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  • 1
    Language: English
    In: Science (American Association for the Advancement of Science), 2018-10-19, Vol.362 (6412), p.343-347
    Description: Morphinan-based painkillers are derived from opium poppy ( L.). We report a draft of the opium poppy genome, with 2.72 gigabases assembled into 11 chromosomes with contig N50 and scaffold N50 of 1.77 and 204 megabases, respectively. Synteny analysis suggests a whole-genome duplication at ~7.8 million years ago and ancient segmental or whole-genome duplication(s) that occurred before the Papaveraceae-Ranunculaceae divergence 110 million years ago. Syntenic blocks representative of phthalideisoquinoline and morphinan components of a benzylisoquinoline alkaloid cluster of 15 genes provide insight into how this cluster evolved. Paralog analysis identified P450 and oxidoreductase genes that combined to form the gene fusion essential for morphinan biosynthesis in opium poppy. Thus, gene duplication, rearrangement, and fusion events have led to evolution of specialized metabolic products in opium poppy.
    Subject(s): Addiction ; Analgesics ; Benzylisoquinolines - metabolism ; Biological evolution ; Biosynthesis ; Chemical properties ; Chromosomes ; Clusters ; Divergence ; Drug abuse ; Drug trafficking ; Evolution, Molecular ; Gene Duplication ; Gene Fusion ; Gene Order ; Gene rearrangement ; Genes ; Genetic aspects ; Genome, Plant ; Genomes ; Metabolism ; Morphinans - metabolism ; Multigene Family ; NADPH-Ferrihemoprotein Reductase - genetics ; Narcotics ; Opiates ; Opioids ; Opium poppy ; Oxidoreductase ; Papaver - genetics ; Papaver - metabolism ; Papaver somniferum ; Phthalideisoquinoline ; Plant Proteins - genetics ; Production processes ; Proteins ; Reproduction (copying) ; Synteny
    ISSN: 0036-8075
    E-ISSN: 1095-9203
    Source: Academic Search Ultimate
    Source: Alma/SFX Local Collection
    Source: Get It Now
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  • 2
    Language: English
    In: Science (American Association for the Advancement of Science), 2015-07-17, Vol.349 (6245), p.309-312
    Description: Morphinan alkaloids from the opium poppy are used for pain relief. The direction of metabolites to morphinan biosynthesis requires isomerization of (S)- to (R)-reticuline. Characterization of high-reticuline poppy mutants revealed a genetic locus, designated STORR [(S)- to (R)-reticuline] that encodes both cytochrome P450 and oxidoreductase modules, the latter belonging to the aldo-keto reductase family. Metabolite analysis of mutant alleles and heterologous expression demonstrate that the P450 module is responsible for the conversion of (S)-reticuline to 1,2-dehydroreticuline, whereas the oxidoreductase module converts 1,2-dehydroreticuline to (R)-reticuline rather than functioning as a P450 redox partner. Proteomic analysis confirmed that these two modules are contained on a single polypeptide in vivo. This modular assembly implies a selection pressure favoring substrate channeling. The fusion protein STORR may enable microbial-based morphinan production.
    Subject(s): Biosynthesis ; Enzymes ; Metabolites ; Modules ; Morphine ; Narcotics ; Pathways ; Poppies ; Proteins ; REPORTS
    ISSN: 0036-8075
    E-ISSN: 1095-9203
    Source: JSTOR Life Sciences
    Source: Academic Search Ultimate
    Source: Alma/SFX Local Collection
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  • 3
    Language: English
    In: Science (American Association for the Advancement of Science), 2012-06-29, Vol.336 (6089), p.1704-1708
    Description: Noscapine is an antitumor alkaloid from opium poppy that binds tubulin, arrests metaphase, and induces apoptosis in dividing human cells. Elucidation of the biosynthetic pathway will enable improvement in the commercial production of noscapine and related bioactive molecules. Transcriptomic analysis revealed the exclusive expression of 10 genes encoding five distinct enzyme classes in a high noscapine-producing poppy variety, HN1. Analysis of an F₂ mapping population indicated that these genes are tightly linked in HN1, and bacterial artificial chromosome sequencing confirmed that they exist as a complex gene cluster for plant alkaloids. Virus-induced gene silencing resulted in accumulation of pathway intermediates, allowing gene function to be linked to noscapine synthesis and a novel biosynthetic pathway to be proposed.
