Article
Cell Biology
Sulhee Kim, Ina Yoon, Jonghyeon Son, Junga Park, Kibum Kim, Ji-Ho Lee, Sam-Yong Park, Beom Sik Kang, Jung Min Han, Kwang Yeon Hwang, Sunghoon Kim
Summary: The study reveals the conformational changes of Leucyl-tRNA synthetase 1 (LARS1) upon leucine binding, providing insights into its mechanism of action in mTORC1 activation.
Article
Biochemistry & Molecular Biology
Ya Chun Yu, Jung Min Han, Sunghoon Kim
Summary: Aminoacyl-tRNA synthetases play essential roles in protein synthesis and recent studies have revealed their previously unknown biological functions beyond catalytic roles. Sensing intracellular nutrients is crucial for cell physiology, and certain types of ARSs may be involved in sensing and signaling their cognate amino acids within cells.
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
(2021)
Article
Microbiology
Uday S. Ganapathy, Ruben Gonzalez del Rio, Monica Cacho-Izquierdo, Fatima Ortega, Joel Lelievre, David Barros-Aguirre, Marissa Lindman, Veronique Dartois, Martin Gengenbacher, Thomas Dick
Summary: This study identified benzoxaborole EC/11770 as a potential treatment for NTM lung disease, showing activity against M. abscessus and M. avium complexes, including drug-tolerant biofilms. The compound was effective in a mouse model, with low resistance frequency, confirming leucyl-tRNA synthetase as the target for antimycobacterial development.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2021)
Article
Plant Sciences
Hongjia Liu, Xue Gong, Hui Deng, Jinjuan Tan, Yanqing Sun, Fang Wang, Wenjuan Wu, Zhongjing Zhou, Rumeng Xu, Haiyan He, Clive Lo
Summary: Aminoacyl tRNA synthetases play a crucial role in protein translation by attaching specific amino acids to tRNAs. However, their functions in regulating plant growth and development are still not well understood. In this study, we identified a rice mutant, ylc3, which exhibited reduced chlorophyll content, altered thylakoid structure, and increased levels of certain amino acids under low temperature conditions. We found that YLC3 encodes an aspartyl-tRNA synthetase localized in the cytosol and mitochondria. Proteomics analysis revealed that thylakoid proteins were down-regulated in the mutant, while proteins involved in amino acid metabolism and protein synthesis were up-regulated, particularly key enzymes that convert aspartate to asparagine. Furthermore, we observed accumulation of uncharged tRNA-Asp and phosphorylation of the translation initiation factor eIF2 alpha in the mutant, suggesting that YLC3 regulates amino acid metabolism and chloroplast thylakoid development through modulation of protein synthesis.
FRONTIERS IN PLANT SCIENCE
(2022)
Article
Chemistry, Medicinal
Dries De Ruysscher, Luping Pang, Stijn M. G. Lenders, Davie Cappoen, Paul Cos, Jef Rozenski, Sergei Strelkov, Stephen D. Weeks, Arthur Van Aerschot
Summary: LeuRS is a clinically validated target for antimicrobial development, and bi-substrate inhibitors have shown potent inhibitory activity against bacterial LeuRS. The results of the study could serve as a suitable starting point for further antibiotic development.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Zezhong Li, Weixiang Xin, Qing Wang, Mingyan Zhu, Huchen Zhou
Summary: New amide compounds were synthesized as inhibitors of T. brucei LeuRS, with compound 74 and 91 showing the highest potency among the series. These compounds represent a new scaffold and potential lead compounds for further development of antitrypanosomal agents.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Biophysics
Xue Sun, Qinggang Li, Yu Wang, Wenjuan Zhou, Yanmei Guo, Jiuzhou Chen, Ping Zheng, Jibin Sun, Yanhe Ma
Summary: In this study, a new strategy for constructing whole-cell biosensors based on aminoacyl-tRNA synthetases (aaRSs) was proposed. By engineering aaRSs, the biosensors showed specificity and potential for developing sensors for various amino acids.
