Article
Chemistry, Multidisciplinary
Lukas Kahlert, Miranda Villanueva, Russell J. Cox, Elizabeth J. Skellam
Summary: The polyketide synthase-like protein TerB, with inactive dehydratase, inactive C-methyltransferase, and functional ketoreductase domains, collaborates with TerA to produce 6-hydroxymellein, a key intermediate in the biosynthesis of fungal natural products. The catalytically inactive dehydratase domain of TerB interacts productively with TerA in a new mode of trans-interaction between iterative PKS components.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2021)
Article
Chemistry, Multidisciplinary
Xiaoli Yan, Jun Zhang, Hongqun Tan, Zhihao Liu, Kai Jiang, Wenya Tian, Mengmeng Zheng, Zhi Lin, Zixin Deng, Xudong Qu
Summary: This study reveals a novel polyketide synthase system involving two unique KAS IIIs in the synthesis of asukamycin. These KAS IIIs exhibit initiation and iterative elongation activity and functionally biased towards different steps. By cooperating with other enzymes, various polyenes can be efficiently synthesized.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2022)
Article
Biochemistry & Molecular Biology
Yanghui Liao, Xue-Jiao Wang, Guang-Lei Ma, Hartono Candra, Sean Lee Qiu En, Srashti Khandelwal, Zhao-Xun Liang
Summary: This study found that sub-inhibitory concentrations of streptomycin induced the production of octacosamicin A in Amycolatopsis azurea DSM 43854T. The biosynthetic gene cluster (oca BGC) encoding a modular polyketide synthase (PKS) system for assembling the polyene-polyol chain of octacosamicin A was identified. The analysis suggested an unconventional and cryptic off-loading mechanism that attaches glycine to the polyene-polyol chain via an intermolecular amidation reaction.
Article
Chemistry, Multidisciplinary
Junya Takino, Akari Kotani, Taro Ozaki, Wenquan Peng, Jie Yu, Yian Guo, Susumu Mochizuki, Kazuya Akimitsu, Masaru Hashimoto, Tao Ye, Atsushi Minami, Hideaki Oikawa
Summary: Highly reducing polyketide synthases (HR-PKSs) are responsible for the production of structurally diverse polyketides (PKs) through a complex stereochemical process. By examining the synthesis of polyhydroxy PKs, researchers were able to determine the absolute configurations of stereogenic centers using chemical degradation and comparison with synthetic standards. This study proposes a stereochemical rule to explain the absolute configurations of reduced PKs and highlights discrepancies in previously reported structures.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2021)
Article
Microbiology
Kyung Taek Heo, Byeongsan Lee, Gwi Ja Hwang, Beomcheol Park, Jun-Pil Jang, Bang Yeon Hwang, Jae-Hyuk Jang, Young-Soo Hong
Summary: This study describes the biosynthesis of C2 moieties in Streptomyces sp. W2061, providing important information for understanding the incorporation of atypical primer units into polyketide products.
FRONTIERS IN MICROBIOLOGY
(2023)
Article
Genetics & Heredity
Christina M. McBride, Eric L. Miller, Louise K. Charkoudian
Summary: Nature provides a wide range of molecules with diverse chemical characteristics, known as natural products, which have various applications in the environment, medicine, and industry. Type II polyketides, produced by enzyme assemblies called polyketide synthases, have significant medicinal benefits including antimicrobial, antifungal, anticancer, and anti-inflammatory properties. A novel bioinformatic workflow was used in this study to identify biosynthetic gene clusters that code for the core enzymes of type II polyketide synthases. Over 6000 putative type II polyketide synthases were identified, many of which were found in non-actinobacteria, expanding the potential sources for these compounds. This work sets an important foundation for future bioprospecting and engineering efforts to access structurally complex molecules with medicinal properties.
MICROBIAL GENOMICS
(2023)
Article
Multidisciplinary Sciences
Saket R. Bagde, Irimpan I. Mathews, J. Christopher Fromme, Chu-Young Kim
Summary: Type I modular polyketide synthases are enzymes that synthesize a variety of polyketide natural products by performing polyketide chain extension and b-keto group modification reactions. The structures of Lsd14 polyketide synthase revealed the positioning of constituent domains, rearrangement depending on the reaction cycle step, and specific interactions formed between domains. Lsd14 contains two reaction chambers, but only one chamber has the full complement of catalytic domains producing the polyketide product at any given time.
