Article
Biochemistry & Molecular Biology
Gakuto Uesugi, Yuho Fukuba, Takayuki Yamamoto, Nozomi Inaba, Haruyuki Furukawa, Satoko Yoshizawa, Chie Tomikawa, Kazuyuki Takai
Summary: In eubacteria, the AUA codon is translated by tRNA(Ile2) with lysidine at the wobble position. Lactobacillus casei can charge tRNA(Ile2)(UAU) with isoleucine, but Lactobacillus plantarum cannot. Ala18 and Gly19 in L. casei IleRS are critical for recognition of tRNA(Ile2)(UAU).
Article
Biochemistry & Molecular Biology
Siqi Wu, Li Zheng, Zhoufei Hei, Jing-Bo Zhou, Guang Li, Peifeng Li, Jiayuan Wang, Hamid Ali, Xiao-Long Zhou, Jing Wang, Pengfei Fang
Summary: The structures of human Lysyl-tRNA synthetases (LysRSs) are more dynamic than those from single-celled organisms. Without the presence of MSC scaffold proteins, human LysRS can exist independently from the multi-tRNA synthetase complex (MSC). The interaction with the scaffold protein AIMP2 stabilizes the closed conformation of LysRS and protects its essential aminoacylation activity under stressed conditions. Deleting AIMP2 from human cells leads to slow cell growth in nutrient deficient mediums. These results suggest that the evolutionary emergence of the MSC in metazoan might be to protect the aminoacyl-tRNA synthetase components from being modified or recruited for use in other cellular pathways.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Jessica M. Warren, Amanda K. Broz, Ana Martinez-Hottovy, Christian Elowsky, Alan C. Christensen, Daniel B. Sloan
Summary: The number of tRNAs encoded in plant mitochondrial genomes varies considerably. The loss of bacterial-like mitochondrial tRNA genes necessitates the import of nuclear-encoded counterparts with little sequence similarity. The evolution of aaRS subcellular localization in Sileneae reveals differing constraints on tRNA/aaRS interactions and alternative coevolutionary paths for maintaining organellar translation in plant cells.
MOLECULAR BIOLOGY AND EVOLUTION
(2023)
Article
Biochemistry & Molecular Biology
Jose R. Jaramillo Ponce, Anne Theobald-Dietrich, Philippe Benas, Caroline Paulus, Claude Sauter, Magali Frugier
Summary: tRip is a specific tRNA import protein for Plasmodium. It can associate with three aminoacyl-tRNA synthetases (aaRS) and form multi-aaRS complexes (MSC) in the parasite. The crystal structure of the N-terminal GST-like domain of one of the aaRS was solved, allowing further investigation of the solution architecture of the complexes. The biological impact of these structural arrangements is discussed.
Article
Medicine, General & Internal
Kyungjong Lee, Mijung Oh, Kyo-Sun Lee, Yoon Jin Cha, Yoon Soo Chang
Summary: The combination of MARS staining with conventional cytology showed increased diagnostic accuracy for diagnosing lung nodules suspected of lung cancer on chest-computed tomography scans.
Article
Microbiology
Jingjing Wang, Alexander Berestetskiy, Qiongbo Hu
Summary: Destruxin A (DA) is a mycotoxin produced by the fungus Metarhizium anisopliae with insecticidal activities, showing affinity to the six aminoacyl tRNA synthetases of Bombyx mori. This interaction inhibits protein synthesis and decreases free amino acid content in cells. The study provides insights into the molecular target of DA against target insects.
Letter
Immunology
Yoshinao Muro, Yuta Yamashita, Haruka Koizumi, Mariko Ogawa-Momohara, Takuya Takeichi, Teruyuki Mitsuma, Masashi Akiyama
Summary: Anti-aminoacyl-tRNA synthetase (anti-ARS) antibodies are helpful in identifying inflammatory myopathy patients. In a study with Japanese patients, autoantibodies against CysARS and ValARS were found in the serum of two dermatomyositis patients. One patient showed features of anti-synthetase syndrome, while the other did not. Further research is needed to explore the clinical differences among different anti-ARS antibodies.
