Primary and Secondary Metabolites
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PLGG1, a Plastidic Glycolate Glycerate Transporter, Is Required for Photorespiration and Defines a Unique Class of Metabolite Transporters
PLGG1, a plastidic glycolate glycerate transporter, is required for photorespiration and defines a unique class of metabolite transporters Thea R. Picka,1, Andrea Bräutigama,1, Matthias A. Schulza, Toshihiro Obatab, Alisdair R. Fernieb, and Andreas P. M. Webera,2 aInstitute of Plant Biochemistry, Cluster of Excellence on Plant Sciences, Heinrich Heine University, 40225 Düsseldorf, Germany; and bMax-Planck Institute for Molecular Plant Physiology, Department of Molecular Physiology, 14476 Potsdam-Golm, Germany Edited by Wolf B. Frommer, Carnegie Institution for Science, Stanford, CA, and accepted by the Editorial Board January 8, 2013 (received for review September 4, 2012) Photorespiratory carbon flux reaches up to a third of photosyn- (PGLP). Glycolate is exported from the chloroplasts to the per- thetic flux, thus contributes massively to the global carbon cycle. oxisomes, where it is oxidized to glyoxylate by glycolate oxidase The pathway recycles glycolate-2-phosphate, the most abundant (GOX) and transaminated to glycine by Ser:glyoxylate and Glu: byproduct of RubisCO reactions. This oxygenation reaction of glyoxylate aminotransferase (SGT and GGT, respectively). Glycine RubisCO and subsequent photorespiration significantly limit the leaves the peroxisomes and enters the mitochondria, where two biomass gains of many crop plants. Although photorespiration is molecules of glycine are deaminated and decarboxylated by the a compartmentalized process with enzymatic reactions in the glycine decarboxylase complex (GDC) and serine hydroxymethyl- chloroplast, the peroxisomes, the mitochondria, and the cytosol, transferase (SHMT) to form one molecule each of serine, ammo- nia, and carbon dioxide. Serine is exported from the mitochondria no transporter required for the core photorespiratory cycle has to the peroxisomes, where it is predominantly converted to glyc- been identified at the molecular level to date. -
The Self-Inhibitory Nature of Metabolic Networks and Its Alleviation Through Compartmentalization
ARTICLE Received 30 Oct 2016 | Accepted 23 May 2017 | Published 10 Jul 2017 DOI: 10.1038/ncomms16018 OPEN The self-inhibitory nature of metabolic networks and its alleviation through compartmentalization Mohammad Tauqeer Alam1,2, Viridiana Olin-Sandoval1,3, Anna Stincone1,w, Markus A. Keller1,4, Aleksej Zelezniak1,5,6, Ben F. Luisi1 & Markus Ralser1,5 Metabolites can inhibit the enzymes that generate them. To explore the general nature of metabolic self-inhibition, we surveyed enzymological data accrued from a century of experimentation and generated a genome-scale enzyme-inhibition network. Enzyme inhibition is often driven by essential metabolites, affects the majority of biochemical processes, and is executed by a structured network whose topological organization is reflecting chemical similarities that exist between metabolites. Most inhibitory interactions are competitive, emerge in the close neighbourhood of the inhibited enzymes, and result from structural similarities between substrate and inhibitors. Structural constraints also explain one-third of allosteric inhibitors, a finding rationalized by crystallographic analysis of allosterically inhibited L-lactate dehydrogenase. Our findings suggest that the primary cause of metabolic enzyme inhibition is not the evolution of regulatory metabolite–enzyme interactions, but a finite structural diversity prevalent within the metabolome. In eukaryotes, compartmentalization minimizes inevitable enzyme inhibition and alleviates constraints that self-inhibition places on metabolism. 1 Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK. 2 Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, UK. 3 Department of Food Science and Technology, Instituto Nacional de Ciencias Me´dicas y Nutricio´n Salvador Zubira´n, Vasco de Quiroga 15, Tlalpan, 14080 Mexico City, Mexico. -
Diversity and Evolution of Secondary Metabolism in the Marine
