Article
Chemistry, Multidisciplinary
Hui Tao, Takahiro Mori, Xingxing Wei, Yudai Matsuda, Ikuro Abe
Summary: This study investigated the biosynthesis mechanism of Calbistrins through heterologous and in vitro reconstitution, as well as a structural biological study. The analysis revealed that the decalin and polyene portions of Calbistrins are synthesized by the single PKS CalA, with the aid of the enzymes CalK and CalH. Additionally, the esterification of the two polyketide parts is catalyzed by the acyltransferase CalD, uncovering a novel dual-functional PKS and broadening the understanding of fungal synthesis of diverse polyketide natural products.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2021)
Article
Chemistry, Multidisciplinary
Andrew J. J. Devine, Alice E. E. Parnell, Catherine R. R. Back, Nicholas R. R. Lees, Samuel T. T. Johns, Ainul Z. Z. Zulkepli, Rob Barringer, Katja Zorn, James E. M. Stach, Matthew P. P. Crump, Martin A. A. Hayes, Marc W. W. van der Kamp, Paul R. R. Race, Christine L. L. Willis
Summary: This study reveals the key epoxidation reaction in the synthesis of Abyssomicin C and the structure of the enzyme AbyV involved in this reaction. The combination of selective carbon-13 labeling with NMR spectroscopy proves to be an important tool in studying enzyme-catalyzed reactions in vitro.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Chemistry, Multidisciplinary
Amy E. Fraley, Cora L. Dieterich, Mathijs F. J. Mabesoone, Hannah A. Minas, Roy A. Meoded, Franziska Hemmerling, Joern Piel
Summary: This study provides the first structural insights into a distinct group of TEs (TE(B)s) that have diverse acylation roles in polyketide and peptide biosynthesis. By analyzing and engineering the active site, the acyl-group acceptance can be modulated. Moreover, the production of longer chain branched oocydins was discovered, positioning this enzyme as a valuable synthetic biology tool for polyketide drug development.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2022)
Article
Biotechnology & Applied Microbiology
Guang-Lei Ma, Lingyi Xin, Yanghui Liao, Zhi-Soon Chong, Hartono Candra, Li Mei Pang, Sean Qiu En Lee, Martin Muthee Gakuubi, Siew Bee Ng, Zhao-Xun Liang
Summary: Angucyclines are structurally diverse, aromatic polyketides with potent bioactivity. The biosynthetic origin of their structural complexity and diversity has attracted considerable attention. In this study, a Streptomyces strain that produces balmoralmycin and related compounds was identified. The biosynthetic gene cluster for balmoralmycin was characterized, and a proposed biosynthetic pathway was established. The elucidation of the biosynthesis of balmoralmycin provides insights into the origin of structural diversity in angucyclines.
APPLIED AND ENVIRONMENTAL MICROBIOLOGY
(2022)
Article
Chemistry, Multidisciplinary
Shanchong Chen, Chi Zhang, Lihan Zhang
Summary: This study provides a global atlas of bacterial aromatic polyketides based on large-scale analysis of type II polyketide synthases. The chain length factor protein is identified as a marker that can predict the chemical class and molecular uniqueness of the biosynthetic product. The results serve as a compass for exploiting the entire type II polyketide synthase-derived aromatic polyketides in bacteria.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2022)
Article
Chemistry, Multidisciplinary
Franziska Hemmerling, Roy A. Meoded, Amy E. Fraley, Hannah A. Minas, Cora L. Dieterich, Michael Rust, Reiko Ueoka, Katja Jensen, Eric J. N. Helfrich, Cedric Bergande, Maurice Biedermann, Nancy Magnus, Birgit Piechulla, Joern Piel
Summary: In this study, a remarkably versatile trans-acyltransferase (trans-AT) PKS from Serratia was characterized, which builds structurally complex macrolides via over ten functionally distinct PKS modules. A new oxygenation module and a halogenating module were identified, along with modular O-acetylation.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2022)
Article
Chemistry, Multidisciplinary
Eveline Vriens, Dries De Ruysscher, Angus N. M. Weir, Sofie Dekimpe, Gert Steurs, Ahmed Shemy, Leentje Persoons, Ana Rita Santos, Christopher Williams, Dirk Daelemans, Matthew P. Crump, Arnout Voet, Wim De Borggraeve, Eveline Lescrinier, Joleen Masschelein
Summary: In this study, the oximidine gene cluster was identified in Pseudomonas baetica, and four novel oximidine variants were characterized, including a structurally simpler intermediate. Through a combination of in vivo, in vitro, and computational approaches, the biosynthetic pathway of oximidine and an unprecedented mechanism for O-methyloxime formation were experimentally elucidated, expanding the catalytic capabilities of trans-AT PKSs and identifying potential strategies for the production of novel oximidine analogues.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Chemistry, Organic
Graham A. Hudson, Annie R. Hooper, Adam J. DiCaprio, David Sarlah, Douglas A. Mitchell
Summary: The study successfully identified and synthesized a new class of natural products, named pyritides, using a combination of bioinformatics, enzymology, and synthetic methods. These pyritides have a unique structure distinct from thiopeptides, with predicted enzymatic reactions leading to the formation of a trisubstituted pyridine-based macrocycle. The research demonstrates the potential of integrating bioinformatics, enzymology, and synthesis to characterize novel natural product scaffolds with interesting structural features and biological activities.
