Publications by authors named "Martin Baunach"

13 Publications

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Biospektrum (Heidelb) 2021 11;27(3):284-285. Epub 2021 May 11.

Erlangen, Würzburg, Deutschland.

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http://dx.doi.org/10.1007/s12268-021-1585-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111371PMC
May 2021

The Landscape of Recombination Events That Create Nonribosomal Peptide Diversity.

Mol Biol Evol 2021 05;38(5):2116-2130

Institute for Biochemistry and Biology, University of Potsdam, Potsdam-Golm, Germany.

Nonribosomal peptides (NRP) are crucial molecular mediators in microbial ecology and provide indispensable drugs. Nevertheless, the evolution of the flexible biosynthetic machineries that correlates with the stunning structural diversity of NRPs is poorly understood. Here, we show that recombination is a key driver in the evolution of bacterial NRP synthetase (NRPS) genes across distant bacterial phyla, which has guided structural diversification in a plethora of NRP families by extensive mixing and matching of biosynthesis genes. The systematic dissection of a large number of individual recombination events did not only unveil a striking plurality in the nature and origin of the exchange units but allowed the deduction of overarching principles that enable the efficient exchange of adenylation (A) domain substrates while keeping the functionality of the dynamic multienzyme complexes. In the majority of cases, recombination events have targeted variable portions of the Acore domains, yet domain interfaces and the flexible Asub domain remained untapped. Our results strongly contradict the widespread assumption that adenylation and condensation (C) domains coevolve and significantly challenge the attributed role of C domains as stringent selectivity filter during NRP synthesis. Moreover, they teach valuable lessons on the choice of natural exchange units in the evolution of NRPS diversity, which may guide future engineering approaches.
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http://dx.doi.org/10.1093/molbev/msab015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8097286PMC
May 2021

Gene Cluster Activation in a Bacterial Symbiont Leads to Halogenated Angucyclic Maduralactomycins and Spirocyclic Actinospirols.

Org Lett 2020 04 20;22(7):2634-2638. Epub 2020 Mar 20.

Leibniz Institute for Natural Product Research and Infection Biology - Hans Knöll Institute (HKI), Beutenbergstraße 11a, 07745 Jena, Germany.

Growth from spores activated a biosynthetic gene cluster in sp. RB29, resulting in the identification of two novel groups of halogenated polyketide natural products, named maduralactomycins and actinospirols. The unique tetracyclic and spirocyclic structures were assigned based on a combination of NMR analysis, chemoinformatic calculations, X-ray crystallography, and C labeling studies. On the basis of HRMS data, genome mining, and gene expression studies, we propose an underlying noncanonical angucycline biosynthesis and extensive post-polyketide synthase (PKS) oxidative modifications.
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http://dx.doi.org/10.1021/acs.orglett.0c00601DOI Listing
April 2020

Unlocking the Spatial Control of Secondary Metabolism Uncovers Hidden Natural Product Diversity in Nostoc punctiforme.

ACS Chem Biol 2019 06 24;14(6):1271-1279. Epub 2019 May 24.

University of Potsdam , Institute for Biochemistry and Biology , Karl-Liebknecht-Str. 24/25 , 14476 Potsdam-Golm , Germany.

Filamentous cyanobacteria belong to the most prolific producers of structurally unique and biologically active natural products, yet the majority of biosynthetic gene clusters predicted for these multicellular collectives are currently orphan. Here, we present a systems analysis of secondary metabolite gene expression in the model strain Nostoc punctiforme PCC73102 using RNA-seq and fluorescence reporter analysis. Our data demonstrate that the majority of the cryptic gene clusters are not silent but are expressed with regular or sporadic pattern. Cultivation of N. punctiforme using high-density fermentation overrules the spatial control and leads to a pronounced upregulation of more than 50% of biosynthetic gene clusters. Our data suggest that a combination of autocrine factors, a high CO level, and high light account for the upregulation of individual pathways. Our overarching study not only sheds light on the strategies of filamentous cyanobacteria to share the enormous metabolic burden connected with the production of specialized molecules but provides an avenue for the genome-based discovery of natural products in multicellular cyanobacteria as exemplified by the discovery of highly unusual variants of the tricyclic peptide microviridin.
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http://dx.doi.org/10.1021/acschembio.9b00240DOI Listing
June 2019

Cryptic indole hydroxylation by a non-canonical terpenoid cyclase parallels bacterial xenobiotic detoxification.

