Staff Publications

Staff Publications

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    'Staff publications' is the digital repository of Wageningen University & Research

    'Staff publications' contains references to publications authored by Wageningen University staff from 1976 onward.

    Publications authored by the staff of the Research Institutes are available from 1995 onwards.

    Full text documents are added when available. The database is updated daily and currently holds about 240,000 items, of which 72,000 in open access.

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CCDC 1535306: Experimental Crystal Structure Determination
Huang, Ancheng C. ; Kautsar, S.A. ; Hong, Young J. ; Medema, M.H. ; Bond, Andrew D. ; Tantillo, Dean J. ; Osbourn, Anne - \ 2017
KAYNEG : 3,6,7a-trimethyl-10-(propan-2-yl)tetradecahydro-4H-spiro[3a,11a-methanoindeno[5,6-e]azulene-12,2'-oxirane]
CCDC 1535307: Experimental Crystal Structure Determination
Huang, Ancheng C. ; Kautsar, S.A. ; Hong, Young J. ; Medema, M.H. ; Bond, Andrew D. ; Tantillo, Dean J. ; Osbourn, Anne - \ 2017
KAYNIK : 3,5a,5b,7a-tetramethyl-10-(propan-2-yl)hexadecahydropentaleno[1',6a':2,3]-s-indaceno[1,8a-b]oxirene
CCDC 1535308: Experimental Crystal Structure Determination
Huang, Ancheng C. ; Kautsar, S.A. ; Hong, Young J. ; Medema, M.H. ; Bond, Andrew D. ; Tantillo, Dean J. ; Osbourn, Anne - \ 2017
YARNOX01 : 3a,8a,12b-trimethyl-7-methylidene-11-(propan-2-yl)octadecahydroindeno[5',6':10,11]oxireno[5,6]cycloundeca[1,2-b]oxirene
CCDC 1535309: Experimental Crystal Structure Determination
Huang, Ancheng C. ; Kautsar, S.A. ; Hong, Young J. ; Medema, M.H. ; Bond, Andrew D. ; Tantillo, Dean J. ; Osbourn, Anne - \ 2017
KAYNUW : 3,5a,6a-trimethyl-9-(propan-2-yl)-1,2,3,3a,4,5,5a,6,6a,7,8,9,9a,10-tetradecahydro-11H-pentaleno[1,6a-a]-s-indacen-11-one
CCDC 1539191: Experimental Crystal Structure Determination
Huang, Ancheng C. ; Kautsar, S.A. ; Hong, Young J. ; Medema, M.H. ; Bond, Andrew D. ; Tantillo, Dean J. ; Osbourn, Anne - \ 2017
KAYPAE : 5,9,13,14a-tetramethyl-3-(propan-2-yl)-1,2,3,3a,4,4a,7,8,11,13a,14,14a-dodecahydrocycloundeca[f]indene
CCDC 1539192: Experimental Crystal Structure Determination
Huang, Ancheng C. ; Kautsar, S.A. ; Hong, Young J. ; Medema, M.H. ; Bond, Andrew D. ; Tantillo, Dean J. ; Osbourn, Anne - \ 2017
KAYPEI : 3,5a,7a-trimethyl-6-methylidene-10-(propan-2-yl)hexadecahydro-1H-pentaleno[6a,1-a]-s-indacene
CCDC 1539193: Experimental Crystal Structure Determination
Huang, Ancheng C. ; Kautsar, S.A. ; Hong, Young J. ; Medema, M.H. ; Bond, Andrew D. ; Tantillo, Dean J. ; Osbourn, Anne - \ 2017
KAYPIM : 3,7a,12-trimethyl-6-methylidene-10-(propan-2-yl)-1,2,3,3a,4,5,6,6a,7,7a,8,9,10,10a,11,11a-hexadecahydrocyclopenta[4,5]cyclo-octa[1,2-f]indene
A translational synthetic biology platform for rapid access to gram-scale quantities of novel drug-like molecules
Reed, James ; Stephenson, Michael J. ; Miettinen, K. ; Brouwer, Bas ; Leveau, Aymeric ; Brett, Paul ; Goss, Rebecca J.M. ; Goossens, A. ; O'Connell, M. ; Osbourn, Anne - \ 2017
Metabolic Engineering 42 (2017). - ISSN 1096-7176 - p. 185 - 193.
Plants are an excellent source of drug leads. However availability is limited by access to source species, low abundance and recalcitrance to chemical synthesis. Although plant genomics is yielding a wealth of genes for natural product biosynthesis, the translation of this genetic information into small molecules for evaluation as drug leads represents a major bottleneck. For example, the yeast platform for artemisinic acid production is estimated to have taken >150 person years to develop. Here we demonstrate the power of plant transient transfection technology for rapid, scalable biosynthesis and isolation of triterpenes, one of the largest and most