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Organic & Biomolecular Chemistry Organic & Biomolecular Chemistry View Article Online REVIEW View Journal | View Issue Recent highlights of biosynthetic studies on marine natural products† Cite this: Org. Biomol. Chem., 2021, 19,123 Jamshid Amiri Moghaddam, *a Theresa Jautzus, a Mohammad Alanjaryb and Christine Beemelmanns *a Marine bacteria are excellent yet often underexplored sources of structurally unique bioactive natural pro- Received 13th August 2020, ducts. In this review we cover the diversity of marine bacterial biomolecules and highlight recent studies Accepted 29th September 2020 on structurally novel natural products. We include different compound classes and discuss the latest pro- DOI: 10.1039/d0ob01677b gress related to their biosynthetic pathway analysis and engineering: examples range from fatty acids over rsc.li/obc terpenes to PKS, NRPS and hybrid PKS–NRPS biomolecules. pounds, nutraceuticals and other potential compounds of Creative Commons Attribution-NonCommercial 3.0 Unported Licence. 1. Introduction commercial value.2,3 The marine environment is unique in terms of pH, tempera- Marine microorganisms with unique biochemical capa- ture, pressure, oxygen, light, and salinity. It also contains most bilities have been found within all areas of the marine of the Earth’s surface and nearly 87% of the world’s biosphere environment, including different water columns of open (fauna and flora),1 and thus represents an exceptional reser- waters, the bottom of the Mariana Trench, known as the voir of microbial diversity and microbial-derived bioactive com- deepest point of the world’s oceans, and many other extreme environments including deep-sea cold-water habitats and deep-sea vents.4 This article is licensed under a aJunior Research Group Chemical Biology of Microbe-Host Interactions, Leibniz In addition, marine macro-organisms mostly belonging to Institute for Natural Product Research and Infection Biology (HKI), Beutenbergstr. 11a, the phyla Porifera (sponges) and Coelenterata (corals),5 have 07745 Jena, Germany. E-mail: [email protected] been found to contain a large portion of host-adapted microor- b Bioinformatics Group, Wageningen University, Wageningen, The Netherlands 6 † ganisms with up to 30% of the hosts biomass. Subsequent Open Access Article. Published on 20 November 2020. Downloaded 2/22/2021 8:41:07 AM. Electronic supplementary information (ESI) available: The similarity network file is available at NDEx36 (https://doi.org/10.18119/N9V31Z). See DOI: 10.1039/ genomic and metagenomics analyses clearly showed that host- d0ob01677b specific and co-evolved symbiotic microbial communities, Jamshid Amiri Moghaddam After obtaining a Master of obtained his PhD under the Science degree in Microbiology at supervision of Prof. Gabriele M. the Friedrich-Schiller-University König at the University of Bonn Jena, Theresa Jautzus joined the (Germany) with the focus on Terrestrial Biofilms group to genome mining of marine bac- perform her PhD under supervi- teria for bioactive metabolites. sion of Prof. Ákos T. Kovács at He also, performed a research FSU Jena. Since end of 2018, she stay at the Scripps Institution of is a postdoctoral researcher in the Oceanography in La Jolla/CA, lab of Christine Beemelmanns at USA with Prof. Bradley Moore. the Leibniz Institute for Natural He is currently working at the Product Research and Infection Jamshid Amiri Moghaddam Leibniz Institute for Natural Theresa Jautzus Biology in Jena. Currently, she is Product Research and Infection working on natural metabolite Biology (Jena, Germany) as a postdoctoral scientist working on the biosynthesis and marine invert- biosynthetic pathways and enzymes involved in the biosynthesis of ebrate–microbe interactions. secondary metabolites in marine bacteria. This journal is © The Royal Society of Chemistry 2021 Org. Biomol. Chem.,2021,19,123–140 | 123 View Article Online Review Organic & Biomolecular Chemistry often non-culturable outside the host environment, are respon- Biosynthesis of secondary metabolites sible for most of the isolated natural products isolated from Secondary metabolites are biosynthesized by dedicated marine macro-organisms.7 enzymatic machineries, which are often encoded within in bio- A comprehensive study aiming at describing the bacterial synthetic gene cluster regions (BGCs) within the genome of diversity within different marine environments identified the producing organisms. To date, more than 1500 BGCs have more than 120 000 molecular operational taxonomic units been experimentally characterized and their products been 18 with 3% sequence dissimilarity threshold (OTU0.03)from investigated. But it is estimated that many more gene cluster 509 global marine samples.8 From the identified taxonomic families still