MIBiG 3.0: a community-driven effort to annotate experimentally validated biosynthetic gene clusters

Barbara R Terlouw¹, Kai Blin², Jorge C Navarro-Muñoz^{1

3}, Nicole E Avalon⁴, Marc G Chevrette⁵, Susan Egbert⁶, Sanghoon Lee⁷, David Meijer¹, Michael J J Recchia⁷, Zachary L Reitz¹, Jeffrey A van Santen^{7

8}, Nelly Selem-Mojica⁹, Thomas Tørring¹⁰, Liana Zaroubi⁷, Mohammad Alanjary¹, Gajender Aleti¹¹, César Aguilar¹², Suhad A A Al-Salihi¹³, Hannah E Augustijn^{1

14}, J Abraham Avelar-Rivas¹⁵, Luis A Avitia-Domínguez^{14

15}, Francisco Barona-Gómez^{14

15}, Jordan Bernaldo-Agüero¹⁶, Vincent A Bielinski¹⁷, Friederike Biermann^{1

18

19}, Thomas J Booth^{2

20}, Victor J Carrion Bravo^{14

21

22}, Raquel Castelo-Branco^{23

24}, Fernanda O Chagas²⁵, Pablo Cruz-Morales², Chao Du¹⁴, Katherine R Duncan²⁶, Athina Gavriilidou^{27

28}, Damien Gayrard²⁹, Karina Gutiérrez-García³⁰, Kristina Haslinger³¹, Eric J N Helfrich^{18

19}, Justin J J van der Hooft^{1

32}, Afif P Jati³³, Edward Kalkreuter³⁴, Nikolaos Kalyvas³, Kyo Bin Kang³⁵, Satria Kautsar³⁴, Wonyong Kim³⁶, Aditya M Kunjapur³⁷, Yong-Xin Li³⁸, Geng-Min Lin³⁹, Catarina Loureiro⁴⁰, Joris J R Louwen¹, Nico L L Louwen¹, George Lund⁴¹, Jonathan Parra^{42

43

44}, Benjamin Philmus⁴⁵, Bita Pourmohsenin^{27

28}, Lotte J U Pronk¹, Adriana Rego^{23

46}, Devasahayam Arokia Balaya Rex⁴⁷, Serina Robinson⁴⁸, L Rodrigo Rosas-Becerra^{14

15}, Eve T Roxborough⁴⁹, Michelle A Schorn⁴⁰, Darren J Scobie²⁶, Kumar Saurabh Singh¹, Nika Sokolova³¹, Xiaoyu Tang⁵⁰, Daniel Udwary⁵¹, Aruna Vigneshwari⁵², Kristiina Vind^{53

54}, Sophie P J M Vromans¹, Valentin Waschulin⁵⁵, Sam E Williams⁵⁶, Jaclyn M Winter⁵⁷, Thomas E Witte⁵⁸, Huali Xie^{1

59}, Dong Yang⁶⁰, Jingwei Yu⁶¹, Mitja Zdouc¹, Zheng Zhong⁴⁰, Jérôme Collemare³, Roger G Linington⁷, Tilmann Weber², Marnix H Medema^{1

