Review
Immunology
Frouwkje A. A. Politiek, Hans R. R. Waterham
Summary: Mevalonate kinase deficiency (MKD) is an autoinflammatory metabolic disorder characterized by life-long recurring episodes of fever and inflammation. It is caused by bi-allelic pathogenic variants in the MVK gene, resulting in decreased activity of mevalonate kinase (MK). Compromised protein prenylation may play a major role in leading to inflammatory episodes in MKD.
FRONTIERS IN IMMUNOLOGY
(2021)
Article
Microbiology
Ethan T. Hillman, Elizabeth M. Frazier, Evan K. Shank, Adrian N. Ortiz-Velez, Jacob A. Englaender, Kevin Solomon
Summary: Anaerobic fungi have rich biosynthetic potential, but their biosynthetic pathways have limited success in model hosts like E. coli. This is due to the extreme AT bias in the genome of anaerobic fungi like P. indianae, which causes growth defects in E. coli. Codon optimization rescues growth and enables gene evaluation in otherwise difficult to express genes.
Article
Plant Sciences
Camille Chalvin, Stephanie Drevensek, Francoise Gilard, Caroline Mauve, Christel Chollet, Halima Morin, Edith Nicol, Eva Heripre, Lucie Kriegshauser, Bertrand Gakiere, Michel Dron, Abdelhafid Bendahmane, Adnane Boualem
Summary: The research revealed that Sclareol, a MEP-derived diterpene, is produced by large capitate glandular trichomes in clary sage, emphasizing the significant role of glandular trichomes as biofactories for the production of specialized metabolites.
HORTICULTURE RESEARCH
(2021)
Article
Pharmacology & Pharmacy
Staci L. Haney, Michelle L. Varney, Yashpal Chhonker, Geoffrey Talmon, Lynette M. Smith, Daryl J. Murry, Sarah A. Holstein
Summary: Combination therapy with GGSI and statins demonstrates potential anti-tumor effects in mice, particularly for multiple myeloma. In vivo experiments show the ability to disrupt protein geranylgeranylation and slow tumor growth.
PHARMACOLOGICAL RESEARCH
(2021)
Article
Multidisciplinary Sciences
Sung-Hwan Cho, Katalin Toth, Daewon Kim, Phuc H Vo, Chung-Ho Lin, Pubudu P. Handakumbura, Albert Rivas Ubach, Sterling Evans, Ljiljana Pasa-Tolic, Gary Stacey
Summary: The mevalonate pathway is crucial for cellular processes in both animals and plants. In plants, it affects growth, development, and response to stress. The interaction between mevalonate kinase and extracellular ATP receptor P2K1, with phosphorylation impacting plant metabolism, emphasizes the significance of purinergic signaling and the role of eATP in influencing plant metabolic pathways.
NATURE COMMUNICATIONS
(2022)
Article
Microbiology
Bailey Marshall, Kaustubh Amritkar, Michael Wolfe, Betul Kacar, Robert Landick
Summary: Terpenoids have diverse applications, but their production still relies on nonrenewable sources. Efforts to engineer microbes for sustainable terpenoid production are ongoing. In this study, comparative genomics analysis revealed potential alternative pathways to bypass the first enzyme Dxs in terpenoid biosynthesis, but no alternative routes were found for enzymes IspG and IspH. These findings have implications for metabolic engineering and the understanding of terpenoid biosynthesis evolution.
FRONTIERS IN MICROBIOLOGY
(2023)
Article
Microbiology
Mutsumi Komeyama, Kohsuke Kanno, Hiroyuki Mino, Yoko Yasuno, Tetsuro Shinada, Tomokazu Ito, Hisashi Hemmi
Summary: The archaeal modified mevalonate pathway in archaea involves the biosynthesis of isopentenyl diphosphate and dimethylallyl diphosphate through trans-anhydromevalonate phosphate. A key enzyme called phosphomevalonate dehydratase catalyzes the formation of trans-anhydromevalonate phosphate from (R)-mevalonate 5-phosphate. This enzyme belongs to the aconitase X family and has a [4Fe-4S] cluster, unlike its bacterial counterparts which have a [2Fe-2S] cluster.
