Article
Chemistry, Multidisciplinary
Nikolai A. Loehr, Frederic Eisen, Wiebke Thiele, Lukas Platz, Jonas Motter, Wolfgang Huettel, Markus Gressler, Michael Mueller, Dirk Hoffmeister
Summary: This study describes an unprecedented class of non-reducing polyketide synthases (NR-PKS) that can synthesize octaketide pigments. The researchers identified CoPKS1 and CoPKS4 of the mushroom genus Cortinarius as new atrochrysone carboxylic acid synthases. These findings illustrate how the biosynthesis of bioactive metabolites evolved independently in different groups of organisms.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2022)
Article
Multidisciplinary Sciences
Aleksandra Nivina, Sur Herrera Paredes, Hunter B. Fraser, Chaitan Khosla
Summary: A genetic element named GRINS has been found in assembly-line PKS genes, potentially accelerating the diversification of related biosynthetic clusters, especially prevalent in the actinobacterial genus Streptomyces.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Microbiology
Qingpei Liu, Dan Zhang, Yao Xu, Shuaibiao Gao, Yifu Gong, Xianhua Cai, Ming Yao, Xiaolong Yang
Summary: This study reported the genome sequence information of the endophytic fungus Preussia isomera and discovered two novel polyketide synthases (PKSs) for synthesizing orsellinic acid derivatives. A non-native PKS was also constructed for the large-scale biosynthesis of orsellinic acid. This work provides valuable insights into the biosynthesis of PKs in P. isomera and offers a new platform for the production of high-level environment-friendly orsellinic acid derivatives and the development of new antimicrobial agents.
FRONTIERS IN MICROBIOLOGY
(2022)
Review
Chemistry, Multidisciplinary
Jacque L. Faylo, Trey A. Ronnebaum, David W. Christianson
Summary: The chemodiversity of terpenoid natural products is largely attributed to the catalysis of prenyltransferases and cyclases, which generate complex hydrocarbon compounds through chain elongation reactions. Terpene cyclization reactions are characterized by changes in chemical bonding of substrate carbon atoms, with different classes of cyclases based on the chemistry of carbocation formation.
ACCOUNTS OF CHEMICAL RESEARCH
(2021)
Review
Biochemistry & Molecular Biology
Russell J. Cox
Summary: Investigations over the past two decades have provided insights into the programming of fungal iterative highly-reducing polyketide synthases. Both in vitro and in vivo experiments have revealed the interaction between intrinsic and extrinsic selectivity of the catalytic domains in these systems. Structural biology has started to provide high resolution structures of hr-PKS that can be utilized for their engineering, although progress in this field is still at an early stage. However, there are significant opportunities to use the current understanding to reengineer these efficient systems for the production of important biologically active compounds through biotechnology.
NATURAL PRODUCT REPORTS
(2023)
Article
Biotechnology & Applied Microbiology
Rong Chen, Tianyuan Hu, Ming Wang, Yuhan Hu, Shu Chen, Qiuhui Wei, Xiaopu Yin, Tian Xie
Summary: This study analyzed the metabolites of Curcuma wenyujin's leaf and tuber tissues, identifying 11 curcuminoid metabolites and revealing the biosynthesis pathway. Two candidate type III polyketide synthases (PKSs) were identified, with CwPKS1 being the first one capable of synthesizing hydrogenated derivatives of curcuminoids. Notably, a mutation (G219D) resulted in the complete inactivation of CwPKS1.
SYNTHETIC AND SYSTEMS BIOTECHNOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Shreya Kishore, Chaitan Khosla
Summary: By mining genomic data from the NCBI database, this study presents an updated catalogue of 8799 non-redundant assembly line polyketide synthase clusters across 4083 species, showing a threefold increase in the past 4 years. Furthermore, 95% of the clusters are 'orphan clusters' with no known chemical or biological characterization. These findings suggest that the diversity of assembly line PKSs remains largely unexplored and highlight the potential of genomics-driven approaches for natural product discovery.