Article
Chemistry, Organic
Haolin Qiu, Yang Xiao, Ling Shen, Tao Han, Qiang He, Aiying Li, Peng Zhang, Xiaofeng Cai
Summary: By expressing the multimodular NRPS gene sefA from Serratia fonticola DSM 4576 in E. coli, four new serrawettin W2 analogues, named sefopeptides A-D, were isolated and structurally characterized. Sefopeptide C exhibited moderate cytotoxic activity against acute promyelocytic leukemia NB4 cells.
ORGANIC & BIOMOLECULAR CHEMISTRY
(2023)
Article
Chemistry, Multidisciplinary
Kevin Becker, Sebastian Pfutze, Eric Kuhnert, Russell J. Cox, Marc Stadler, Frank Surup
Summary: The study investigated the diversity of azaphilones in stromatal extracts of the fungus Hypoxylon fragiforme and linked them to their biosynthetic machineries through bioinformatics. It identified four unprecedented bis-azaphilones and a hybrid azaphilone with strong inhibition of Staphylococcus aureus biofilm formation. Genome analysis revealed two separate biosynthetic gene clusters responsible for azaphilone formation, representing the first example of distant cross-acting fungal BGCs collaborating to produce different families of azaphilones.
CHEMISTRY-A EUROPEAN JOURNAL
(2021)
Article
Biochemistry & Molecular Biology
Yanan Du, Anyarat Thanapipatsiri, Kenichi Yokoyama
Summary: Nucleoside natural products have diverse biological activities and can be used for various applications, including medicine and agriculture. Previous studies have revealed the biosynthetic mechanisms of these nucleosides, involving early steps classified into two types and downstream tailoring enzymes for structural diversity. By investigating two enzymes representing these types of modifications, it is possible to discover putative nucleoside biosynthetic gene clusters and predict core nucleoside structures, suggesting the potential for future discovery of novel nucleoside natural products.
Article
Chemistry, Multidisciplinary
Hannah. A. A. Minas, Romain M. M. Francois, Franziska Hemmerling, Amy. E. E. Fraley, Cora. L. L. Dieterich, Simon. H. H. Ruedisser, Roy. A. A. Meoded, Sabrina Collin, Kira. J. J. Weissman, Arnaud Gruez, Jorn Piel
Summary: Modular trans-acyltransferase polyketide synthases (trans-AT PKSs) are enzymatic assembly lines that introduce remarkable chemical diversity into their polyketide products. This study focuses on the lobatamide A PKS, which incorporates a methylated oxime. By analyzing the structure and mutagenesis of the oxygenase, the authors propose a catalysis model and identify key protein-protein interactions. This work expands the biomolecular toolbox for trans-AT PKS engineering and enables the introduction of masked aldehyde functionalities into diverse polyketides.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Chemistry, Multidisciplinary
Cedric Couturier, Sebastian Gross, Alexander von Tesmar, Judith Hoffmann, Selina Deckarm, Anouchka Fievet, Nelly Dubarry, Thomas Taillier, Christoph Poeverlein, Heike Stump, Michael Kurz, Luigi Toti, Sabine Haag Richter, Dietmar Schummer, Philippe Sizun, Michael Hoffmann, Ram Prasad Awal, Nestor Zaburannyi, Kirsten Harmrolfs, Joachim Wink, Emilie Lessoud, Thierry Vermat, Veronique Cazals, Sandra Silve, Armin Bauer, Michael Mourez, Laurent Fraisse, Corinne Leroi-Geissler, Astrid Rey, Stephanie Versluys, Eric Bacque, Rolf Mueller, Stephane Renard
Summary: This article describes the myxobacterial natural product Corramycin isolated from Corallococcus coralloides. Corramycin exhibits anti-Gram-negative activity against Escherichia coli and is taken up via two transporter systems. The biosynthetic gene cluster (BGC) of Corramycin was identified and a biosynthesis model was proposed. The absolute configuration of the molecule was elucidated through bioinformatic analysis and total synthesis. Animal experiments confirmed the antibacterial effect of Corramycin.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2022)
Article
Biochemistry & Molecular Biology
Aileen Ute Geers, Yannick Buijs, Mikael Lenz Strube, Lone Gram, Mikkel Bentzon-Tilia
Summary: As we approach the post-antibiotic era, the need for new antimicrobial compounds is urgent. Microorganisms have been a rich source of antibiotics, but the rediscovery of known antibiotics and the limited accessibility of most microorganisms in the environment have prompted the exploration of natural microbial communities using novel approaches. This review discusses how sequence-based analyses have revealed the abundant potential for secondary metabolite production in soil, marine, and host-associated microbiomes, with a focus on non-ribosomal peptides and polyketides. However, the complexity of natural microbiomes and the lack of standardized methodology pose challenges in comparing different biomes. Nevertheless, even commonly sampled microbiomes hold promise for discovering novel natural products, and the development of approaches to harness the vast biosynthetic diversity of natural microbiomes for the procurement of new antibiotics is discussed.
COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL
(2022)
Article
Chemistry, Organic
Guangwei Wu, Xuan Qian, Yeqiang Huang, Yujia Liu, Luning Zhou, Wei Wang, Jing Li, Tianjiao Zhu, Qianqun Gu, Dehai Li
Summary: A nonenzymatic self-assembly program was used to synthesize 14 clavatol-based pseudonatural products (PNPs), including two compounds with a novel structure that exhibited cytotoxicity. This study demonstrates the significance of this program in constructing bioactive PNPs.
Article
Biochemistry & Molecular Biology
Akimasa Miyanaga, Koichi Kawada, Taichi Chisuga, Fumitaka Kudo, Tadashi Eguchi
Summary: This study presents the crystal structure of a covalent VinK-VinP1ACP(L) complex, providing detailed insights into the transient interactions between VinK and VinP1ACP(L) and elucidating the mechanism of this binding. Site-directed mutational analyses confirmed the importance of residues in the binding interface. The ACP orientation and interaction mode observed in the VinK-VinP1ACP(L) complex differ from those observed in other AT-ACP complexes.
Article
Biochemistry & Molecular Biology
Fumitaka Kudo, Kosuke Kishikawa, Kazuma Tsuboi, Takafusa Kido, Takeo Usui, Junko Hashimoto, Kazuo Shin-ya, Akimasa Miyanaga, Tadashi Eguchi
Summary: In this study, the biosynthetic gene cluster for virustomycin A, an antibiotic produced by Streptomyces graminofaciens A-8890, was identified. The study also demonstrated the exchangeability of the acyltransferase domain between the PKSs involved in FD-891 biosynthesis and the Vsm PKSs. By exchanging the malonyltransferase domain in the loading module of the PKSs, a two-carbon-elongated analog 26-ethyl-FD-891 was successfully produced with potent cytotoxic activity.
Article
Biochemistry & Molecular Biology
Ippei Watanabe, Akimasa Miyanaga, Hirotaka Hoshi, Kiyoshi Suzuki, Tadashi Eguchi
Summary: O-sulfated N-acetyl-d-galactosamine residues in chondroitin sulfate play a crucial role in the activity of chondroitinase ABC I. Chondroitin sulfate E, containing mainly 4,6-O-disulfated GalNAc, is resistant to enzyme digestion and attenuates the enzyme activity. The interaction between the disulfated GalNAc residues and the enzyme seems to interfere with its function, resulting in reduced reactivity.
Article
Biochemistry & Molecular Biology
Taichi Chisuga, Satoshi Murakami, Akimasa Miyanaga, Fumitaka Kudo, Tadashi Eguchi
Summary: KSQ domains are found in the loading modules of modular type I polyketide synthases (PKSs) and are responsible for decarboxylation. In this study, the authors investigated the interactions between the KSQ domain and the acyl carrier protein (ACP) in the GfsA loading module. They determined the crystal structure of the GfsA KSQ-acyltransferase (AT) didomain in complex with ACP and identified key amino acid residues involved in the interactions. The findings provide important insights into the recognition mechanism and overall architecture of type I PKS modules.
ACS CHEMICAL BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Fumitaka Kudo, Takuji Chikuma, Mizuki Nambu, Taichi Chisuga, Shimpei Sumimoto, Arihiro Iwasaki, Kiyotake Suenaga, Akimasa Miyanaga, Tadashi Eguchi
Summary: In this study, we analyzed the genome sequence of Moorena bouillonii, a marine cyanobacterium that produces lyngbyapeptin B, and identified a gene cluster responsible for its biosynthesis. We characterized two unique enzymatic activities: O-methylation by LynB2 and oxidative decarboxylation by LynB7. These findings provide insights into the biosynthetic mechanisms of lyngbyapeptin B.
ACS CHEMICAL BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Akimasa Miyanaga, Kenji Nagata, Joji Nakajima, Taichi Chisuga, Fumitaka Kudo, Tadashi Eguchi
Summary: Adenylation enzymes activate amino acid substrates and transfer them onto carrier proteins for selective incorporation in natural product biosynthesis. VinM, an amide-forming adenylation enzyme, transfers an l-alanyl group onto the amino group of the aminoacyl unit attached to the carrier protein VinL in vicenistatin biosynthesis. Structural and biochemical analyses reveal that interactions with both the phosphopantetheine arm and VinL are critical for VinM's amide-forming activity.
ACS CHEMICAL BIOLOGY
(2023)