structurally diverse families of plant natural products. Using pathway engineering and improved agro-infiltration methodology we are able to generate gram-scale quantities of purified triterpene in just a few weeks. In contrast to heterologous expression in microbes, this system does not depend on re-engineering of the host. We next exploit agro-infection for quick and easy combinatorial biosynthesis without the need for generation of multi-gene constructs, so affording an easy entrée to suites of molecules, some new-to-nature, that are recalcitrant to chemical synthesis. We use this platform to purify a suite of bespoke triterpene analogs and demonstrate differences in anti-proliferative and anti-inflammatory activity in bioassays, providing proof of concept of this system for accessing and evaluating medicinally important bioactives. Together with new genome mining algorithms for plant pathway discovery and advances in plant synthetic biology, this advance provides new routes to synthesize and access previously inaccessible natural products and analogs and has the potential to reinvigorate drug discovery pipelines.
Unearthing a sesterterpene biosynthetic repertoire in the Brassicaceae through genome mining reveals convergent evolution
Huang, Ancheng C. ; Kautsar, Satria A. ; Hong, Young J. ; Medema, Marnix H. ; Bond, Andrew D. ; Tantillo, Dean J. ; Osbourn, Anne - \ 2017
Proceedings of the National Academy of Sciences of the United States of America 114 (2017)29. - ISSN 0027-8424 - p. E6005 - E6014.
Brassicaceae - Convergent evolution - Cyclization mechanism - Plant natural products - Sesterterpene biosynthesis
Sesterterpenoids are a rare terpene class harboring untapped chemo-diversity and bioactivities. Their structural diversity originates primarily from the scaffold-generating sesterterpene synthases (STSs). In fungi, all six known STSs are bifunctional, containing C-terminal trans-prenyltransferase (PT) and N-terminal terpene synthase (TPS) domains. In plants, two colocalized PT and TPS gene pairs from Arabidopsis thaliana were recently reported to synthesize sesterterpenes. However, the landscape of PT and TPS genes in plant genomes is unclear. Here, using a customized algorithm for systematically searching plant genomes, we reveal a suite of physically colocalized pairs of PT and TPS genes for the biosynthesis of a large sesterterpene repertoire in the wider Brassicaceae. Transient expression of seven TPSs from A. thaliana, Capsella rubella, and Brassica oleracea in Nicotiana benthamiana yielded fungal-type sesterterpenes with tri-, tetra-, and pentacyclic scaffolds, and notably (−)-ent-quiannulatene, an enantiomer of the fungal metabolite (+)-quiannulatene. Protein and structural modeling analysis identified an amino acid site implicated in structural diversification. Mutation of this site in one STS (AtTPS19) resulted in premature termination of carbocation intermediates and accumulation of bi-, tri-, and tetracyclic sesterterpenes, revealing the cyclization path for the pentacyclic sesterterpene (−)-retigeranin B. These structural and mechanistic insights, together with phylogenetic analysis, suggest convergent evolution of plant and fungal STSs, and also indicate that the colocalized PT–TPS gene pairs in the Brassicaceae may have originated from a common ancestral gene pair present before speciation. Our findings further provide opportunities for rapid discovery and production of sesterterpenes through metabolic and protein engineering.
PlantiSMASH : Automated identification, annotation and expression analysis of plant biosynthetic gene clusters
Kautsar, Satria A. ; Suarez Duran, Hernando G. ; Blin, Kai ; Osbourn, Anne ; Medema, Marnix H. - \ 2017
Nucleic Acids Research 45 (2017)W1. - ISSN 0305-1048 - p. W55 - W63.