Nat Commun 2017 06 15;8:15804. Epub 2017 Jun 15.

Department of Biomolecular Chemistry, Leibniz Institute for Natural Product Research and Infection Biology (HKI), Beutenbergstr. 11a, 07745 Jena, Germany.

Terpenoid natural products comprise a wide range of molecular architectures that typically result from C-C bond formations catalysed by classical type I/II terpene cyclases. However, the molecular diversity of biologically active terpenoids is substantially increased by fully unrelated, non-canonical terpenoid cyclases. Their evolutionary origin has remained enigmatic. Here we report the in vitro reconstitution of an unusual flavin-dependent bacterial indoloterpenoid cyclase, XiaF, together with a designated flavoenzyme-reductase (XiaP) that mediates a key step in xiamycin biosynthesis. The crystal structure of XiaF with bound FADH (at 2.4 Å resolution) and phylogenetic analyses reveal that XiaF is, surprisingly, most closely related to xenobiotic-degrading enzymes. Biotransformation assays show that XiaF is a designated indole hydroxylase that can be used for the production of indigo and indirubin. We unveil a cryptic hydroxylation step that sets the basis for terpenoid cyclization and suggest that the cyclase has evolved from xenobiotics detoxification enzymes.
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http://dx.doi.org/10.1038/ncomms15804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5481743PMC
June 2017

Natural 1,3-Dipolar Cycloadditions.

Angew Chem Int Ed Engl 2015 Oct 7;54(43):12550-2. Epub 2015 Sep 7.

Department of Biomolecular Chemistry, Leibniz Institute for Natural Product Research and Infection Biology (HKI), Beutenbergstr. 11a, 07745 Jena (Germany).

[3+2] in the wild: Biomimetic natural product syntheses and theoretical considerations have indicated that 1,3-dipolar cycloadditions take place in nature. Now, the structure, biosynthesis, and function of a heavily modified prenylated flavin cofactor have been elucidated. In the azomethine ylide form, it undergoes [3+2] cycloadditions with aromatic acids and promotes their decarboxylation.
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http://dx.doi.org/10.1002/anie.201507120DOI Listing
October 2015

Bacterial Synthesis of Unusual Sulfonamide and Sulfone Antibiotics by Flavoenzyme-Mediated Sulfur Dioxide Capture.

Angew Chem Int Ed Engl 2015 Nov 14;54(45):13279-83. Epub 2015 Sep 14.

Department of Biomolecular Chemistry, and Bio Pilot Plant, Leibniz Institute for Natural Product Research and Infection Biology, HKI, Beutenbergstrasse 11a, 07745 Jena (Germany).

Sulfa drugs, such as sulfonilamide and dapsone, are classical antibiotics that have been in clinical use worldwide. Despite the relatively simple architectures, practically no natural products are known to feature such aromatic sulfonamide or diarylsulfone substructures. We report the unexpected discovery of three fully unprecedented, sulfonyl-bridged alkaloid dimers (sulfadixiamycins A-C) from recombinant Streptomyces species harboring the entire xiamycin biosynthesis gene cluster. Sulfadixiamycins exhibit moderate antimycobacterial activities and potent antibiotic activities even against multidrug-resistant bacteria. Gene inactivation, complementation, and biotransformation experiments revealed that a flavin-dependent enzyme (XiaH) plays a key role in sulfadixiamycin biosynthesis. XiaH mediates a radical-based, three-component reaction involving two equivalents of xiamycin and sulfur dioxide, which is reminiscent of radical styrene/SO2 copolymerization.
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http://dx.doi.org/10.1002/anie.201506541DOI Listing
November 2015

Terpenoid biosynthesis off the beaten track: unconventional cyclases and their impact on biomimetic synthesis.