await characterization and even with conservative units, Gammaproteobacteria and Alphaproteobacteria were assumptions, the total number of bacterial BGC families – dominant in ocean waters, followed by a high proportion present in the biosphere may be estimated to be ∼6000.19 21 of Flavobacteria and Cyanobacteria. The dominant AntiSMASH,22 the most versatile platform to predict BGCs, groups in benthic communities were Gammaproteobacteria, lists 46 different families of BGCs in its database (until 1st Deltaproteobacteria, Planctomycetes, Actinobacteria, and August, 2020), which contain 172 395 BGCs from 24 776 Acidobacteria. The microbial community composition, unique species/strains. The most abundant BGCs encode for however, differed greatly depending on their sampling nonribosomal peptide-synthetases (NRPS) (23%), polyketide origin. synthases (PKS) (17%), ribosomally synthesized and post-trans- Research in marine ecology and natural product chemistry lationally modified peptides (RiPPs) (9%) and/or bacteriocin has also shown that bacterial taxonomy, ecological role and biosynthesis (13%) as well as terpene synthases (12%). – metabolic diversity are likely fundamentally interrelated,9 12 Catalyzed by the availability genomic dereplication tools with low nutrient concentrations, high dilution rates, and/or such as antiSMASH22 or Antibiotic Resistant Target Seeker highly competitive environments within host and surface- (ARTS),23 many emerging (meta)genomic studies are now associated microbial communities as major driving forces for directed at exploring the biosynthetic capacities of rare or non- 13–15 Creative Commons Attribution-NonCommercial 3.0 Unported Licence. the evolution of regulated biosynthetic traits. Many of the culturable microbes and/or microbial communities for yet produced marine natural products are assumed to serve as undescribed transformations and potentially novel natural defensive metabolites or siderophores, but also as chemical products.24,25 Today, low genome sequencing costs, the avail- language allowing communication among species and with ability of easy-to-use web-based genome mining and metabolo- other organisms and thereby conferring a significant survival mic analysis tools26 allow for the efficient dereplication of advantage. Bacterial lineages specifically adapted to a host- known metabolites from complex metabolite mixtures result- dependent life style, are assumed to secrete metabolites that ing in increasing discovery rates of novel metabolites and bio- – might even influence physiological processes of the host in synthetic traits.27 29 Many research groups have also picked up favor of the associated microorganisms.16 the challenge to fully characterize and manipulate the under- This article is licensed under a Overall, the analyses of bacterial symbionts and/or lying biosynthetic transformations thereby applying or devel- microbial communities in general are likely to reveal unique oping state-of-the art biotechnological approaches.24 Although biosynthetic traits and new natural products, which can be many approaches were of mixed success, steadily improving exploited for human welfare.14,15,17 computational power and methods are beginning to provide Open Access Article. Published on 20 November 2020. Downloaded 2/22/2021 8:41:07 AM. Dr Mohammad Alanjary is a Christine Beemelmanns per- post-doctoral researcher focused formed her PhD under the super- on developing computational vision of Prof. Hans-Ulrich platforms to accelerate drug dis- Reissig at the FU Berlin. After covery. In 2018 he received his two postdoctoral stays in the PhD in bioinformatics at the group of Prof. Keisuke Suzuki at University of Tübingen, Germany the Tokyo Institute of Technology where he developed genome- (Tokyo, Japan) and Prof. Jon mining tools for gene cluster Clardy at Harvard Medical prioritization and antibiotic re- School (USA), she joined the sistance detection. Previously he Leibniz Institute for Natural aided in the launch of the first Product Research and Infection Mohammad Alanjary commercial semi-conductor gene Christine Beemelmanns Biology (Jena, Germany) as sequencing system and developed junior research group leader in several procedures for performance optimization at IonTorrent. the end of 2013. Her research focuses of the isolation, characteriz- Since then he is focused on leveraging comparative genomics for ation and total synthesis of microbial signalling molecules. natural product discovery and engineering at the University of Wageningen, Netherlands. 124 | Org. Biomol. Chem.,2021,19,123–140 This journal is © The Royal Society of Chemistry 2021 View Article Online Organic & Biomolecular Chemistry Review solutions to leverage these complex systems making semi-auto- mostly biosynthesized by
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