Article
Microbiology
Ram Prasad Awal, Patrick A. Haack, Chantal D. Bader, Cornelius N. Riese, Dirk Schueler, Rolf Mueller
Summary: Genomic analysis of magnetotactic bacteria revealed a potential source of bioactive natural products beyond their magnetosome formation ability, with the discovery of a novel polyketide sesbanimide R in Magnetospirillum gryphiswaldense. The structure of sesbanimide R, which exhibits cytotoxic activity against carcinoma cell lines, suggests a previously unexplored diversity in secondary metabolites from magnetotactic bacteria with potential for future discoveries in this field.
Article
Biotechnology & Applied Microbiology
Lilu Liu, Wenzhao Wang, Meng Chen, Yuwei Zhang, Huijin Mao, Dacheng Wang, Yihua Chen, Pengwei Li
Summary: Polyketides are a class of natural products known for their structural diversities, biological activities, and numerous applications. This study identified three acyltransferases (ATs) responsible for introducing succinyl units into the polyketide chain assembly. These ATs enrich the toolbox of polyketide biosynthetic enzymes and provide a foundation for incorporating succinyl units into polyketide backbones using synthetic biological approaches.
APPLIED MICROBIOLOGY AND BIOTECHNOLOGY
(2023)
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)
Review
Biochemistry & Molecular Biology
Ariana Sulpizio, Callie E. W. Crawford, Rebecca S. Koweek, Louise K. Charkoudian
Summary: Type II polyketide synthases (PKSs) are protein assemblies that manufacture complex molecules with the help of acyl carrier proteins (ACPs). Understanding the dynamics and interactions of ACPs is crucial for redesigning type II PKSs. By utilizing chemical probes and molecular dynamic simulations, insights into the structure and function of type II PKS ACPs can be gained, potentially unlocking new biosynthetic potential.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Sarah Bonhomme, Carlos Contreras-Martel, Andrea Dessen, Pauline Macheboeuf
Summary: The genotoxin colibactin produced by Escherichia coli is involved in the development of colorectal cancers. In this study, we characterized the structure of the ClbK megaenzyme, which is responsible for the synthesis of colibactin. We found that the ClbK enzyme is a hybrid of PKS-NRPS and has specific structural features. These findings provide insights into the transfer of colibactin precursors and can potentially be used to engineer hybrid enzymes for the generation of diverse metabolites.
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
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
Microbiology
Martin Muthee Gakuubi, Kuan Chieh Ching, Madhaiyan Munusamy, Mario Wibowo, Chun Teck Lim, Guang-Lei Ma, Zhao-Xun Liang, Yoganathan Kanagasundaram, Siew Bee Ng
Summary: Lophiotrema is a genus of fungi that can be found in various host plants and plant debris. One member of this genus, Lophiotrema sp. F6932, was isolated from white mangrove in Singapore and exhibited strong antibacterial activity. Through genome sequencing and gene editing, the involvement of a specific gene in the biosynthesis of bioactive compounds from this fungus was confirmed, providing a potential approach for studying other gene clusters in this understudied fungal strain.
FRONTIERS IN MICROBIOLOGY
(2022)
Article
Biotechnology & Applied Microbiology
D. Moeller, S. Kushnir, M. Grote, A. Ismail-Ali, K. R. M. Koopmans, F. Calo, S. Heinrich, B. Diehl, F. Schulz
LETTERS IN APPLIED MICROBIOLOGY
(2018)
Article
Biochemistry & Molecular Biology
Michael Dirkmann, Julia Nowack, Frank Schulz
Article
Biochemistry & Molecular Biology
Marius Grote, Frank Schulz
Article
Biochemistry & Molecular Biology
Xiaohua Zhang, Fei Chen, Alessandro Petrella, Franklin Chacon-Huete, Jason Covone, Teng-Wei Tsa, Ching-Ching Yu, Pat Forgione, David H. Kwan
ACS CHEMICAL BIOLOGY
(2019)
Article
Biochemical Research Methods
Laura M. Y. Leclerc, Guy Soffer, David H. Kwan, Steve C. C. Shih
Article
Biochemistry & Molecular Biology
Maxim Soroko, David H. Kwan
Article
Biochemistry & Molecular Biology
F. Ifthiha Mohideen, Lan Huong Nguyen, Joel D. Richard, Sara Ouadhi, David H. Kwan
Summary: Many small molecule natural products rely on sugar moieties for their biological activity. In this study, the biosynthesis of dTDP-L-daunosamine, an essential sugar moiety in the anticancer drugs daunorubicin and doxorubicin, was investigated. By reconstituting the enzymes involved in the biosynthetic pathway, the authors gained insights into the assembly of this precursor and identified a bottleneck and competing reactions. Kinetic analysis was performed to understand a limiting step in the pathway. The study also demonstrated the potential for enzymatic synthesis of nucleotide-activated sugars with tailored properties, opening up possibilities for the glycodiversification of natural products.