    Subject(s): Alkaloids ; Anticancer properties ; Antineoplastic Agents, Phytogenic - biosynthesis ; Biological and medical sciences ; Biosynthesis ; Capsules ; Classical genetics, quantitative genetics, hybrids ; Clusters ; Cough ; Enzymes ; Flowers & plants ; Fundamental and applied biological sciences. Psychology ; Gene silencing ; Genes ; Genes, Plant ; Genetic aspects ; Genetics of eukaryotes. Biological and molecular evolution ; Genomes ; Latex ; Libraries ; Low level ; Molecular Sequence Data ; Morphinans ; Multigene Family ; Narcotics ; Noscapine - metabolism ; Open reading frames ; Papaver - enzymology ; Papaver - genetics ; Papaver - metabolism ; Papaver somniferum ; Pharmaceutical sciences ; Physiological aspects ; Plant biology ; Poppies ; Pteridophyta, spermatophyta ; REPORTS ; Synthesis ; Vegetals
    ISSN: 0036-8075
    E-ISSN: 1095-9203
    Source: JSTOR Life Sciences
    Source: Academic Search Ultimate
    Source: Alma/SFX Local Collection
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  • 4
    Language: English
    In: Analytica chimica acta, 1996, Vol.318 (3), p.309-317
    Description: A flow-injection (FI) methodology using tris(2,2′-bipyridyl)ruthenium(II) chemiluminescence was developed and evaluated for the determination of codeine in process streams. For the samples analysed codeine exhibited high sensitivity and selectivity over various other similar Papaver alkaloids, especially morphine (10 4 times more sensitive). A simple, computer controlled FI manifold incorporating a heterogenous lead dioxide/silica reactor was utilised to analyse an artificial sample and two process samples. The results were compared with those obtained by an established ion-pair liquid chromatography (LC) method. Calibration was linear between 1.0 × 10 −8 to 1.0 × 10 −6 M with a 3σ detection limit of 5 × 10 −9 M. The internal calibration method compared most favourably with the LC determinations which highlighted complicated matrix effects observed at differing process sample points. The efficacy of the solid phase reactor and the suitability of the methodology for application to continuous on-line analysis of codeine process streams was assessed.
    Subject(s): Analysis ; Biological and medical sciences ; Chemiluminescence ; Flow injection ; General pharmacology ; Medical sciences ; Papaver alkaloids ; Pharmacology. Drug treatments ; Process streams ; Tris(2,2′-bipyridyl)ruthenium(II)
    ISSN: 0003-2670
    E-ISSN: 1873-4324
    Source: Backfile Package - All of Back Files EBS [ALLOFBCKF]
    Source: Alma/SFX Local Collection
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  • 5
    Language: English
    In: Analytica chimica acta, 1993, Vol.282 (3), p.551-557
    Description: Flow analysis methodology is presented for the determination of morphine in process streams. Detection is achieved by monitoring the resultant chemiluminescence (CL) emission from the reaction of morphine and acidic potassium permanganate in the presence of tetraphosphoric acid. Calibration graphs are linear over two orders of magnitude of concentration with a detection limit (3:1 signal-to-noise ratio) of 5×10 −8 M and relative standard deviation of 0.4% at 1.4×10 −4 M. Interferences from other alkaloids in the extract are negligible due either to lack of CL response or to low concentrations of the concomitants. Some discussions regarding the nature of the emitting species is presented based on CL spectra from morphine and other structurally related alkaloids. The analytical results obtained on process samples compared most favourably with results from a validated liquid chromatographic method.