14}

Affiliations

¹ Bioinformatics Group, Wageningen University, Droevendaalsesteeg, 6708 PB Wageningen, The Netherlands.
² The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Kgs. Lyngby, Denmark.
³ Westerdijk Fungal Biodiversity Institute, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands.
⁴ Scripps Institution of Oceanography, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0212, USA.
⁵ Department of Microbiology and Cell Science, University of Florida, Gainesville, FL 32611, USA.
⁶ Department of Chemistry, University of Manitoba, 66 Chancellors Cir, Winnipeg, MB R3T 2N2, Canada.
⁷ Department of Chemistry, Simon Fraser University, 8888 University Drive, Burnaby, British Columbia V5A 1S6, Canada.
⁸ Unnatural Products, 2161 Delaware Ave. Suite A, Santa Cruz, CA 95060, USA.
⁹ Centro de Ciencias Matemáticas UNAM, Morelia, México.
¹⁰ Department of Biological and Chemical Engineering, Aarhus University, Denmark.
¹¹ Food and Animal Sciences, Department of Agricultural and Environmental Sciences, Tennessee State University, Nashville, TN 37209, USA.
¹² Department of Chemistry, Purdue University, West Lafayette, IN, USA.
¹³ Department of Applied Sciences, University of Technology, Iraq.
¹⁴ Institute of Biology, Leiden University, Sylviusweg 72, 2333BE Leiden, The Netherlands.
¹⁵ Laboratorio Nacional de Genómica para la Biodiversidad-Unidad de Genómica Avanzada, Cinvestav. Km 9.6 Libramiento Norte Carretera Irapuato-León, CP 36824 Irapuato, Gto., México.
¹⁶ Departamento de Microbiología Molecular, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Cuernavaca, Morelos, México.
¹⁷ Synthetic Biology and Bioenergy Group, J. Craig Venter Institute, La Jolla, CA 92037, USA.
¹⁸ Institute of Molecular Bio Science, Goethe-University Frankfurt, D-60438 Frankfurt am Main, Germany.
¹⁹ LOEWE Center for Translational Biodiversity Genomics (TBG), Senckenberganlage 25, 60325 Frankfurt am Main, Germany.
²⁰ School of Molecular Sciences, University of Western Australia, Perth, Australia.
²¹ Departamento de Microbiología, Instituto de Hortofruticultura Subtropical y Mediterránea 'La Mayora', Universidad de Málaga-Consejo Superior de Investigaciones Científicas (IHSM-UMA-CSIC), Universidad de Málaga, Málaga, Spain.
²² Department of Microbial Ecology, Netherlands Institute of Ecology (NIOO-KNAW), Wageningen, The Netherlands.
²³ Interdisciplinary Centre of Marine and Environmental Research (CIIMAR), University of Porto, Portugal.
²⁴ Faculty of Sciences, University of Porto, 4150-179 Porto, Portugal.
²⁵ Instituto de Pesquisas de Produtos Naturais Walter Mors, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, 21941-599, Brazil.
²⁶ University of Strathclyde, Strathclyde Institute of Pharmacy and Biomedical Sciences, 141 Cathedral Street, Glasgow, G4 ORE UK.
²⁷ Translational Genome Mining for Natural Products, Interfaculty Institute of Microbiology and Infection Medicine Tübingen (IMIT), University of Tübingen, Tübingen, Germany.
²⁸ Interfaculty Institute for Biomedical Informatics (IBMI), University of Tübingen, Tübingen, Germany.
²⁹ Department of Molecular Microbiology, John Innes Centre, Norwich Research Park, Norwich, NR4 7UH, UK.
³⁰ Department of Embryology, Carnegie Institution for Science, 3520 San Martin Drive, Baltimore, MD 21218, USA.
³¹ Department of Chemical and Pharmaceutical Biology, Groningen Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
³² Department of Biochemistry, University of Johannesburg, Auckland Park, Johannesburg 2006, South Africa.
³³ Indonesian Society of Bioinformatics And Biodiversity, Indonesia.
³⁴ Department of Chemistry, University of Florida Scripps Biomedical Research, 110 Scripps Way, Jupiter, FL 33458, USA.
³⁵ College of Pharmacy, Sookmyung Women's University, Seoul, South Korea.
³⁶ Korean Lichen Research Institute, Sunchon National Universtiy, Suncheon, South Korea.
³⁷ Department of Chemical & Biomolecular Engineering, University of Delaware, Newark, DE 19716, USA.
³⁸ Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, P.R. China.
³⁹ Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁴⁰ Laboratory of Microbiology, Wageningen University, Stippeneng 4, 6708WE, Wageningen, The Netherlands.
⁴¹ Sustainable Soils and Crops, Rothamsted Research, Harpenden, Hertfordshire, UK.
⁴² Instituto de Investigaciones Farmacéuticas (INIFAR), Facultad de Farmacia, Universidad de Costa Rica, San José, 11501-2060, Costa Rica.
⁴³ Centro de Investigaciones en Productos Naturales (CIPRONA), Universidad de Costa Rica, San José, 11501-2060, Costa Rica.
⁴⁴ Centro Nacional de Innovaciones Biotecnológicas (CENIBiot), CeNAT-CONARE, 1174-1200, San José, Costa Rica.
⁴⁵ Department of Pharmaceutical Sciences, Oregon State University, USA.
⁴⁶ Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Portugal.
⁴⁷ Centre for Integrative Omics Data Science, Yenepoya (Deemed to be University), Mangalore 575018, India.
⁴⁸ Department of Environmental Microbiology, Eawag: Swiss Federal Institute for Aquatic Science and Technology, Überlandstrasse 133, CH-8600 Dübendorf, Switzerland.
⁴⁹ School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, UK.
⁵⁰ Institute of Chemical Biology, Shenzhen Bay Laboratory, Shenzhen 518132, China.
⁵¹ DOE Joint Genome Institute, Lawrence Berkeley National Lab, Berkeley, CA, USA.
⁵² Department of Microbiology, University of Szeged, Hungary.
⁵³ Host-Microbe Interactomics Group, Wageningen University, 6708 WD Wageningen, The Netherlands.
⁵⁴ NAICONS Srl, 20139 Milan, Italy.
⁵⁵ School of Life Sciences, The University of Warwick, Coventry CV4 7AL, UK.
⁵⁶ School of Biochemistry, University of Bristol, University Walk, Bristol BS8 1TD, UK.
⁵⁷ Department of Medicinal Chemistry, University of Utah, Salt Lake City, UT 84112, USA.
⁵⁸ Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, Canada.
⁵⁹ Key laboratory of Detection for Biotoxins, Ministry of Agriculture and Rural Affairs and Oil Crops Research Institute, Chinese Academy of Agricultural Sciences, Wuhan 430061, China.
⁶⁰ Department of Chemistry and Natural Products Discovery Center, UF Scripps Biomedical Research, University of Florida, Jupiter, FL 33458, USA.
⁶¹ SUSTech-PKU Institute of Plant and Food Science, Department of Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China.