Plant specialized metabolites are chemically highly diverse, play key roles in host-microbe interactions, have important nutritional value in crops and are frequently applied as medicines. It has recently become clear that plant biosynthetic pathway-encoding genes are sometimes densely clustered in specific genomic loci: Biosynthetic gene clusters (BGCs). Here, we introduce plantiSMASH, a versatile online analysis platform that automates the identification of candidate plant BGCs. Moreover, it allows integration of transcriptomic data to prioritize candidate BGCs based on the coexpression patterns of predicted biosynthetic enzyme-coding genes, and facilitates comparative genomic analysis to study the evolutionary conservation of each cluster. Applied on 48 high-quality plant genomes, plantiSMASH identifies a rich diversity of candidate plant BGCs. These results will guide further experimental exploration of the nature and dynamics of gene clustering in plant metabolism. Moreover, spurred by the continuing decrease in costs of plant genome sequencing, they will allow genome mining technologies to be applied to plant natural product discovery.

Computational genomic identification and functional reconstitution of plant natural product biosynthetic pathways
Medema, Marnix H. ; Osbourn, Anne - \ 2016
Natural Product Reports 33 (2016)8. - ISSN 0265-0568 - p. 951 - 962.

Covering: 2003 to 2016 The last decade has seen the first major discoveries regarding the genomic basis of plant natural product biosynthetic pathways. Four key computationally driven strategies have been developed to identify such pathways, which make use of physical clustering, co-expression, evolutionary co-occurrence and epigenomic co-regulation of the genes involved in producing a plant natural product. Here, we discuss how these approaches can be used for the discovery of plant biosynthetic pathways encoded by both chromosomally clustered and non-clustered genes. Additionally, we will discuss opportunities to prioritize plant gene clusters for experimental characterization, and end with a forward-looking perspective on how synthetic biology technologies will allow effective functional reconstitution of candidate pathways using a variety of genetic systems.