AUTOIMMUNITY REVIEWS
(2022)
Article
Biochemistry & Molecular Biology
Oliver Podmanicky, Fei Gao, Benjamin Munro, Matthew J. Jennings, Veronika Boczonadi, Denisa Hathazi, Juliane S. Mueller, Rita Horvath
Summary: This study investigates the molecular mechanisms triggered by three different mt-ARS defects caused by biallelic mutations in AARS2, EARS2, and RARS2, using an in vitro model of human neuronal cells. The findings highlight the unique compensatory mechanisms in proliferating neuronal progenitor cells, the dysregulation of neuronal differentiation and protein translation, and provide valuable insights into the tissue-specific compensatory mechanisms potentially underlying the phenotypes of patients with mt-ARS defects.
HUMAN MOLECULAR GENETICS
(2023)
Article
Oncology
Krishnendu Khan, Valentin Gogonea, Paul L. Fox
Summary: Aminoacyl-tRNA synthetases (AARS) are important enzymes in mammalian cells that play a key role in protein translation. Recent studies have found that they exist in the cytoplasmic multi-tRNA synthetase complex (MSC) and have non-canonical functions in addition to their role in protein translation. These findings have the potential to be new therapeutic targets for cancer and other diseases.
TRANSLATIONAL ONCOLOGY
(2022)
Review
Genetics & Heredity
Tamara L. Hendrickson, Whitney N. Wood, Udumbara M. Rathnayake
Summary: The selection of the twenty amino acids in the standard genetic code and the fixation of aminoacyl-tRNA synthetases (aaRSs) before LUCA were influenced by the chemical reactivity of amino acid side chains. Some amino acid properties delayed or prohibited the emergence of corresponding aaRSs, playing critical roles in defining the amino acids in the genetic code.
Article
Genetics & Heredity
Nina Boegershausen, Hannah E. Krawczyk, Rami A. Jamra, Sheng-Jia Lin, Goekhan Yigit, Irina Huening, Anna M. Polo, Barbara Vona, Kevin Huang, Julia Schmidt, Janine Altmueller, Johannes Luppe, Konrad Platzer, Beate B. Doergeloh, Andreas Busche, Saskia Biskup, Marisa Mendes, Desiree E. C. Smith, Gajja S. Salomons, Arne Zibat, Eva Bueltmann, Peter Nuernberg, Malte Spielmann, Johannes R. Lemke, Yun Li, Martin Zenker, Gaurav K. Varshney, Hauke S. Hillen, Christian P. Kratz, Bernd Wollnik
Summary: Aminoacylation of tRNA is a crucial step in protein biosynthesis and is associated with various genetic disorders. This study reports five individuals with biallelic missense variants in WARS1 or SARS1, who exhibited similar phenotypes including microcephaly, developmental delay, intellectual disability, and brain anomalies. The identified variants were found to negatively affect protein function, providing functional insights into the pathogenesis of WARS1-related syndrome and expanding the disease spectrum of ARS-related developmental disorders with or without microcephaly.
Article
Multidisciplinary Sciences
Krishnendu Khan, Briana Long, Valentin Gogonea, Gauravi M. Deshpande, Kommireddy Vasu, Paul L. Fox
Summary: Aminoacyl-tRNA synthetases (aaRSs) are essential enzymes in the translation process that ligate amino acids to their corresponding transfer RNAs (tRNAs). In mammalian cells, these enzymes, along with AIMPs proteins, form a large multi-tRNA synthetase complex (MSC), whose assembly mechanism and function are still unclear. This study reveals the importance of cotranslational interactions, particularly involving AIMPs proteins, in the assembly process of the MSC. Interestingly, these cotranslational interactions sometimes involve more than two proteins, suggesting a diverse pathway for the ordered assembly of small subcomplexes into larger complexes.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Review
Immunology
Angeles S. Galindo-Feria, Antonella Notarnicola, Ingrid E. Lundberg, Begum Horuluoglu
Summary: Anti-synthetase syndrome is an autoimmune disease characterized by the presence of autoantibodies targeting aminoacyl t-RNA synthetases along with various clinical features. This review summarizes the functions of aaRSs, their autoantigenic properties, and their association with ASSD.