Article
Biotechnology & Applied Microbiology
Jie Zhang, Ramesh Bista, Takeshi Miyazawa, Adrian T. Keatinge-Clay
Summary: By attenuating the strength of T7 promoter and increasing the concentration of propionate, the productivity of modular polyketide synthases was significantly improved, providing a more efficient approach for the synthesis of designer polyketides and commodity chemicals.
METABOLIC ENGINEERING
(2023)
Article
Biochemistry & Molecular Biology
Zeping Cai, Xingkun Zhao, Chaoye Zhou, Ting Fang, Guodao Liu, Jiajia Luo
Summary: In this study, we identified 3087 tandem duplicated genes in the S. tora genome and found 14 PKS genes involved in secondary metabolite pathways. Through phylogenetic analysis, we classified the PKS genes into three groups and identified seven genes with high expression in the seeds, which may be associated with the biosynthesis of anthraquinones.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Genetics & Heredity
Ramanujam Pothiraj, Manohar Jebakumar Ravikumar, Backiyarani Suthanthiram, Uma Subbaraya, Panneerselvam Krishnamurthy
Summary: The study conducted comparative analyses of banana genomes, revealing certain PKS genes with higher expression in various parts of banana and showing defense response after hormone treatments. Through analysis, most promising candidate genes were selected for flavonoid, phenylphenalenone, and sporopollenin biosynthesis in banana.
Article
Biochemistry & Molecular Biology
Wachiraporn Toopaang, Kullyanee Panyawicha, Chettida Srisuksam, Wei-Chen Hsu, Ching-Chih Lin, Morakot Tanticharoen, Yu-Liang Yang, Alongkorn Amnuaykanjanasin
Summary: This study investigated the metabolite profiles of pks14 and pks15 gene overexpression strains in B. bassiana and compared them to their knockout strains using LC-MS/MS with GNPS. The results showed that pks14 and pks15 clusters interacted with biosynthetic clusters encoding insect-virulent metabolites and upregulated certain secondary metabolites. This suggests that pks14 and pks15 may be directly or indirectly associated with key pathways in insect pathogenesis of B. bassiana.
Review
Biochemistry & Molecular Biology
Shengling Xie, Lihan Zhang
Summary: Bioinformatics has become an essential tool in natural products research, particularly in converting sequence data of biosynthetic gene clusters into chemical information. Type II polyketide synthase, a well-studied class of non-modular biosynthetic machinery, serves as a model system to demonstrate the applications of bioinformatics in this field. This review highlights the contributions of bioinformatics in enhancing the understanding of type II polyketide synthases in terms of enzymology, evolution, structural prediction of biosynthetic products, genome mining, and global analysis of polyketide products.
Article
Biochemical Research Methods
Matthias Schmidt, Namil Lee, Chunjun Zhan, Jacob B. Roberts, Alberto A. Nava, Leah S. Keiser, Aaron A. Vilchez, Yan Chen, Christopher J. Petzold, Robert W. Haushalter, Lars M. Blank, Jay D. Keasling
Summary: In this study, the influence of 11 different codon variants on heterologous expression was analyzed. The best-performing codon variants resulted in a 50-fold increase in protein levels and successful synthesis of unnatural polyketides in different hosts. Additionally, an online tool for codon optimization was developed.
ACS SYNTHETIC BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Maybelle Kho Go, Tingting Zhu, Kevin Jie Han Lim, Yossa Dwi Hartono, Bo Xue, Hao Fan, Wen Shan Yew
Summary: We have discovered enzymes from the berberine bridge enzyme (BBE) superfamily that can catalyze the oxidative cyclization of the monoterpene moiety in cannabigerolic acid (CBGA) to form cannabielsoin (CBE). These previously uncharacterized enzymes were found in various organisms. Among 232 homologues chosen from the enzyme superfamily, four orthologues were identified to accept CBGA as a substrate and catalyze the biosynthesis of CBE. The recombinantly expressed and purified enzymes, obtained from Pichia pastoris, are the first reported heterologous expression of BBEs that can produce cannabinoids using CBGA as a substrate. This study presents a novel approach for the discovery and production of natural and unnatural cannabinoids.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Melina Shamshoum, Filipe Natalio
Summary: Glycosyltransferases (GTs) are important enzymes that catalyze the formation of glycosidic bonds between donor and acceptor molecules. In this study, it was found that bacterial cellulose and chitin synthases share a conserved active site motif, despite their low sequence and structural similarities. This discovery challenges the current understanding that these enzymes are substrate specific, and opens up new possibilities for future experimental assessments.