Diversity and evolution of secondary metabolism in the PNAS PLUS marine actinomycete genus Salinispora Nadine Ziemert, Anna Lechner, Matthias Wietz, Natalie Millán-Aguiñaga, Krystle L. Chavarria, and Paul Robert Jensen1 Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California, San Diego, La Jolla, CA 92093 Edited* by Christopher T. Walsh, Harvard Medical School, Boston, MA, and approved February 6, 2014 (received for review December 30, 2013) Access to genome sequence data has challenged traditional natural The pathways responsible for secondary metabolite biosynthesis product discovery paradigms by revealing that the products of most are among the most rapidly evolving genetic elements known (5). bacterial biosynthetic pathways have yet to be discovered. Despite It has been shown that gene duplication, loss, and HGT have all the insight afforded by this technology, little is known about the played important roles in the distribution of PKSs among diversity and distributions of natural product biosynthetic pathways microbes (8, 9). Changes within PKS and NRPS genes also include among bacteria and how they evolve to generate structural di- mutation, domain rearrangement, and module duplication (5), all versity. Here we analyze genome sequence data derived from 75 of which can account for the generation of new small-molecule strains of the marine actinomycete genus Salinispora for pathways diversity. The evolutionary histories of specific PKS and NRPS associated with polyketide and nonribosomal peptide biosynthesis, domains have proven particularly informative, with KS and C the products of which account for some of today’s most important domains providing insight into enzyme architecture and function medicines. -
Physiological and Transcriptomic Analyses Reveal the Roles Of
Jia et al. BMC Genomics (2020) 21:861 https://doi.org/10.1186/s12864-020-07279-2 RESEARCH ARTICLE Open Access Physiological and transcriptomic analyses reveal the roles of secondary metabolism in the adaptive responses of Stylosanthes to manganese toxicity Yidan Jia1,2†, Xinyong Li1†, Qin Liu3, Xuan Hu1, Jifu Li1,2, Rongshu Dong1, Pandao Liu1, Guodao Liu1, Lijuan Luo2* and Zhijian Chen1,2* Abstract Background: As a heavy metal, manganese (Mn) can be toxic to plants. Stylo (Stylosanthes) is an important tropical legume that exhibits tolerance to high levels of Mn. However, little is known about the adaptive responses of stylo to Mn toxicity. Thus, this study integrated both physiological and transcriptomic analyses of stylo subjected to Mn toxicity. Results: Results showed that excess Mn treatments increased malondialdehyde (MDA) levels in leaves of stylo, resulting in the reduction of leaf chlorophyll concentrations and plant dry weight. In contrast, the activities of enzymes, such as peroxidase (POD), phenylalanine ammonia-lyase (PAL) and polyphenol oxidase (PPO), were significantly increased in stylo leaves upon treatment with increasing Mn levels, particularly Mn levels greater than 400 μM. Transcriptome analysis revealed 2471 up-regulated and 1623 down-regulated genes in stylo leaves subjected to Mn toxicity. Among them, a set of excess Mn up-regulated genes, such as genes encoding PAL, cinnamyl-alcohol dehydrogenases (CADs), chalcone isomerase (CHI), chalcone synthase (CHS) and flavonol synthase (FLS), were enriched in secondary metabolic processes based on gene ontology (GO) analysis. Numerous genes associated with transcription factors (TFs), such as genes belonging to the C2H2 zinc finger transcription factor, WRKY and MYB families, were also regulated by Mn in stylo leaves. -
Understanding Drug-Drug Interactions Due to Mechanism-Based Inhibition in Clinical Practice
pharmaceutics Review Mechanisms of CYP450 Inhibition: Understanding Drug-Drug Interactions Due to Mechanism-Based Inhibition in Clinical Practice Malavika Deodhar 1, Sweilem B Al Rihani 1 , Meghan J. Arwood 1, Lucy Darakjian 1, Pamela Dow 1 , Jacques Turgeon 1,2 and Veronique Michaud 1,2,* 1 Tabula Rasa HealthCare Precision Pharmacotherapy Research and Development Institute, Orlando, FL 32827, USA; [email protected] (M.D.); [email protected] (S.B.A.R.); [email protected] (M.J.A.); [email protected] (L.D.); [email protected] (P.D.); [email protected] (J.T.) 2 Faculty of Pharmacy, Université de Montréal, Montreal, QC H3C 3J7, Canada * Correspondence: [email protected]; Tel.: +1-856-938-8697 Received: 5 August 2020; Accepted: 31 August 2020; Published: 4 September 2020 Abstract: In an ageing society, polypharmacy has become a major public health and economic issue. Overuse of medications, especially in patients with chronic diseases, carries major health risks. One common consequence of polypharmacy is the increased emergence of adverse drug events, mainly from drug–drug interactions. The majority of currently available drugs are metabolized by CYP450 enzymes. Interactions