PMID: 36399496
PMCID: PMC9825592
DOI: 10.1093/nar/gkac1049

MIBiG 3.0: a community-driven effort to annotate experimentally validated biosynthetic gene clusters

Barbara R Terlouw et al. Nucleic Acids Res. 2023.

. 2023 Jan 6;51(D1):D603-D610.

doi: 10.1093/nar/gkac1049.

Authors

Affiliations

¹ Bioinformatics Group, Wageningen University, Droevendaalsesteeg, 6708 PB Wageningen, The Netherlands.
² The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Kgs. Lyngby, Denmark.
³ Westerdijk Fungal Biodiversity Institute, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands.
⁴ Scripps Institution of Oceanography, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0212, USA.
⁵ Department of Microbiology and Cell Science, University of Florida, Gainesville, FL 32611, USA.
⁶ Department of Chemistry, University of Manitoba, 66 Chancellors Cir, Winnipeg, MB R3T 2N2, Canada.
⁷ Department of Chemistry, Simon Fraser University, 8888 University Drive, Burnaby, British Columbia V5A 1S6, Canada.
⁸ Unnatural Products, 2161 Delaware Ave. Suite A, Santa Cruz, CA 95060, USA.
⁹ Centro de Ciencias Matemáticas UNAM, Morelia, México.
¹⁰ Department of Biological and Chemical Engineering, Aarhus University, Denmark.
¹¹ Food and Animal Sciences, Department of Agricultural and Environmental Sciences, Tennessee State University, Nashville, TN 37209, USA.
¹² Department of Chemistry, Purdue University, West Lafayette, IN, USA.
¹³ Department of Applied Sciences, University of Technology, Iraq.
¹⁴ Institute of Biology, Leiden University, Sylviusweg 72, 2333BE Leiden, The Netherlands.
¹⁵ Laboratorio Nacional de Genómica para la Biodiversidad-Unidad de Genómica Avanzada, Cinvestav. Km 9.6 Libramiento Norte Carretera Irapuato-León, CP 36824 Irapuato, Gto., México.
¹⁶ Departamento de Microbiología Molecular, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Cuernavaca, Morelos, México.
¹⁷ Synthetic Biology and Bioenergy Group, J. Craig Venter Institute, La Jolla, CA 92037, USA.
¹⁸ Institute of Molecular Bio Science, Goethe-University Frankfurt, D-60438 Frankfurt am Main, Germany.
¹⁹ LOEWE Center for Translational Biodiversity Genomics (TBG), Senckenberganlage 25, 60325 Frankfurt am Main, Germany.
²⁰ School of Molecular Sciences, University of Western Australia, Perth, Australia.
²¹ Departamento de Microbiología, Instituto de Hortofruticultura Subtropical y Mediterránea 'La Mayora', Universidad de Málaga-Consejo Superior de Investigaciones Científicas (IHSM-UMA-CSIC), Universidad de Málaga, Málaga, Spain.
²² Department of Microbial Ecology, Netherlands Institute of Ecology (NIOO-KNAW), Wageningen, The Netherlands.
²³ Interdisciplinary Centre of Marine and Environmental Research (CIIMAR), University of Porto, Portugal.
²⁴ Faculty of Sciences, University of Porto, 4150-179 Porto, Portugal.
²⁵ Instituto de Pesquisas de Produtos Naturais Walter Mors, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, 21941-599, Brazil.
²⁶ University of Strathclyde, Strathclyde Institute of Pharmacy and Biomedical Sciences, 141 Cathedral Street, Glasgow, G4 ORE UK.
²⁷ Translational Genome Mining for Natural Products, Interfaculty Institute of Microbiology and Infection Medicine Tübingen (IMIT), University of Tübingen, Tübingen, Germany.