Article
Biochemistry & Molecular Biology
Jian-Jun Jia, Roni M. Lahr, Michael T. Solgaard, Bruno J. Moraes, Roberta Pointet, An-Dao Yang, Giovanna Celucci, Tyson E. Graber, Huy-Dung Hoang, Marius R. Niklaus, Izabella A. Pena, Anne K. Hollensen, Ewan M. Smith, Malik Chaker-Margot, Leonie Anton, Christopher Dajadian, Mark Livingstone, Jaclyn Hearnden, Xu-Dong Wang, Yonghao Yu, Timm Maier, Christian K. Damgaard, Andrea J. Berman, Tommy Alain, Bruno D. Fonseca
Summary: The study reveals that mTORC1 controls TOP mRNA translation repression activity through phosphorylating LARP1, with some residues being especially sensitive to rapamycin. This phosphorylation affects the RNA-binding and translation inhibitory activities of LARP1, providing insights into a new model of translation control involving differentially regulated regions of LARP1.
NUCLEIC ACIDS RESEARCH
(2021)
Article
Chemistry, Medicinal
Tihomir Tomasic, Said Rabbani, Roman P. Jakob, Andreas Reisner, Ziga Jakopin, Timm Maier, Beat Ernst, Marko Anderluh
Summary: Bacterial resistance poses a significant challenge in treating urinary tract infections, and targeting the lectin FimH of uropathogenic E. coli with antiadhesive methods may be a promising approach. A novel series of FimH antagonists based on the 1-(alpha-D-mannopyranosyl)-4-phenyl-1,2,3-triazole scaffold have shown improved binding affinities, suggesting potential new strategies for combating bacterial resistance.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Raphael Boehm, Stefan Imseng, Roman P. Jakob, Michael N. Hall, Timm Maier, Sebastian Hiller
Summary: The study reveals that mTORC1 achieves hierarchical phosphorylation of 4E-BP1 through specific interactions, facilitating efficient activation of translation. Furthermore, mTORC1 is capable of recognizing both free and eIF4E-bound 4E-BP1, enabling rapid phosphorylation of the entire 4E-BP1 pool.
Article
Multidisciplinary Sciences
Hundeep Kaur, Roman P. Jakob, Jan K. Marzinek, Robert Green, Yu Imai, Jani Reddy Bolla, Elia Agustoni, Carol Robinson, Peter J. Bond, Kim Lewis, Timm Maier, Sebastian Hiller
Summary: Developing new antibiotics that target Gram-negative bacteria is crucial for addressing the antimicrobial resistance crisis. Through studying the mode of action of darobactin at the atomic level, it was revealed that darobactin can bind to the lateral gate of BamA with superior ability, highlighting the lateral gate as a functional hotspot in BamA.
Review
Biochemistry & Molecular Biology
Stefania Battaglioni, Don Benjamin, Matthias Waelchli, Timm Maier, Michael N. Hall
Summary: The target of rapamycin (TOR), a highly conserved serine/threonine protein kinase, plays a central role in regulating cell growth and metabolism by responding to nutrients, growth factors, and cellular energy. Forming two distinct complexes, TORC1 and TORC2, TOR signaling activates cell growth by stimulating anabolic metabolism and inhibiting catabolic processes. This comprehensive review focuses on mammalian TOR (mTOR) and discusses the phosphorylation of different substrates by mTORC1 and mTORC2, despite sharing a common catalytic subunit. The conclusion is that these two complexes recruit different substrates to phosphorylate a common, minimal motif.
Article
Biochemistry & Molecular Biology
Malik Chaker-Margot, Sebastiaan Werten, Theresia Dunzendorfer-Matt, Stefan Lechner, Angela Ruepp, Klaus Scheffzek, Timm Maier
Summary: This study reveals the structural features and activation mechanism of neurofibromin, providing important insights into disease-causing mutations and cancer susceptibility. The findings suggest a role for nucleotides in the regulation of neurofibromin, and may lead to new therapeutic approaches for modulating the Ras signaling pathway.