FRONTIERS IN IMMUNOLOGY
(2022)
Review
Biochemistry & Molecular Biology
Swadha Gupta, Jaykumar Jani, Jigneshkumar Vijayasurya, Jigneshkumar Mochi, Saba Tabasum, Akash Sabarwal, Anju Pappachan
Summary: Aminoacyl-tRNA synthetases (AaRSs) play essential roles in translating genetic information and have diverse functions in cellular activities such as transcription, apoptosis, angiogenesis, inflammation, and cancer. Their multifunctionality suggests their potential as therapeutic targets.
Article
Chemistry, Multidisciplinary
Ji Chen, Mengyin Chen, Ting F. Zhu
Summary: The study demonstrates the feasibility of translating protein enzymes without the need for aaRS using flexizyme-charged tRNAs, and successfully produced an active aaRS in the process. This research has made progress in achieving mirror-image translation.
Article
Biochemistry & Molecular Biology
Siqi Wu, Li Zheng, Zhoufei Hei, Jing-Bo Zhou, Guang Li, Peifeng Li, Jiayuan Wang, Hamid Ali, Xiao-Long Zhou, Jing Wang, Pengfei Fang
Summary: The structures of human Lysyl-tRNA synthetases (LysRSs) are more dynamic than those from single-celled organisms. Without the presence of MSC scaffold proteins, human LysRS can exist independently from the multi-tRNA synthetase complex (MSC). The interaction with the scaffold protein AIMP2 stabilizes the closed conformation of LysRS and protects its essential aminoacylation activity under stressed conditions. Deleting AIMP2 from human cells leads to slow cell growth in nutrient deficient mediums. These results suggest that the evolutionary emergence of the MSC in metazoan might be to protect the aminoacyl-tRNA synthetase components from being modified or recruited for use in other cellular pathways.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2022)
Review
Pharmacology & Pharmacy
Xin Cao, Xiaojing Du, Heng Jiao, Quanlin An, Ruoxue Chen, Pengfei Fang, Jing Wang, Biao Yu
Summary: Carbohydrates are essential molecules with diverse roles in life, and their derivatives have been extensively studied as therapeutic agents for various diseases. This review provides a comprehensive overview of the chemical structures, activities, and clinical trial results of carbohydrate-based drugs, categorized by their indications.
ACTA PHARMACEUTICA SINICA B
(2022)
Article
Multidisciplinary Sciences
Maowu Luo, Lei Bao, Yan Chen, Yuanyuan Xue, Yong Wang, Bo Zhang, Chenliang Wang, Chase D. Corley, Jeffrey G. McDonald, Ashwani Kumar, Chao Xing, Yisheng Fang, Erik R. Nelson, Jennifer E. Wang, Yingfei Wang, Weibo Luo
Summary: The histone reader ZMYND8 is selectively expressed in breast cancer stem cells (BCSCs) and promotes breast tumor initiation through its epigenetic functions by regulating 27-HC metabolism, leading to the accumulation of 27-HC in BCSCs and activation of liver X receptor.
Article
Chemistry, Medicinal
Yang Liu, Yuting Chen, Jiheng Jiang, Xianglin Chu, Qinglong Guo, Li Zhao, Feng Feng, Wenyuan Liu, Xiaolong Zhang, Siyu He, Peng Yang, Pengfei Fang, Haopeng Sun
Summary: AKR1C3 is overexpressed in hormone-related cancers and is correlated with tumor development and aggressiveness. A new class of AKR1C3 inhibitors with potent inhibitory activity and selectivity for closely related isoforms has been developed. Co-administration of these inhibitors with doxorubicin can significantly reverse drug resistance in breast cancer cells. These AKR1C3 inhibitors may serve as effective adjuvants to overcome drug resistance in breast cancer treatment.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Tingting Yu, Yi Zhang, Wen-Qiang Zheng, Siqi Wu, Guoqiang Li, Yong Zhang, Niu Li, Ruen Yao, Pengfei Fang, Jian Wang, Xiao-Long Zhou
Summary: Mitochondrial translation is crucial for cellular energy homeostasis, and variations in mitochondrial aaRSs can lead to various human diseases. This study identified two novel variants of SARS2 that cause a multisystem disorder. These variants exhibited reduced tRNA binding and aminoacylation capacities, resulting in mitochondrial dysfunction and decreased tRNA abundance due to RNA degradation. The findings highlight the importance of reduced tRNA(Ser)(AGY) abundance in the development of SARS2-related diseases.