BIOSENSORS & BIOELECTRONICS
(2021)
Article
Biochemistry & Molecular Biology
Ji-Hyun Bae, Jong Hyun Kim
Summary: In TSC-null cells, leucine is essential for cell proliferation through the activation of LARS1-mTORC1 pathway, and LARS1 inhibitors may be considered as novel tools for reversing tumor growth and proliferation in TSC-null tumor cells.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2021)
Article
Biochemistry & Molecular Biology
Takumi Yokosawa, Keisuke Wakasugi
Summary: The study shows that Trp-deficient condition is critical for Trp uptake, not only in cells with added TrpRS protein but also in TrpRS-overexpressing cells. Tryptophanyl-AMP production by TrpRS is essential for high-affinity Trp uptake.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Jae Hyun Kim, Kilsoo Jung, Chulho Lee, Doona Song, Kibum Kim, Hee Chan Yoo, Seung Joon Park, Jong Soon Kang, Kyeong-Ryoon Lee, Sunghoon Kim, Jung Min Han, Gyoonhee Han
Summary: The enzyme leucyl-tRNA synthetase (LRS) and leucine play a key role in regulating the mTOR signaling pathway, with leucine-dependent mTORC1 activation being mediated by LRS. Previous research on compound BC-LI-0186 showed that inhibiting the LRS-RagD interaction could interfere with the mTORC1 pathway, but the compound had issues with solubility and metabolism. By analyzing the physicochemical properties and metabolites of BC-LI-0186, new compounds 7b and 8a were identified to have improved properties while still maintaining inhibitory activity against mTORC1, offering a potential strategy for developing novel drug candidates for mTORC1-related diseases.
BIOORGANIC CHEMISTRY
(2021)
Article
Infectious Diseases
Hong-Ju Lee, Byungchan Kim, Suhyun Kim, Do-Hyun Cho, Heeju Jung, Wooseong Kim, Yun-Gon Kim, Jae-Seok Kim, Hwang-Soo Joo, Sang-Ho Lee, Yung-Hun Yang
Summary: This study discovered the antimicrobial potency of D-norvaline, which can act synergistically with oxacillin, against MRSA. It was found that D-norvaline decreased the overall amount of phospholipid fatty acid (PLFA) in the bacterial cell membrane, increasing its fluidity and decreasing hydrophobicity. This new combination of D-norvaline and oxacillin provides an effective strategy to combat MRSA infection.
Article
Biochemistry & Molecular Biology
Jessica J. Hobson, Zhijie Li, Hao Hu, Charles W. Carter
Summary: Aminoacyl-tRNA synthetases (aaRS)/tRNA pairs play a crucial role in translating the genetic code. The study of urzymes, which are experimental models for the early evolution of aaRS, has provided insights into their catalytic activities. In this study, a new urzyme (LeuAC) was described and shown to catalyze both amino acid activation and tRNA aminoacylation. Additionally, LeuAC was found to have a non-canonical enzymatic function of producing ADP.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Microbiology
Wenye Wu, Siyuan He, Anqi Li, Qi Guo, Zhili Tan, Shicong Liu, Xinghai Wang, Zhemin Zhang, Bing Li, Haiqing Chu
Summary: MRX-6038 exhibits high anti-M. abscessus activity both in vitro and in vivo, and shows potential for the treatment of M. abscessus infections. It demonstrates synergy with certain antibiotics and does not show antagonism with commonly used antimicrobials.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2022)
Article
Biology
Luping Pang, Vladimir Zanki, Sergei Strelkov, Arthur Van Aerschot, Ita Gruic-Sovulj, Stephen D. Weeks
Summary: Crystal structures of leucyl-tRNA synthetase in Neisseria gonorrhoeae reveal conformational changes and a peptide-plane flip in the active site that correlate with catalytic steps. These structural alterations have a significant impact on the enzyme's activity.