FRONTIERS IN MICROBIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Man-Yu Xiao, Fang-Fang Li, Peng Xie, Yan-Shuang Qi, Jin-Bo Xie, Wen-Jing Pei, Hao-Tian Luo, Mei Guo, Yu-Long Gu, Xiang-Lan Piao
Summary: The study found that Gyp can inhibit the progression of hepatocellular carcinoma (HCC) by inhibiting cholesterol synthesis, reducing proliferation, migration, and inducing apoptosis. Gyp targets lipid metabolism and cholesterol biosynthesis, limits cholesterol production, and targets the HMGCS1 protein. Gyp suppresses cholesterol synthesis mediated by the mevalonate pathway by inhibiting the transcription factor SREBP2 and suppresses the progression of HCC.
CHEMICO-BIOLOGICAL INTERACTIONS
(2023)
Article
Chemistry, Multidisciplinary
Devi Prasanna, Ashish Runthala
Summary: Terpenoids are a diverse group of organic compounds with important properties. The study aims to analyze the evolutionary conservation of a key protein involved in terpenoid synthesis, in order to develop new methods for producing specific terpenoids.
Article
Microbiology
Qixuan Su, Ping Cheng, Jiyuan Sun, Yulin Zhang, Yang Zheng, Xiao-Ran Jiang, Xiancai Rao
Summary: In this study, H. bluephagenesis strain was engineered to produce lycopene by introducing a heterologous MVA pathway. By optimizing downstream genes and promoters, the lycopene yield was significantly increased to 1.22 mg/g. This research demonstrates that genetic engineering and optimization of production systems can enhance lycopene overproduction.
FRONTIERS IN MICROBIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Ricardo de la Pena, Elizabeth S. Sattely
Summary: The study successfully revealed a complete biosynthetic pathway to momilactones by conducting gene screening in Nicotiana benthamiana and significantly increasing their production yield. In addition to validating the inhibitory activity of momilactones, similar success was achieved in the production of other compounds by applying the same approach.
NATURE CHEMICAL BIOLOGY
(2021)
Article
Chemistry, Multidisciplinary
Yumi Koga, Eileen M. Hoang, Yongho Park, Alexander F. A. Keszei, Jason Murray, Sichen Shao, Brian B. Liau
Summary: Cycloheximide (CHX) has been used for over half a century to study protein synthesis, but its rapid reversibility often leads to incomplete translation inhibition, prompting the need for improved reagents. The concise synthesis of C13-amide-functionalized CHX derivatives with increased potencies towards protein synthesis inhibition has been reported. These new compounds, particularly C13-aminobenzoyl CHX, have shown superior performance in ribosome profiling experiments, allowing for more effective capture of ribosome conformations.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2021)
Article
Multidisciplinary Sciences
Joel Haywood, Karen J. Breese, Jingjing Zhang, Mark T. Waters, Charles S. Bond, Keith A. Stubbs, Joshua S. Mylne
Summary: Decades of herbicide use has resulted in weed resistance, posing a threat to food security. By studying the crystal structure of an enzyme in plants, specific herbicides can be designed, and resistance traits can be developed through gene sequence analysis.
NATURE COMMUNICATIONS
(2022)
Article
Biochemistry & Molecular Biology
Huan Zhang, Jie Liu, Hanlin Wang, Huan Fang, Ping Zhao, Qingyou Xia, Pengchao Guo
Summary: The crystal structure of insect PMK from Bombyx mori (BmPMK) has been reported, revealing its binding mode with cofactors and substrates. The optimal enzyme activity of BmPMK was determined, along with its key role in JH biosynthesis in silkworms.