²⁸ Interfaculty Institute for Biomedical Informatics (IBMI), University of Tübingen, Tübingen, Germany.
²⁹ Department of Molecular Microbiology, John Innes Centre, Norwich Research Park, Norwich, NR4 7UH, UK.
³⁰ Department of Embryology, Carnegie Institution for Science, 3520 San Martin Drive, Baltimore, MD 21218, USA.
³¹ Department of Chemical and Pharmaceutical Biology, Groningen Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
³² Department of Biochemistry, University of Johannesburg, Auckland Park, Johannesburg 2006, South Africa.
³³ Indonesian Society of Bioinformatics And Biodiversity, Indonesia.
³⁴ Department of Chemistry, University of Florida Scripps Biomedical Research, 110 Scripps Way, Jupiter, FL 33458, USA.
³⁵ College of Pharmacy, Sookmyung Women's University, Seoul, South Korea.
³⁶ Korean Lichen Research Institute, Sunchon National Universtiy, Suncheon, South Korea.
³⁷ Department of Chemical & Biomolecular Engineering, University of Delaware, Newark, DE 19716, USA.
³⁸ Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, P.R. China.
³⁹ Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁴⁰ Laboratory of Microbiology, Wageningen University, Stippeneng 4, 6708WE, Wageningen, The Netherlands.
⁴¹ Sustainable Soils and Crops, Rothamsted Research, Harpenden, Hertfordshire, UK.
⁴² Instituto de Investigaciones Farmacéuticas (INIFAR), Facultad de Farmacia, Universidad de Costa Rica, San José, 11501-2060, Costa Rica.
⁴³ Centro de Investigaciones en Productos Naturales (CIPRONA), Universidad de Costa Rica, San José, 11501-2060, Costa Rica.
⁴⁴ Centro Nacional de Innovaciones Biotecnológicas (CENIBiot), CeNAT-CONARE, 1174-1200, San José, Costa Rica.
⁴⁵ Department of Pharmaceutical Sciences, Oregon State University, USA.
⁴⁶ Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Portugal.
⁴⁷ Centre for Integrative Omics Data Science, Yenepoya (Deemed to be University), Mangalore 575018, India.
⁴⁸ Department of Environmental Microbiology, Eawag: Swiss Federal Institute for Aquatic Science and Technology, Überlandstrasse 133, CH-8600 Dübendorf, Switzerland.
⁴⁹ School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, UK.
⁵⁰ Institute of Chemical Biology, Shenzhen Bay Laboratory, Shenzhen 518132, China.
⁵¹ DOE Joint Genome Institute, Lawrence Berkeley National Lab, Berkeley, CA, USA.
⁵² Department of Microbiology, University of Szeged, Hungary.
⁵³ Host-Microbe Interactomics Group, Wageningen University, 6708 WD Wageningen, The Netherlands.
⁵⁴ NAICONS Srl, 20139 Milan, Italy.
⁵⁵ School of Life Sciences, The University of Warwick, Coventry CV4 7AL, UK.
⁵⁶ School of Biochemistry, University of Bristol, University Walk, Bristol BS8 1TD, UK.
⁵⁷ Department of Medicinal Chemistry, University of Utah, Salt Lake City, UT 84112, USA.
⁵⁸ Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, Canada.
⁵⁹ Key laboratory of Detection for Biotoxins, Ministry of Agriculture and Rural Affairs and Oil Crops Research Institute, Chinese Academy of Agricultural Sciences, Wuhan 430061, China.
⁶⁰ Department of Chemistry and Natural Products Discovery Center, UF Scripps Biomedical Research, University of Florida, Jupiter, FL 33458, USA.
⁶¹ SUSTech-PKU Institute of Plant and Food Science, Department of Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China.