Article
Biochemistry & Molecular Biology
Inayathulla Mohammed, Kai A. Schmitz, Niko Schenck, Dimitrios Balasopoulos, Annika Topitsch, Timm Maier, Jan Pieter Abrahams
Summary: The mitochondrial Lon protease, LonP1, plays a crucial role in maintaining mitochondrial health by removing redundant proteins from the mitochondrial matrix. Cryo-EM analysis revealed eight nucleotide-dependent conformational states of LonP1. The study also showed how sequential ATP hydrolysis controls the translocation of substrate proteins in a 6-fold binding change mechanism.
Article
Microbiology
Ryan D. Miller, Akira Iinishi, Seyed Majed Modaresi, Byung-Kuk Yoo, Thomas D. Curtis, Patrick J. Lariviere, Libang Liang, Sangkeun Son, Samantha Nicolau, Rachel Bargabos, Madeleine Morrissette, Michael F. Gates, Norman Pitt, Roman P. Jakob, Parthasarathi Rath, Timm Maier, Andrey G. Malyutin, Jens T. Kaiser, Samantha Niles, Blake Karavas, Meghan Ghiglieri, Sarah E. J. Bowman, Douglas C. Rees, Sebastian Hiller, Kim Lewis
Summary: This study uses computational search to identify a novel peptide antibiotic called dynobactin A, which is effective in killing Gram-negative bacteria. Dynobactin A targets BamA, a protein involved in the outer membrane insertion of Gram-negative species. The study demonstrates the utility of computational approaches in antibiotic discovery and suggests dynobactin A as a promising lead for drug development.
NATURE MICROBIOLOGY
(2022)
Article
Multidisciplinary Sciences
Yves U. Tittes, Dominik A. Herbst, Solene F. X. Martin, Hugo Munoz-Hernandez, Roman P. Jakob, Timm Maier
Summary: Polyketide synthases (PKSs) are microbial biosynthetic enzymes that can assemble potent bioactive natural products. The modular architecture of PKS assembly lines plays a crucial role in substrate transfer and enzyme sequestration.
Article
Biochemistry & Molecular Biology
Lei Zhang, Marina Toplak, Raspudin Saleem-Batcha, Lars Hoeing, Roman Jakob, Nico Jehmlich, Martin von Bergen, Timm Maier, Robin Teufel
Summary: Antimicrobial resistance is a serious threat to human health, and understanding the underlying mechanisms is crucial. This study discovered and characterized oxidoreductases that inactivate the broad-spectrum antibiotic chloramphenicol through dual oxidation of the C3-hydroxyl group. These enzymes also enable the inactivation of related compounds but not the fluorinated derivative. Phylogenetic analyses suggest that distinct isofunctional enzymes evolved independently in Gram-positive and Gram-negative bacteria. Mechanistic and structural studies provide insights into the catalytic mechanisms of these enzymes, which have both negative and positive impacts on antibiotic resistance and chloramphenicol bioremediation.
Article
Biology
Mitsugu Shimobayashi, Amandine Thomas, Sunil Shetty, Irina C. Frei, Bettina K. Wolnerhanssen, Diana Weissenberger, Anke Vandekeere, Melanie Planque, Nikolaus Dietz, Danilo Ritz, Anne Christin Meyer-Gerspach, Timm Maier, Nissim Hay, Ralph Peterli, Sarah-Maria Fendt, Nicolas Rohner, Michael N. Hall
Summary: Chronically high blood glucose leads to diabetes and fatty liver disease. Obesity is a major risk factor for hyperglycemia, but the underlying mechanism is unknown. This study shows that a high-fat diet causes early loss of expression of the glycolytic enzyme Hexokinase 2 specifically in adipose tissue, leading to reduced glucose disposal and lipogenesis and enhanced fatty acid release. Furthermore, the study identifies adipose HK2 as a critical mediator of glucose homeostasis and suggests that obesity-induced loss of adipose HK2 is an evolutionarily conserved mechanism for the development of selective insulin resistance and hyperglycemia.