due to shared CYP450-mediated metabolic pathways for two or more drugs are frequent, especially through reversible or irreversible CYP450 inhibition. The magnitude of these interactions depends on several factors, including varying affinity and concentration of substrates, time delay between the administration of the drugs, and mechanisms of CYP450 inhibition. Various types of CYP450 inhibition (competitive, non-competitive, mechanism-based) have been observed clinically, and interactions of these types require a distinct clinical management strategy. This review focuses on mechanism-based inhibition, which occurs when a substrate forms a reactive intermediate, creating a stable enzyme–intermediate complex that irreversibly reduces enzyme activity. -
Consistency, Inconsistency, and Ambiguity of Metabolite Names in Biochemical Databases Used for Genome-Scale Metabolic Modelling
H OH metabolites OH Article Consistency, Inconsistency, and Ambiguity of Metabolite Names in Biochemical Databases Used for Genome-Scale Metabolic Modelling Nhung Pham , Ruben G. A. van Heck † , Jesse C. J. van Dam , Peter J. Schaap , Edoardo Saccenti and Maria Suarez-Diez * Laboratory of Systems and Synthetic Biology; Wageningen University & Research, 6708 WE, Wageningen, The Netherlands; [email protected] (N.P.); [email protected] (R.G.A.v.H.); [email protected] (J.C.J.v.D.); [email protected] (P.J.S.); [email protected] (E.S.) * Correspondence: [email protected] † Current address: EDP Patent Attorneys, 6708 WH, Wageningen, The Netherlands. Received: 28 December 2018; Accepted: 31 January 2019; Published: 6 February 2019 Abstract: Genome-scale metabolic models (GEMs) are manually curated repositories describing the metabolic capabilities of an organism. GEMs have been successfully used in different research areas, ranging from systems medicine to biotechnology. However, the different naming conventions (namespaces) of databases used to build GEMs limit model reusability and prevent the integration of existing models. This problem is known in the GEM community, but its extent has not been analyzed in depth. In this study, we investigate the name ambiguity and the multiplicity of non-systematic identifiers and we highlight the (in)consistency in their use in 11 biochemical databases of biochemical reactions and the problems that arise when mapping between different namespaces and databases. We found that such inconsistencies can be as high as 83.1%, thus emphasizing the need for strategies to deal with these issues. Currently, manual verification of the mappings appears to be the only solution to remove inconsistencies when combining models. -
Ranking Metabolite Sets by Their Activity Levels
H OH metabolites OH Article Ranking Metabolite Sets by Their Activity Levels Karen McLuskey 1,† , Joe Wandy 1,† , Isabel Vincent 2 , Justin J. J. van der Hooft 3 , Simon Rogers 4 , Karl Burgess 5 and Rónán Daly 1,* 1 Glasgow Polyomics, University of Glasgow, Glasgow G61 1QH, UK; [email protected] (K.M.); [email protected] (J.W.) 2 IBioIC, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G1 1XQ, UK; [email protected] 3 Bioinformatics Group, Wageningen University, 6708 PB Wageningen, The Netherlands; [email protected] 4 School of Computing Science, University of Glasgow, Glasgow G12 8QQ, UK; [email protected] 5 Centre for Synthetic and Systems Biology, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3JG, UK; [email protected] * Correspondence: [email protected] † These authors contributed equally to this work. Abstract: Related metabolites can be grouped into sets in many ways, e.g., by their participation in series of chemical reactions (forming metabolic pathways), or based on fragmentation spectral similarities or shared chemical substructures. Understanding how such metabolite sets change in relation to experimental factors can be incredibly useful in the interpretation and understanding of complex metabolomics data sets. However, many of the available tools that are used to perform this analysis are not entirely suitable for the analysis of untargeted metabolomics measurements. Here, we present PALS (Pathway Activity Level Scoring), a Python library, command line tool, and Web application that performs the ranking of significantly changing metabolite sets over different experimental conditions. -
Placenta, Pericarp, and Seeds of Tabasco Chili Pepper Fruits Show a Contrasting Diversity of Bioactive Metabolites