COMMUNICATIONS BIOLOGY
(2022)
Article
Biochemical Research Methods
Jessica T. Stieglitz, Priyanka Lahiri, Matthew Stout, James A. Van Deventer
Summary: Archaeal pyrrolysyl-tRNA synthetases (PylRSs) have been used to genetically encode over 200 distinct noncanonical amino acids (ncAAs) in proteins in Escherichia coli and mammalian cells. This study demonstrates the potential of using Methanomethylophilus alvus PylRS (MaPylRS) in yeast to incorporate ncAAs into proteins. The addition of MaPylRS to the toolkit of translation machinery in Saccharomyces cerevisiae opens up possibilities for expanding the range of genetically encodable ncAAs.
ACS SYNTHETIC BIOLOGY
(2022)
Article
Oncology
Sarah Courtois, Maria Haykal, Clement Bodineau, Elodie Sifre, Lamia Azzi-Martin, Armelle Menard, Francis Megraud, Philippe Lehours, Raul V. Duran, Christine Varon, Emilie Bessede
Summary: The infection of Helicobacter pylori can induce autophagy, which in turn affects the formation of gastric cancer stem cells. Inhibiting autophagy may be a potential therapeutic target for gastric cancer.
Article
Urology & Nephrology
Hannah Kaminski, Gabriel Marseres, Nathalie Yared, Marie-Julie Nokin, Vincent Pitard, Atika Zouine, Isabelle Garrigue, Severine Loizon, Myriam Capone, Xavier Gauthereau, Maria Mamani-Matsuda, Roxane Coueron, Raul V. Duran, Benoit Pinson, Isabelle Pellegrin, Rodolphe Thiebaut, Lionel Couzi, Pierre Merville, Julie Dechanet-Merville
Summary: mTOR inhibitors have been shown to enhance T cell function and reduce the incidence of CMV infection in kidney transplant recipients. This effect may be achieved by reducing the number of dysfunctional T cells.
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
(2022)
Editorial Material
Cell Biology
Clement Bodineau, Mercedes Tome, Piedad del Socorro Murdoch, Raul V. Duran
Summary: The study reveals that glutamine metabolism regulates the AMPK-MTORC1 signaling pathway not only through glutaminolysis, but also through the ASNS-GABA shunt, demonstrating a crucial metabolic network.
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
Physics, Multidisciplinary
Auxiliadora Sarmiento, Ivan Duran-Diaz, Irene Fondon, Mercedes Tome, Clement Bodineau, Raul Duran
Summary: This article presents a fully automatic and unsupervised method for comparative biomarker quantification in histopathological brightfield images. The method relies on a color separation method that discriminates between two chromogens expressed as brown and blue colors. By determining the feature vector of each image and using a k-means clustering algorithm, the method produces consistent results for the semi-quantitative scoring of images.
Article
Multidisciplinary Sciences
Charlotte K. Y. Ng, Eva Dazert, Tuyana Boldanova, Mairene Coto-Llerena, Sandro Nuciforo, Caner Ercan, Aleksei Suslov, Marie-Anne Meier, Thomas Bock, Alexander Schmidt, Sylvia Ketterer, Xueya Wang, Stefan Wieland, Matthias S. Matter, Marco Colombi, Salvatore Piscuoglio, Luigi M. Terracciano, Michael N. Hall, Markus H. Heim
Summary: This study presents a comprehensive proteogenomic and phosphoproteomic analysis of HCCs from patients with multiple etiologies and stages, revealing the major pathways altered in the (phospho)proteome.
NATURE COMMUNICATIONS
(2022)
Article
Endocrinology & Metabolism
Manuel Blandino-Rosano, Joshua O. Scheys, Joao Pedro Werneck-de-Castro, Ruy A. Louzada, Joana Almaca, Gil Leibowitz, Markus A. Ruegg, Michael N. Hall, Ernesto Bernal-Mizrachi
Summary: This study reveals that mTORC2 regulates glucose-stimulated insulin secretion by promoting actin filament remodeling, and GLP-1 can rescue defects in insulin secretion by improving actin polymerization in the beta islets.