PMID: 36399496
PMCID: PMC9825592
DOI: 10.1093/nar/gkac1049

Abstract

With an ever-increasing amount of (meta)genomic data being deposited in sequence databases, (meta)genome mining for natural product biosynthetic pathways occupies a critical role in the discovery of novel pharmaceutical drugs, crop protection agents and biomaterials. The genes that encode these pathways are often organised into biosynthetic gene clusters (BGCs). In 2015, we defined the Minimum Information about a Biosynthetic Gene cluster (MIBiG): a standardised data format that describes the minimally required information to uniquely characterise a BGC. We simultaneously constructed an accompanying online database of BGCs, which has since been widely used by the community as a reference dataset for BGCs and was expanded to 2021 entries in 2019 (MIBiG 2.0). Here, we describe MIBiG 3.0, a database update comprising large-scale validation and re-annotation of existing entries and 661 new entries. Particular attention was paid to the annotation of compound structures and biological activities, as well as protein domain selectivities. Together, these new features keep the database up-to-date, and will provide new opportunities for the scientific community to use its freely available data, e.g. for the training of new machine learning models to predict sequence-structure-function relationships for diverse natural products. MIBiG 3.0 is accessible online at https://mibig.secondarymetabolites.org/.

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Figures

**Graphical Abstract**
MIBiG version 3.0 provides an updated database of experimentally characterized biosynthetic gene clusters. It includes 661 new entries, as well as new structures, bioactivities and enzyme domain substrate specificities.

**Figure 1.**
Overview of MIBiG 3.0. (A) Added, removed and updated entries since MIBiG 2.0. (B) Improvements in the annotation of compounds, bioactivities, molecular targets and NRPS domain substrates.

**Figure 2.**
Similarity network of annotated NRPS substrates. Each node represents one of 274 unique NRPS substrate structures in MIBiG 3.0. Colours indicate substrate categories, and node size correlates with the number of annotations for that substrate in the MIBiG database. Substrates were clustered based on Tanimoto similarity of ECFP-4 molecular fingerprints (25) (edge cut-off = 0.46).

See this image and copyright information in PMC

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MIBiG 3.0: a community-driven effort to annotate experimentally validated biosynthetic gene clusters

Affiliations

MIBiG 3.0: a community-driven effort to annotate experimentally validated biosynthetic gene clusters

Authors

Affiliations

Abstract

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References

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MeSH terms

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