ACS CHEMICAL BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Sascha Heinrich, Marius Grote, Sonja Sievers, Susanna Kushnir, Frank Schulz
Summary: This study reveals the substrate promiscuity of the polyether cyclization cascade enzymes in monensin biosynthesis, demonstrating their remarkable flexibility in acting on derivatized polyketide backbones to produce altered polyether structures.
Article
Biochemical Research Methods
Mohamed A. Nasr, Logan R. Timmins, Vincent J. J. Martin, David H. Kwan
Summary: Allosteric transcription factor (aTF) biosensors are valuable tools for engineering microbes, and the limited identified and characterized aTFs can be overcome through extensive bioprospecting and aTF ligand-specificity engineering. In this study, aTF genetic circuits functioning as salicylate biosensors were constructed using the CmeR protein from Campylobacter jejuni, and their responsiveness to multiple inducers was demonstrated.
ACS SYNTHETIC BIOLOGY
(2022)
Review
Biochemistry & Molecular Biology
Sara Ouadhi, Dulce Maria Valdez Lopez, F. Ifthiha Mohideen, David H. Kwan
Summary: Glycosylated small molecule natural products and glycoprotein biologics have important applications in therapy and industry. Controlling their glycosylation is valuable, and enzyme engineering strategies have been developed to address limitations in catalytic efficiency, substrate specificity, regiospecificity, stereospecificity, and stability. Recent research has focused on engineering enzymes to tailor glycosylation of small molecule natural products and protein biologics.
PROTEIN ENGINEERING DESIGN & SELECTION
(2023)
Article
Biochemistry & Molecular Biology
Mohamed A. Nasr, Vincent J. J. Martin, David H. Kwan
Summary: Reprogramming cellular behavior is a key aspect of synthetic biology, and in this study, researchers developed a biosensor that can respond to specific compounds using a modified transcription factor. Through iterative evolution, they also identified new inducer specificities and successfully transferred these engineered transcription factors into yeast. This research provides a framework for efficiently engineering synthetic transcription factors and has broad applications in protein and metabolic engineering, as well as diagnostics.
NUCLEIC ACIDS RESEARCH
(2023)
Article
Behavioral Sciences
Jasmin Obermanns, Hanna Meiser, Saskia Hoberg, Cynthia Segura Vesterager, Frank Schulz, Georg Juckel, Barbara Emons
Summary: This study found higher concentrations of AEA and decreased concentrations of 2-AG in patients with depression compared to healthy participants. Lower concentrations of 2-AG were correlated with higher levels of anxiety symptoms. Male patients had increased concentrations of 2-AG, while female patients had increased anxiety symptoms. Genotypic variations of 5-HT1A rs6295 and 5-HT2A rs6311 were associated with altered serotonergic activity and serotonin content in patients.
BRAIN AND BEHAVIOR
(2023)
Article
Chemistry, Multidisciplinary
Daniel P. Demarque, Sascha Heinrich, Frank Schulz, Christian Merten
CHEMICAL COMMUNICATIONS
(2020)
Article
Chemistry, Organic
Marius Grote, Susanna Kushnir, Niclas Pryk, David Moeller, Julian Erver, Ahmed Ismail-Ali, Frank Schulz
ORGANIC & BIOMOLECULAR CHEMISTRY
(2019)
Article
Biochemistry & Molecular Biology
Michael Dirkmann, Javier Iglesias-Fernandez, Victor Munoz, Pandian Sokkar, Christoph Rumancev, Andreas von Gundlach, Oktavian Krenczyk, Tobias Voepel, Julia Nowack, Martin A. Schroer, Simon Ebbinghaus, Christian Herrmann, Axel Rosenhahn, Elsa Sanchez-Garcia, Frank Schulz