NUCLEIC ACIDS RESEARCH
(2022)
Article
Biology
Hang Qiao, Mingyu Xia, Yiyuan Cheng, Jintong Zhou, Li Zheng, Wei Li, Jing Wang, Pengfei Fang
Summary: This study reports the discovery of a novel drug, obafluorin, which can covalently inhibit the protein synthesis enzyme Threonyl-tRNA synthetase, offering potential for cancer and infectious disease treatment.
COMMUNICATIONS BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Yuhan Dai, Yiyuan Cheng, Weizhong Ding, Hang Qiao, Derundong Zhang, Guannan Zhong, Mingyu Xia, Jiang Tao, Peng Sun, Pengfei Fang, Wen Liu
Summary: In this study, we report the crystal structures of LmbT in the S-glycosylation of EGT during lincomycin A biosynthesis. We found that LmbT has a characteristic glycosyltransferase type B fold and forms a symmetric homotetramer. The substrates are deeply bound in the catalytic cleft. Site-directed mutagenesis was performed to propose a catalytic mechanism for the unusual EGT-mediated S-glycosylation.
ACS CHEMICAL BIOLOGY
(2023)
Article
Cell Biology
Yuqi Lin, Biao Yu, Pengfei Fang, Jing Wang
Summary: Autophagy is a cellular stress response mechanism that cancer cells often exploit for survival and growth under unfavorable conditions. It also contributes to tumor resistance to various cancer therapies. Inhibition of autophagy shows promise as a tumor treatment strategy, but effective clinical autophagy inhibitors are still lacking. Most drug development efforts have focused on enzymes involved in autophagy, but our discovery of Eltrombopag, which directly inhibits the transcription factor TFEB, provides a new approach for inhibiting autophagy. This drug improves the therapeutic effect of Temozolomide on glioblastoma treatment, further highlighting the importance of autophagy inhibition in cancer treatment.
Article
Biochemistry & Molecular Biology
Qi-Yu Zeng, Fan Zhang, Jian-Hui Zhang, Zhoufei Hei, Zi-Han Li, Meng-Han Huang, Pengfei Fang, En-Duo Wang, Xiao-Jian Sun, Xiao-Long Zhou
Summary: TARSL2, the only duplicated aaRS gene in vertebrates, does not play a significant role in mRNA translation in vivo but is essential for mouse development. Deletion of Tarsl2 does not affect tRNAThrs abundance or charging levels, indicating a reliance on Tars1. It is also a peripheral member of the multiple tRNA synthetase complex.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2023)
Article
Chemistry, Multidisciplinary
Yiyuan Cheng, Xuan Yi, Yan Zhang, Qingli He, Dandan Chen, Weiguo Cao, Pengfei Fang, Wen Liu
Summary: By reconstituting the biosynthetic route of ABCH-containing unit, we found that the formation of ABCH is completed by an oxidase heterotetramer with the association of NRPS. DADH precursor was prepared and offloaded from an amino-group carrier protein. DADH was processed to form an aziridine ring and further cyclized to form a fused five-membered nitrogen heterocycle in the NRPS. The catalytic mechanism of the oxidase heterotetramer was rationalized through biochemical characterization, crystal structure, and site-specific mutagenesis.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Article
Biochemistry & Molecular Biology
Zhoufei Hei, Pengfei Fang
Summary: A crystal structure of human LysRS reveals that the enzyme's two enzymatic pockets are in different states, one devoid of ATP and the other in an intermediate state of ATP recognition. The structures elucidate the order of binding for the three magnesium ions and provide critical insights into the magnesium-dependent enzyme activity of class II aaRSs.