    Subject(s): Analytical chemistry ; Chemical and thermal methods ; Chemiluminescence ; Chemistry ; Exact sciences and technology ; Flow injection ; Morphine
    ISSN: 0003-2670
    E-ISSN: 1873-4324
    Source: Backfile Package - All of Back Files EBS [ALLOFBCKF]
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  • 6
    Language: English
    In: Science (American Association for the Advancement of Science), 2015-07-17, Vol.349 (6245), p.309-312
    Description: Morphinan alkaloids from the opium poppy are used for pain relief. The direction of metabolites to morphinan biosynthesis requires isomerization of (S)- to (R)-reticuline. Characterization of high-reticuline poppy mutants revealed a genetic locus, designated STORR [(S)- to (R)-reticuline] that encodes both cytochrome P450 and oxidoreductase modules, the latter belonging to the aldo-keto reductase family. Metabolite analysis of mutant alleles and heterologous expression demonstrate that the P450 module is responsible for the conversion of (S)-reticuline to 1,2-dehydroreticuline, whereas the oxidoreductase module converts 1,2-dehydroreticuline to (R)-reticuline rather than functioning as a P450 redox partner. Proteomic analysis confirmed that these two modules are contained on a single polypeptide in vivo. This modular assembly implies a selection pressure favoring substrate channeling. The fusion protein STORR may enable microbial-based morphinan production.
    Subject(s): Base Sequence ; Benzylisoquinolines - chemistry ; Benzylisoquinolines - metabolism ; Cytochrome P-450 Enzyme System - genetics ; Cytochrome P-450 Enzyme System - metabolism ; Genetic Loci ; Isoquinolines - chemistry ; Isoquinolines - metabolism ; Molecular Sequence Data ; Morphinans - chemistry ; Morphinans - metabolism ; Mutation ; Oxidation-Reduction ; Papaver - enzymology ; Papaver - genetics ; Plant Proteins - genetics ; Plant Proteins - metabolism ; Quaternary Ammonium Compounds - chemistry ; Quaternary Ammonium Compounds - metabolism
    E-ISSN: 1095-9203
    Source: JSTOR Life Sciences
    Source: Academic Search Ultimate
    Source: Alma/SFX Local Collection
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  • 7
    Language: English
    In: Analytical proceedings, 1995, Vol.32 (2), p.57-59
    Subject(s): Analytical chemistry ; Applied sciences ; Chemistry ; Chromatographic methods and physical methods associated with chromatography ; Exact sciences and technology ; Metals. Metallurgy ; Other chromatographic methods
    ISSN: 0144-557X
    Source: Royal Society of Chemistry Journals Archive (1841-2007)
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  • 8
    Language: English
    In: Systematic biology, 2007-08, Vol.56 (4), p.684-689
    Description: Furthermore, the classification is intended to facilitate future modification in light of improved phylogenetic information, without requiring a cascade of name changes. The World Health Report (2004) ranked respiratory tract infections, diarrheal diseases, and malaria respectively as first, fourth, and sixth in number of deaths caused by communicable diseases, maternal and perinatal conditions, and nutritional deficiencies.
    Subject(s): Animal names ; Animals ; Biological Evolution ; Biological taxonomies ; Biology ; Classification ; Codes ; Crop damage ; DNA, Protozoan - genetics ; Eukaryota - classification ; Eukaryota - genetics ; Eukaryotic cells ; Fungi ; Genetic Variation ; Name changes ; Phylogenetics ; Plants ; Points of View ; Species ; Taxa ; Taxonomy ; Terminology ; Traditions ; Zoology
    ISSN: 1063-5157
    E-ISSN: 1076-836X
    Source: JSTOR Life Sciences
    Source: Academic Search Ultimate
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  • 9
    Language: English
    In: Journal of industrial microbiology & biotechnology, 2020-06-07, Vol.47 (6-7), p.449-464
    Description: Cytochrome P450 enzymes catalyse reactions of significant industrial interest but are underutilised in large-scale bioprocesses due to enzyme stability, cofactor requirements and the poor aqueous solubility and microbial toxicity of typical substrates and products. In this work, we investigate the potential for preparative-scale N -demethylation of the opium poppy alkaloid noscapine by a P450 BM3 (CYP102A1) mutant enzyme in a whole-cell biotransformation system. We identify and address several common limitations of whole-cell P450 biotransformations using this model N -demethylation process. Mass transfer into Escherichia coli cells was found to be a major limitation of biotransformation rate and an alternative Gram-positive expression host Bacillus megaterium provided a 25-fold improvement in specific initial rate. Two methods were investigated to address poor substrate solubility. First, a biphasic biotransformation system was developed by systematic selection of potentially biocompatible solvents and in silico solubility modelling using Hansen solubility parameters. The best-performing biphasic system gave a 2.3-fold improvement in final product titre compared to a single-phase system but had slower initial rates of biotransformation due to low substrate concentration in the aqueous phase. The second strategy aimed to improve aqueous substrate solubility using cyclodextrin and hydrophilic polymers. This approach provided a fivefold improvement in initial biotransformation rate and allowed a sixfold increase in final product concentration. Enzyme stability and cell viability were identified as the next parameters requiring optimisation to improve productivity. The approaches used are also applicable to the development of other pharmaceutical P450-mediated biotransformations.