INSECT BIOCHEMISTRY AND MOLECULAR BIOLOGY
(2022)
Article
Multidisciplinary Sciences
Meiyun Niu, Yuping Xiong, Haifeng Yan, Xinhua Zhang, Yuan Li, Jaime A. Teixeira da Silva, Guohua Ma
Summary: Sandalwood is highly valued for its fragrant heartwood and oil extraction, with santalols being the main components synthesized via the MVA pathway. The isolation and identification of SaMK and SaPMK genes in S. album, their high homology with genes from other plants, and their functional complementation in yeast indicate their crucial role in MVA biosynthesis. SaMK and SaPMK are constitutively expressed in various tissues and upregulated by methyl jasmonate, providing insights for further research on santalol biosynthesis.
SCIENTIFIC REPORTS
(2021)
Article
Chemistry, Organic
Mahmoud S. Tolba, Mahmoud M. Hamed, Mostafa Sayed, Adel M. Kamal El-Dean, Shawkat A. Abdel-Mohsen, Omneya A. Ibrahim, Walid A. M. Elgaher, Anna K. H. Hirsch, Abdelreheem Abdelfatah Saddik
Summary: In this study, a facile procedure for synthesizing new diclofenac analogous was presented. The chemical structures of the synthesized compounds were confirmed using elemental and spectral analysis techniques. The synthesized compounds showed moderate to high in-vitro antimicrobial activity, and a molecular docking approach was used to investigate their molecular mechanism.
POLYCYCLIC AROMATIC COMPOUNDS
(2023)
Article
Biochemistry & Molecular Biology
Stefan Wimmer, Katharina Hoff, Benedikt Martin, Martin Grewer, Laura Denni, Raquel Lascorz Massanet, Maria Valeria Raimondi, Emre F. Buelbuel, Jelena Melesina, Sven-Kevin Hotop, Jorg Haupenthal, Holger Rohde, Peter Heisig, Anna K. H. Hirsch, Mark Bronstrup, Wolfgang Sippl, Ralph Holl
Summary: To develop inhibitors for bacterial deacetylase LpxC, a series of aldotetronic acid-based hydroxamic acids were synthesized and tested for their inhibitory activity. The most potent inhibitor, benzyl ether 17a, was further evaluated for antibacterial activity, bacterial uptake, and susceptibility to efflux pumps. Molecular docking studies were performed to explain the observed structure-activity relationships.
BIOORGANIC CHEMISTRY
(2023)
Review
Biochemistry & Molecular Biology
Sebastian Walesch, Joy Birkelbach, Gwenaelle Jezequel, F. P. Jake Haeckl, Julian D. Hegemann, Thomas Hesterkamp, Anna K. H. Hirsch, Peter Hammann, Rolf Mueller
Summary: Antibacterial resistance is a significant threat to human health, and the development of new therapeutics has slowed down since the first antibiotics were approved in the 20(th) century. Most of the current drug leads are modifications of existing antibacterials, many of which come from natural products. This review highlights the challenges, advancements, and current status of the clinical and preclinical antibacterial research pipeline, and advocates for renewed investment and enthusiasm in the antibacterial discovery process.
Article
Chemistry, Multidisciplinary
Sangeun Lee, Sarah Nasr, Sari Rasheed, Yun Liu, Olga Hartwig, Cansu Kaya, Annette Boese, Marcus Koch, Jennifer Herrmann, Rolf Mueller, Brigitta Loretz, Eric Buhler, Anna K. H. Hirsch, Claus-Michael Lehr
Summary: The recent success of mRNA vaccines using lipid-based vectors highlights the importance of strategies for nucleotide delivery under the pandemic situation. Although current mRNA delivery is focused on lipid-based vectors, still they need to be optimized for increasing stability, targeting, and efficiency, and for reducing toxicity. In this regard, other vector systems featuring smart strategies such as pH-responsive degradability and endosomal escape ability hold the potential to overcome the current limitations.