BIOCHEMISTRY AND BIOPHYSICS REPORTS
(2023)
Article
Chemistry, Medicinal
Siyu He, Xianglin Chu, Yujia Wu, Jiheng Jiang, Pengfei Fang, Yuting Chen, Yang Liu, Zhixia Qiu, Yibei Xiao, Zhiyu Li, Di Pan, Qian Zhang, Huanfang Xie, Shuaishuai Xing, Feng Feng, Wenyuan Liu, Qinglong Guo, Li Zhao, Peng Yang, Haopeng Sun
Summary: Aldo-keto reductase 1C3 (AKR1C3) has been found to be associated with tumor development and chemotherapy resistance. Inhibition of AKR1C3 activity can restore the chemosensitivity in ANT-resistant cancers. Biaryl-containing AKR1C3 inhibitors, particularly S07-1066, selectively block AKR1C3-mediated reduction and significantly enhance the cytotoxicity of doxorubicin (DOX) in MCF-7 cells overexpressing AKR1C3. The synergistic effect of S07-1066 and DOX has been demonstrated in vitro and in vivo, suggesting that AKR1C3 inhibitors may serve as effective adjuvants to overcome AKR1C3-mediated chemotherapy resistance.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Cell Biology
Zaizhou Liu, Kaige Chen, Jun Dai, Peng Xu, Wei Sun, Wanlin Liu, Zhixin Zhao, Steven P. Bennett, Peifeng Li, Tiancheng Ma, Yuqi Lin, Akinori Kawakami, Jing Yu, Fei Wang, Chunxi Wang, Miao Li, Peter Chase, Peter Hodder, Timothy P. Spicer, Louis Scampavia, Chunyang Cao, Lifeng Pan, Jiajia Dong, Yong Chen, Biao Yu, Min Guo, Pengfei Fang, David E. Fisher, Jing Wang
Summary: The researchers discovered that the structure of MITF is hyperdynamic and vulnerable to dimer-disrupting mutations. They also identified a small molecule compound, TT-012, that specifically binds to MITF and inhibits its transcriptional activity in melanoma cells. Furthermore, TT-012 inhibits the growth of high-MITF melanoma cells and suppresses tumor growth and metastasis in animal models. This study provides insights into the unique dimer interface of the melanoma oncoprotein MITF and presents a potential therapeutic approach to suppress MITF activity.
Article
Biochemistry & Molecular Biology
Yingke Tang, Ryan T. Behrens, Corine St Gelais, Siqi Wu, Saravanan Vivekanandan, Ehud Razin, Pengfei Fang, Li Wu, Nathan Sherer, Karin Musier-Forsyth
Summary: Human lysyl-tRNA synthetase (LysRS) is re-localized from cytoplasm to nucleus in HIV-1 infected cells through phosphorylation. Phosphorylation promotes HIV-1 transcription, and nuclear pS207-LysRS generates Ap4A, which also activates HIV-1 transcription. Additionally, MSC-derived peptide stabilizes LysRS MSC binding and inhibits HIV-1 replication.
NUCLEIC ACIDS RESEARCH
(2023)
Article
Nanoscience & Nanotechnology
Baisen Zhong, Weiyu Peng, Shan Du, Bingyi Chen, Yajuan Feng, Xinfeng Hu, Qi Lai, Shujie Liu, Zhong-Wei Zhou, Pengfei Fang, Yan Wu, Feng Gao, Huihao Zhou, Litao Sun
Summary: Three herbal compounds, Salvianolic acid A, (-)-Epigallocatechin gallate, and Oridonin, have been identified to directly inhibit the activity of SARS-CoV-2 3CLpro. Oridonin, in particular, has shown to block viral infectivity in cell-based experiments.