H OH metabolites OH Article Placenta, Pericarp, and Seeds of Tabasco Chili Pepper Fruits Show a Contrasting Diversity of Bioactive Metabolites Felipe Cervantes-Hernández, Paul Alcalá-González, Octavio Martínez and José Juan Ordaz-Ortiz * Unidad de Genómica Avanzada, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV), Km. 9.6, Libramiento Norte Carretera Irapuato-León, Irapuato, Gto. 36824, Mexico; [email protected] (F.C.-H.); [email protected] (P.A.-G.); [email protected] (O.M.) * Correspondence: [email protected] Received: 26 August 2019; Accepted: 23 September 2019; Published: 28 September 2019 Abstract: Chili pepper (Capsicum spp.) is one of the most important horticultural crops worldwide, and its unique organoleptic properties and health benefits have been established for centuries. However, there is little knowledge about how metabolites are distributed throughout fruit parts. This work focuses on the use of liquid chromatography coupled with high resolution mass spectrometry (UHPLC-ESI-HRMS) to estimate the global metabolite profiles of the pericarp, placenta, and seeds of Tabasco pepper fruits (Capsicum frutescens L.) at the red mature stage of ripening. Our main results putatively identified 60 differential compounds between these tissues and seeds. Firstly, we found that pericarp has a higher content of glycosides, showing on average a fold change of 5 and a fold change of 14 for terpenoids when compared with other parts of the fruit. While placenta was the richest tissue in capsaicinoid-related compounds, alkaloids, and tocopherols, with a 35, 3, and 7 fold change, respectively. However, the seeds were richer in fatty acids and saponins with fold changes of 86 and 224, respectively. -
Analysis of Secondary Metabolite Production in Somatic Embryo of Pasak Bumi (Eurycoma Longifoliajack.)
Available online at www.sciencedirect.com ScienceDirect Procedia Chemistry 13 ( 2014 ) 112 – 118 International Seminar on Natural Product Medicines, ISNPM 2012 Analysis of Secondary Metabolite Production in Somatic Embryo of Pasak Bumi (Eurycoma longifoliaJack.) Iriawatia*, Andira Rahmawatia, Rizkita R. Esyantia 1School of Life Sciences and Technology, Bandung Institute of Technology, Jalan Ganesa No. 10 Bandung 40132, Indonesia Abstract Pasak bumi (Eurycoma longifolia Jack.) has been known as a plants that can produce secondary metabolites for medicinal purposes such as: aphrosidiac, antimalaria, dysentri, antitumor, etc. Poor seed germination of pasak bumi will affect the avaibility of plant material for drug extraction. Over exploitation of this plant will also reduce plant population in its natural habitat. In vitro culture, i.e. through somatic embryogenesis, therefore, can be used as one of an alternative method for plant regeneration as well as for in vitro metabolite production. Based on this reason, the research has been done with an objective to analyze the presence of secondary metabolite in somatic embryo of pasak bumi. Seed-derived callus was used as an explant. This callus was maintained to proliferate in MS (Murashige&Skoog, 1962) medium supplemented with 2.25 mg/L 2,4-D and 2.0 mg/L kinetin. A half gram of callus from proliferation medium was transferred into the MS liquid medium containing 1.0 or 2.25 mg/L 2,4-D, and 2.0 mg/L BAP or 2.0 mg/L kinetin. Histochemical examination using Jeffrey’s reagen and neutral red showed that alkaloid and terpenoid substances were presence in somatic embryo of pasakbumi. -
Honeybees and Nectar Nicotine: Deterrence and Reduced
1 Honeybees and nectar nicotine: deterrence and reduced 2 survival versus potential health benefits 3 4 5 Angela Köhler*, Christian W.W. Pirk and Susan W. Nicolson 6 7 8 Department of Zoology and Entomology, University of Pretoria, Pretoria 0002, South Africa 9 10 11 *Author for correspondence 12 Email: [email protected] 13 Postal address: Dept. Zoology & Entomology, University of Pretoria, Private Bag X20, Hatfield 14 0028, Pretoria, South Africa 15 Phone +27 12 420 4872 16 Fax +27 12 362 5242 17 1 18 Abstract 19 Secondary metabolites produced by plants for herbivore defence are often found in floral nectar, 20 but their effect on the foraging behaviour and physiological performance of pollinators is largely 21 unknown. Nicotine is highly toxic to most herbivores, and nicotine-based insecticides may 22 contribute to current pollinator declines. We examined the effects of nectar nicotine on honeybee 23 foraging choices and worker longevity. Free-flying honeybee (Apis mellifera scutellata) workers 24 from six colonies were given a choice between multiple nicotine concentrations (0–1000 µM) in 25 artificial nectar (0.15–0.63 M sucrose). The dose-dependent deterrent effect of nicotine was 26 stronger in lower sugar concentrations, but even the highest nicotine concentrations did not 27 completely repel honeybees, i.e. bees did not stop feeding on these diets. Nicotine in nectar acts 28 as a partial repellent, which may keep pollinators moving between plants and enhance cross- 29 pollination. In the second part of the study, newly emerged workers from 12 colonies were caged 30 and fed one of four nicotine concentrations (0–300 µM) in 0.63 M sucrose for 21 days. -
