3390/molecules27103157