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM
(2022)
Article
Endocrinology & Metabolism
Irina C. Frei, Diana Weissenberger, Danilo Ritz, Wolf Heusermann, Marco Colombi, Mitsugu Shimobayashi, Michael N. Hall
Summary: This study identifies a network of sensory neurons in murine white adipose tissue and reveals the involvement of adipose mTORC2 in the development and maintenance of these neurons. The loss of sensory innervation in adipose tissue is found to coincide with systemic insulin resistance, suggesting a potential role of sensory neurons in whole-body energy homeostasis.
MOLECULAR METABOLISM
(2022)
Article
Oncology
Don Benjamin, Michael N. Hall
Summary: Inhibiting lactate export and mitochondrial respiration can lead to synthetic lethality in cancer cells. Combining lactate transport inhibitors with metformin may exploit this synergistic interaction in anti-cancer therapy.
FRONTIERS IN ONCOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Sunil Shetty, Jon Hofstetter, Stefania Battaglioni, Danilo Ritz, Michael N. Hall
Summary: Target of rapamycin complex 1 (TORC1) promotes ribosome biogenesis and inhibits degradation in response to nutrient availability. The dormant 80S ribosomes formed under nutrient-limited conditions are regulated by the ribosome preservation factor Stm1, which is inhibited by TORC1 upon nutrient replenishment to reactivate translation. Furthermore, the mammalian ortholog of Stm1, SERBP1, is also required for the formation of dormant ribosomes in mammalian cells upon mTORC1 inhibition, suggesting an evolutionarily conserved mechanism for ribosomal dormancy regulation.
Article
Biochemistry & Molecular Biology
Sujin Park, Dirk Mossmann, Qian Chen, Xueya Wang, Eva Dazert, Marco Colombi, Alexander Schmidt, Brendan Ryback, Charlotte K. Y. Ng, Luigi M. Terracciano, Markus H. Heim, Michael N. Hall
Summary: Acetyl-CoA plays a crucial role in various cellular processes. This study reveals that acetyl-CoA levels are decreased in hepatocellular carcinoma (HCC), leading to hypo-acetylation of non-histone proteins. Repression of acetyl-CoA synthesis promotes the dedifferentiation and proliferation of cancer cells.
Article
Endocrinology & Metabolism
Irina C. Frei, Diana Weissenberger, Michael N. Hall, Mitsugu Shimobayashi
Summary: Mammalian target of rapamycin complex 2 (mTORC2) is a protein kinase complex that plays an important role in energy homeostasis. Loss of adipose mTORC2 reduces lipogenic enzyme expression and de novo lipogenesis in adipose tissue. Adipose-specific mTORC2 knockout mice also display triglyceride accumulation in the liver.
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM
(2023)
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.
Article
Biochemistry & Molecular Biology
Dirk Mossmann, Christoph Mueller, Sujin Park, Brendan Ryback, Marco Colombi, Nathalie Ritter, Diana Weissenberger, Eva Dazert, Mairene Coto-Llerena, Sandro Nuciforo, Lauriane Blukacz, Caner Ercan, Veronica Jimenez, Salvatore Piscuoglio, Fatima Bosch, Luigi M. Terracciano, Uwe Sauer, Markus H. Heim, Michael N. Hall
Summary: Metabolic reprogramming is a hallmark of cancer, and arginine is identified as a second messenger-like molecule that promotes tumor growth by controlling the expression of metabolic genes.
Article
Multidisciplinary Sciences
Maurizio Cortada, Soledad Levano, Michael N. Hall, Daniel Bodmer
Summary: The mTORC2 signaling pathway plays a crucial role in regulating auditory hair cell (HC) structure and function through the regulation of the actin cytoskeleton. This study provides molecular insights into the central regulator of cochlear HCs and hearing.