    Subject(s): Bacillus megaterium - metabolism ; Biocatalysis - Original Paper ; Biochemistry ; Biocompatibility ; Bioinformatics ; Biomedical and Life Sciences ; Biotechnology ; Biotransformation ; Catalysis ; Cell viability ; Computer Simulation ; Cyclodextrin ; Cyclodextrins ; Cyclodextrins - chemistry ; Cytochrome ; Cytochrome P-450 Enzyme System - metabolism ; Cytochrome P450 ; Cytochromes P450 ; Demethylation ; E coli ; Enzymes ; Escherichia coli - metabolism ; general ; Genetic Engineering ; Industrial Microbiology - methods ; Inorganic Chemistry ; Life Sciences ; Mass transfer ; Mathematical models ; Microbiology ; Microorganisms ; Mutation ; Noscapine - chemistry ; Optimization ; Organic Chemicals - metabolism ; Oxidation-Reduction ; Parameter identification ; Polymers ; Polymers - chemistry ; Solubility ; Solubility parameters ; Solvents ; Stability ; Substrates ; Toxicity
    ISSN: 1367-5435
    E-ISSN: 1476-5535
    Source: Academic Search Ultimate
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  • 10
    Language: English
    In: Biotechnology reports (Amsterdam, Netherlands), 2019-12, Vol.24, p.e00372
    Description: •Mutants of P450BM3 can metabolise noscapine.•Noscapine is N-demethylated with high selectivity.•The metabolites produced are of interest for drug development.•The profile of metabolites generated resembles that of mammalian CYP3A4. Cytochrome P450 enzymes are a promising tool for the late-stage diversification of lead drug candidates and can provide an alternative route to structural modifications that are difficult to achieve with synthetic chemistry. In this study, a library of P450BM3 mutants was produced using site-directed mutagenesis and the enzymes screened for metabolism of the opium poppy alkaloid noscapine, a drug with anticancer activity. Of the 18 enzyme mutants screened, 12 showed an ability to metabolise noscapine that was not present in the wild-type enzyme. Five noscapine metabolites were detected by LC-MS/MS, with the major metabolite for all mutants being N-demethylated noscapine. The highest observed regioselectivity for N-demethylation was 88%. Two hydroxylated metabolites, a catechol and two C-C cleavage products were also detected. P450-mediated production of hydroxylated and N-demethylated noscapine structures may be useful for the development of noscapine analogues with improved biological activity. The variation in substrate turnover, coupling efficiency and product distribution between the active mutants was considered alongside in silico docking experiments to gain insight into structural and functional effects of the introduced mutations. Selected mutants were identified as targets for further mutagenesis to improve activity and when coupled with an optimised process may provide a route for the preparative-scale production of noscapine metabolites.
    Subject(s): Biocatalysis ; Cytochrome P450 ; DMSO, dimethyl sulfoxide ; Hydroxylation ; IPTG, isopropyl β-D-1-thiogalactopyranoside ; LC-MS ; MOPS, 3-(N-morpholino)propanesulfonic acid ; MS, liquid chromatography-tandem mass spectrometry ; N-demethylation ; NADPH, nicotinamide adenine dinucleotide phosphate ; P450, cytochrome P450 ; P450BM3, CYP102A1 from Bacillus megaterium ; QTOF, quadrupole time-of-flight ; Site-directed mutagenesis ; WT, wild-type
    ISSN: 2215-017X
    E-ISSN: 2215-017X
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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