Minimum Information about a Biosynthetic Gene cluster
Medema, M.H. ; Kottmann, Renzo ; Yilmaz, Pelin ; Cummings, Matthew ; Biggins, J.B. ; Blin, Kai ; Bruijn, Irene De; Chooi, Yit Heng ; Claesen, Jan ; Coates, R.C. ; Cruz-Morales, Pablo ; Duddela, Srikanth ; Düsterhus, Stephanie ; Edwards, Daniel J. ; Fewer, David P. ; Garg, Neha ; Geiger, Christoph ; Gomez-Escribano, Juan Pablo ; Greule, Anja ; Hadjithomas, Michalis ; Haines, Anthony S. ; Helfrich, Eric J.N. ; Hillwig, Matthew L. ; Ishida, Keishi ; Jones, Adam C. ; Jones, Carla S. ; Jungmann, Katrin ; Kegler, Carsten ; Kim, Hyun Uk ; Kötter, Peter ; Krug, Daniel ; Masschelein, Joleen ; Melnik, Alexey V. ; Mantovani, Simone M. ; Monroe, Emily A. ; Moore, Marcus ; Moss, Nathan ; Nützmann, Hans Wilhelm ; Pan, Guohui ; Pati, Amrita ; Petras, Daniel ; Reen, F.J. ; Rosconi, Federico ; Rui, Zhe ; Tian, Zhenhua ; Tobias, Nicholas J. ; Tsunematsu, Yuta ; Wiemann, Philipp ; Wyckoff, Elizabeth ; Yan, Xiaohui ; Yim, Grace ; Yu, Fengan ; Xie, Yunchang ; Aigle, Bertrand ; Apel, Alexander K. ; Balibar, Carl J. ; Balskus, Emily P. ; Barona-Gómez, Francisco ; Bechthold, Andreas ; Bode, Helge B. ; Borriss, Rainer ; Brady, Sean F. ; Brakhage, Axel A. ; Caffrey, Patrick ; Cheng, Yi Qiang ; Clardy, Jon ; Cox, Russell J. ; Mot, René De; Donadio, Stefano ; Donia, Mohamed S. ; Donk, Wilfred A. Van Der; Dorrestein, Pieter C. ; Doyle, Sean ; Driessen, Arnold J.M. ; Ehling-Schulz, Monika ; Entian, Karl Dieter ; Fischbach, Michael A. ; Gerwick, Lena ; Gerwick, William H. ; Gross, Harald ; Gust, Bertolt ; Hertweck, Christian ; Höfte, Monica ; Jensen, Susan E. ; Ju, Jianhua ; Katz, Leonard ; Kaysser, Leonard ; Klassen, Jonathan L. ; Keller, Nancy P. ; Kormanec, Jan ; Kuipers, Oscar P. ; Kuzuyama, Tomohisa ; Kyrpides, Nikos C. ; Kwon, Hyung Jin ; Lautru, Sylvie ; Lavigne, Rob ; Lee, Chia Y. ; Linquan, Bai ; Liu, Xinyu ; Liu, Wen ; Luzhetskyy, Andriy ; Mahmud, Taifo ; Mast, Yvonne ; Méndez, Carmen ; Metsä-Ketelä, Mikko ; Micklefield, Jason ; Mitchell, Douglas A. ; Moore, Bradley S. ; Moreira, Leonilde M. ; Müller, Rolf ; Neilan, Brett A. ; Nett, Markus ; Nielsen, Jens ; O'Gara, Fergal ; Oikawa, Hideaki ; Osbourn, Anne ; Osburne, Marcia S. ; Ostash, Bohdan ; Payne, Shelley M. ; Pernodet, Jean Luc ; Petricek, Miroslav ; Piel, Jörn ; Ploux, Olivier ; Raaijmakers, Jos M. ; Salas, José A. ; Schmitt, Esther K. ; Scott, Barry ; Seipke, Ryan F. ; Shen, Ben ; Sherman, David H. ; Sivonen, Kaarina ; Smanski, Michael J. ; Sosio, Margherita ; Stegmann, Evi ; Süssmuth, Roderich D. ; Tahlan, Kapil ; Thomas, Christopher M. ; Tang, Yi ; Truman, Andrew W. ; Viaud, Muriel ; Walton, Jonathan D. ; Walsh, Christopher T. ; Weber, Tilmann ; Wezel, Gilles P. Van; Wilkinson, Barrie ; Willey, Joanne M. ; Wohlleben, Wolfgang ; Wright, Gerard D. ; Ziemert, Nadine ; Zhang, Changsheng ; Zotchev, Sergey B. ; Breitling, Rainer ; Takano, Eriko ; Glöckner, Frank Oliver - \ 2015
Nature Chemical Biology 11 (2015)9. - ISSN 1552-4450 - p. 625 - 631.

A wide variety of enzymatic pathways that produce specialized metabolites in bacteria, fungi and plants are known to be encoded in biosynthetic gene clusters. Information about these clusters, pathways and metabolites is currently dispersed throughout the literature, making it difficult to exploit. To facilitate consistent and systematic deposition and retrieval of data on biosynthetic gene clusters, we propose the Minimum Information about a Biosynthetic Gene cluster (MIBiG) data standard.

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