Angew Chem Int Ed Engl 2015 Feb 8;54(9):2604-26. Epub 2014 Dec 8.

Department of Biomolecular Chemistry, Leibniz Institute for Natural Product Research and Infection Biology (HKI), Beutenbergstrasse 11a, 07745 Jena (Germany).

Terpene and terpenoid cyclizations are counted among the most complex chemical reactions occurring in nature and contribute crucially to the tremendous structural diversity of this largest family of natural products. Many studies were conducted at the chemical, genetic, and biochemical levels to gain mechanistic insights into these intriguing reactions that are catalyzed by terpene and terpenoid cyclases. A myriad of these enzymes have been characterized. Classical textbook knowledge divides terpene/terpenoid cyclases into two major classes according to their structure and reaction mechanism. However, recent discoveries of novel types of terpenoid cyclases illustrate that nature's enzymatic repertoire is far more diverse than initially thought. This Review outlines novel terpenoid cyclases that are out of the ordinary.
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http://dx.doi.org/10.1002/anie.201407883DOI Listing
February 2015

Bioinspired total synthesis of sespenine.

Angew Chem Int Ed Engl 2014 Aug 24;53(34):9012-6. Epub 2014 Jun 24.

State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032 (China).

The first total synthesis of sespenine, a rare indole sesquiterpenoid from a mangrove endophyte, has been accomplished. A bioinspired aza-Prins/Friedel-Crafts/retro Friedel-Crafts cascade reaction assembles the bridged tetrahydroquinoline core. Further investigations on the aza-Prins cyclization imply that the C3 configuration of the hydroxyindolenine intermediate is crucial to the biosynthesis of sespenine and its congener xiamycin A.
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http://dx.doi.org/10.1002/anie.201404191DOI Listing
August 2014

Biosynthetic code for divergolide assembly in a bacterial mangrove endophyte.

Chembiochem 2014 Jun 27;15(9):1274-9. Epub 2014 May 27.

Department of Biomolecular Chemistry, Leibniz Institute for Natural Product Research and Infection Biology (HKI), Beutenbergstrasse 11a, 07745 Jena (Germany).

Divergolides are structurally diverse ansamycins produced by a bacterial endophyte (Streptomyces sp.) of the mangrove tree Bruguiera gymnorrhiza. By genomic analyses a gene locus coding for the divergolide pathway was detected. The div gene cluster encodes genes for the biosynthesis of 3-amino-5-hydroxybenzoate and the rare extender units ethylmalonyl-CoA and isobutylmalonyl-CoA, polyketide assembly by a modular type I polyketide synthase (PKS), and enzymes involved in tailoring reactions, such as a Baeyer-Villiger oxygenase. A detailed PKS domain analysis confirmed the stereochemical integrity of the divergolides and provided valuable new insights into the formation of the diverse aromatic chromophores. The bioinformatic analyses and the isolation and full structural elucidation of four new divergolide congeners led to a revised biosynthetic model that illustrates the formation of four different types of ansamycin chromophores from a single polyketide precursor.
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http://dx.doi.org/10.1002/cbic.201402071DOI Listing
June 2014

Regiodivergent N-C and N-N aryl coupling reactions of indoloterpenes and cycloether formation mediated by a single bacterial flavoenzyme.

Angew Chem Int Ed Engl 2013 Aug 10;52(34):9040-3. Epub 2013 Jul 10.

Dept. of Biomolecular Chemistry, Leibniz Institute for Natural Product Research and Infection Biology, HKI, Beutenbergstr. 11a, 07745 Jena, Germany.

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http://dx.doi.org/10.1002/anie.201303733DOI Listing
August 2013

Bacterial synthesis of diverse indole terpene alkaloids by an unparalleled cyclization sequence.

Angew Chem Int Ed Engl 2012 Oct 11;51(41):10293-7. Epub 2012 Sep 11.

Dept. of Biomolecular Chemistry, Leibniz Institute for Natural Product Research and Infection Biology, HKI, Beutenbergstrasse 11a, 07745 Jena, Germany.

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http://dx.doi.org/10.1002/anie.201204087DOI Listing
October 2012
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