JOURNAL OF CONTROLLED RELEASE
(2023)
Article
Microbiology
Thomas Steiner, Marie Zachary, Susanne Bauer, Martin J. Mueller, Markus Krischke, Sandra Radziej, Maximilian Klepsch, Bruno Huettel, Wolfgang Eisenreich, Thomas Rudel, Dagmar Beier
Summary: Through transcriptome and metabolome analysis, we have demonstrated the significant role of the sibling sRNAs NgncR_162/163 in the regulation of metabolic pathways, particularly in the biosynthesis of amino acids and nucleotides.
Article
Biochemistry & Molecular Biology
Dominik Kolling, Joerg Haupenthal, Anna K. H. Hirsch, Jesko Koehnke
Summary: The human pathogen Pseudomonas aeruginosa possesses various virulence factors that are crucial in infection progression. LasB, a major virulence factor, plays a role in dissolving connective tissue and deactivating host defense proteins. In this study, we present a new protocol for high-level production of native LasB in Escherichia coli, allowing for easier access to LasB and acceleration in the development of inhibitors targeting this important virulence factor.
Article
Chemistry, Medicinal
Sandra Johannsen, Robin M. Gierse, Aleksandra Olshanova, Ellie Smerznak, Christian Laggner, Lea Eschweiler, Zahra Adeli, Rawia Hamid, Alaa Alhayek, Norbert Reiling, Joerg Haupenthal, Anna K. H. Hirsch
Summary: This work emphasizes the importance of investigating both on-target activity and antibiotic activity against critical pathogens. The authors focused on the 1-deoxy-d-xylulose 5-phosphate synthase (DXPS) as a potential new target and conducted virtual screening and activity studies. While no improvement in activity was observed in the synthesized derivatives, they found that the compounds showed good inhibition against Escherichia coli in their tests against various pathogens.
Article
Crystallography
Victor Oliveira Gawriljuk, Rick Oerlemans, Robin M. Gierse, Riya Jotwani, Anna K. H. Hirsch, Matthew R. Groves
Summary: The development of new antibiotics is stagnant, highlighting the need for drugs with novel modes of action to combat antibiotic resistance. A study focuses on 1-deoxy-D-xylulose 5-phosphate synthase (DXPS), the rate-limiting enzyme in the methylerythritol phosphate pathway used by bacteria to synthesize important precursors. The crystal structure of M. tuberculosis DXPS in complex with the inhibitor butylacetylphosphonate (BAP) reveals its binding mode and provides insights for enhancing the activity of alkylacetylphosphonates (alkylAPs) against M. tuberculosis.
Article
Biochemistry & Molecular Biology
Yun Liu, Salma Ashmawy, Lorenz Latta, Agnes-Valencia Weiss, Alexander F. Kiefer, Sarah Nasr, Brigitta Loretz, Anna K. H. Hirsch, Sangeun Lee, Claus-Michael Lehr
Summary: Gene knockdown by siRNA is limited by the negative charge, large size, and susceptibility to enzymatic degradation of siRNA. In this study, a protein-based biodynamic polymer (biodynamer) was developed as a siRNA transfection vector, showing excellent biocompatibility, easy tunability, and dynamic polymerization under acidic conditions. The optimized biodynamers formed stable nanocomplexes with siRNA, exhibited pH-dependent size change and degradability, and effectively delivered siRNA into cells, resulting in potent gene knockdown and apoptosis of carcinoma cells. These findings suggest that the biodynamers hold immense potential as a promising platform for siRNA delivery.