Unbiased Profiling of Volatile Organic Compounds in the Headspace Of
Kusano et al. BMC Res Notes (2016) 9:133 DOI 10.1186/s13104-016-1942-5 BMC Research Notes RESEARCH ARTICLE Open Access Unbiased profiling of volatile organic compounds in the headspace of Allium plants using an in‑tube extraction device Miyako Kusano1,2*, Makoto Kobayashi2, Yumiko Iizuka2,3, Atsushi Fukushima2 and Kazuki Saito2,4 Abstract Background: Plants produce and emit important volatile organic compounds (VOCs), which have an essential role in biotic and abiotic stress responses and in plant–plant and plant–insect interactions. In order to study the bouquets from plants qualitatively and quantitatively, a comprehensive, analytical method yielding reproducible results is required. Results: We applied in-tube extraction (ITEX) and solid-phase microextraction (SPME) for studying the emissions of Allium plants. The collected HS samples were analyzed by gas chromatography–time-of-flight–mass spectrometry (GC-TOF–MS), and the results were subjected to multivariate analysis. In case of ITEX-method Allium cultivars released more than 300 VOCs, out of which we provisionally identified 50 volatiles. We also used the VOC profiles of Allium samples to discriminate among groups of A. fistulosum, A. chinense (rakkyo), and A. tuberosum (Oriental garlic). As we found 12 metabolite peaks including dipropyl disulphide with significant changes in A. chinense and A. tuberosum when compared to the control cultivar, these metabolite peaks can be used for chemotaxonomic classification of A. chinense, tuberosum, and A. fistulosum. Conclusions: Compared to SPME-method our ITEX-based VOC profiling technique contributes to automatic and reproducible analyses. Hence, it can be applied to high-throughput analyses such as metabolite profiling. -
Natural Products (Secondary Metabolites)
Biochemistry & Molecular Biology of Plants, B. Buchanan, W. Gruissem, R. Jones, Eds. © 2000, American Society of Plant Physiologists CHAPTER 24 Natural Products (Secondary Metabolites) Rodney Croteau Toni M. Kutchan Norman G. Lewis CHAPTER OUTLINE Introduction Introduction Natural products have primary ecological functions. 24.1 Terpenoids 24.2 Synthesis of IPP Plants produce a vast and diverse assortment of organic compounds, 24.3 Prenyltransferase and terpene the great majority of which do not appear to participate directly in synthase reactions growth and development. These substances, traditionally referred to 24.4 Modification of terpenoid as secondary metabolites, often are differentially distributed among skeletons limited taxonomic groups within the plant kingdom. Their functions, 24.5 Toward transgenic terpenoid many of which remain unknown, are being elucidated with increas- production ing frequency. The primary metabolites, in contrast, such as phyto- 24.6 Alkaloids sterols, acyl lipids, nucleotides, amino acids, and organic acids, are 24.7 Alkaloid biosynthesis found in all plants and perform metabolic roles that are essential 24.8 Biotechnological application and usually evident. of alkaloid biosynthesis Although noted for the complexity of their chemical structures research and biosynthetic pathways, natural products have been widely per- 24.9 Phenylpropanoid and ceived as biologically insignificant and have historically received lit- phenylpropanoid-acetate tle attention from most plant biologists. Organic chemists, however, pathway metabolites have long been interested in these novel phytochemicals and have 24.10 Phenylpropanoid and investigated their chemical properties extensively since the 1850s. phenylpropanoid-acetate Studies of natural products stimulated development of the separa- biosynthesis tion techniques, spectroscopic approaches to structure elucidation, and synthetic methodologies that now constitute the foundation of 24.11 Biosynthesis of lignans, lignins, contemporary organic chemistry.