Article
Chemistry, Medicinal
Henni-Karoliina Ropponen, Eleonora Diamanti, Sandra Johannsen, Boris Illarionov, Rawia Hamid, Miriam Jaki, Peter Sass, Markus Fischer, Joerg Haupenthal, Anna K. H. Hirsch
Summary: This study reports a multiparameter optimization of a fragment-like hit identified through a structure-based virtual-screening campaign on Escherichia coli IspE crystal structure. The resultant novel class of E. coli IspE inhibitors showed activity against Pseudomonas aeruginosa and Acinetobacter baumannii. However, cytotoxicity still remains a challenge. This research provides insights on balancing enzymatic target and bacterial activities simultaneously, as well as new starting points for the development of IspE inhibitors with a predicted new mode of action.
Article
Biochemistry & Molecular Biology
Franziska Fries, Andreas Kany, Sari Rasheed, Anna Hirsch, Rolf Mueller, Jennifer Herrmann
Summary: A zebrafish embryo model was established to evaluate the in vivo efficacy of potential antimicrobials, providing a novel screening platform for antibiotic discovery. Consideration of the appropriate administration route based on the physicochemical properties of tested drugs was also provided.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Chemistry, Medicinal
Aylin Berwanger, Saskia C. Stein, Andreas M. Kany, Melissa Gartner, Brigitta Loretz, Claus-Michael Lehr, Anna K. H. Hirsch, Thomas F. Schulz, Martin Empting
Summary: This study aims to inhibit Kaposi's sarcoma-associated herpesvirus (KSHV) latent replication by targeting the LANA-DNA interaction using small molecular entities. Through STD-NMR and cell-free tests via electrophoretic mobility shift assays (EMSA), the SAR of the compounds was better understood. The most potent compounds successfully inhibit LANA-mediated replication in cell-based assays and possess favorable in vitro ADMET-profiles.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Serena Della Volpe, Roberta Listro, Francesca Alessandra Ambrosio, Martina Garbagnoli, Pasquale Linciano, Daniela Rossi, Giosue Costa, Stefano Alcaro, Francesca Vasile, Anna K. H. Hirsch, Simona Collina
Summary: RNA binding protein HuR plays a role in the regulation of oncogenes and tumor suppressor genes, and its dysregulation is associated with cancer. This study utilized protein-templated dynamic combinatorial chemistry to search for novel HuR ligands that can interfere with the HuR-RNA complex. Several compounds were identified and shown to effectively interfere with HuR-RNA binding, indicating their potential as anticancer agents targeting HuR-RNA interactions.
ACS MEDICINAL CHEMISTRY LETTERS
(2023)
Article
Chemistry, Multidisciplinary
Philippe Diederich, Alexander Ruf, Thomas Geisberger, Leopold Weidner, Christian Seitz, Wolfgang Eisenreich, Claudia Huber, Philippe Schmitt-Kopplin
Summary: Chemical complexity is crucial for the origin of life and biological evolution. The chemical evolution of a complex prebiotic mixture containing acetylene, carbon monoxide, and nickel sulfide has been analyzed using mass spectrometry. Isotopic labeling reveals the presence of diverse compounds within the reaction mixture. Different degrees of labeling enable robust characterization of functional groups. The study also reveals a characteristic addition pattern and a high diversity of sulfur-containing compounds. The temporal analysis provides insights into the role of sulfur in the origin of life.
COMMUNICATIONS CHEMISTRY
(2023)
Review
Veterinary Sciences
Shereen Basiouni, Guillermo Tellez-Isaias, Juan D. Latorre, Brittany D. Graham, Victor M. Petrone-Garcia, Hesham R. El-Seedi, Sakine Yalcin, Amr Abd El-Wahab, Christian Visscher, Helen L. May-Simera, Claudia Huber, Wolfgang Eisenreich, Awad A. Shehata
Summary: Chronic stress and inflammation have detrimental impacts on the health and performance of animals, including poultry. This review discusses the mechanistic pathways of oxidative stress and inflammation associated with the main stressors in poultry, such as heat stress, dysbiosis, leaky gut syndrome, and mycotoxins. The use of phytogenic bioactive substances to mitigate oxidative stress and inflammation in poultry is also explored.
VETERINARY SCIENCES
(2023)