Article
Chemistry, Multidisciplinary
Iredia D. Iyamu, Jonah Z. Vilseck, Ravi Yadav, Nicholas Noinaj, Rong Huang
Summary: The study reports the first cell-potent NNMT bisubstrate inhibitor II399, which demonstrates strong binding affinity and selectivity for NNMT. The inhibition mechanism and crystal structure analysis reveal the interactions between II399 and both the substrate and cofactor binding pockets. This research provides a valuable probe for studying NNMT biology and introduces a strategy for developing cell-potent inhibitors for SAM-dependent methyltransferases.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2022)
Article
Biochemistry & Molecular Biology
Dongxing Chen, Ying Meng, Dan Yu, Nicholas Noinaj, Xiaodong Cheng, Rong Huang
Summary: Understanding the selectivity of a bisubstrate inhibitor for methyltransferases is crucial for dissecting their functions, as shown in a chemoproteomic study on NTMT1. This study not only identified NTMT1 as a target, but also discovered potent inhibition of a methyltransferase complex HemK2-Trm112 by the same inhibitor.
ACS CHEMICAL BIOLOGY
(2021)
Article
Biotechnology & Applied Microbiology
Wanfeng Xu, Ling Hou, Ping Li, Ling Li
Summary: The interference of NNMT expression was found to reduce lipid accumulation and triglyceride content, as well as decrease the expression of certain genes and proteins related to lipid metabolism. This suggests that NNMT plays an important role in the function and metabolism of adipocytes.
Review
Endocrinology & Metabolism
Annalisa Roberti, Agustin F. Fernandez, Mario F. Fraga
Summary: NNMT acts as a key link between cellular metabolism and epigenetic gene regulation, playing a central role in various pathologies. Targeting NNMT pathways represents a current pharmaceutical challenge for treating a range of metabolic-related diseases and cancers.
MOLECULAR METABOLISM
(2021)
Article
Chemistry, Medicinal
Vivek Makwana, Philip Ryan, Alpeshkumar K. Malde, Shailendra Anoopkumar-Dukie, Santosh Rudrawar
Summary: OGT is a key enzyme involved in the modification of various nuclear and cytosolic proteins with O-GlcNAc. Rational design of bisubstrate analogue inhibitors for OGT sheds light on the potential role of OGT in regulating cellular functions.
Article
Biochemistry & Molecular Biology
Aimo Kannt, Sridharan Rajagopal, Mahanandeesha S. Hallur, Indu Swamy, Rajendra Kristam, Saravanakumar Dhakshinamoorthy, Joerg Czech, Gernot Zech, Herman Schreuder, Sven Ruf
Summary: Nicotinamide-N-methyltransferase (NNMT) is a cytosolic enzyme that catalyzes the transfer of a methyl group from S-adenosyl-methionine (SAM) to nicotinamide (Nam). Its expression in various tissues has been linked to metabolic diseases, and potent small molecule inhibitors with different binding modes have been identified through X-ray crystallographic studies.
Article
Biochemistry & Molecular Biology
Roberto Campagna, Lukasz Mateuszuk, Kamila Wojnar-Lason, Patrycja Kaczara, Anna Tworzydlo, Agnieszka Kij, Robert Bujok, Jacek Mlynarski, Yu Wang, Davide Sartini, Monica Emanuelli, Stefan Chlopicki
Summary: Nicotinamide N-methyltransferase (NNMT) plays an important role in endothelial cells by regulating cell viability, possibly through the modulation of SIRT1 expression levels under oxidative stress insult.
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
(2021)
Article
Chemistry, Medicinal
Arindam Talukdar, Ayan Mukherjee, Debomita Bhattacharya
Summary: The abnormal expression of protein methyltransferase (PMT) is related to various diseases, and the focus of current research is on the evolution from nucleoside inhibitors to selective competitive non-nucleoside inhibitors to solve the inherent problems of nucleoside analogues.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Oksana Stepinska, Dorota Dymkowska, Lukasz Mateuszuk, Krzysztof Zablocki
Summary: This study aimed to investigate the potential role of nicotinamide N-methyltransferase in the metabolic response of human aortic endothelial cells. The findings suggest that this enzyme may affect NAD(+) synthesis and epigenetic modifications of chromatin by regulating intracellular nicotinamide and S-adenosylmethionine levels. The specific metabolic role of nicotinamide N-methyltransferase in vascular endothelium is still unclear and further research is needed.
INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY
(2022)
Article
Oncology
Jun Yang, Qingchao Tong, Ying Zhang, Shijin Yuan, Yuzhen Gao, Ke Deng, Yanzhong Wang, Jie Lu, Xinyou Xie, Zhe Zhang, Jun Zhang
Summary: This study investigated the distribution of NNMT expression in CRC and found that its overexpression was associated with unfavorable clinical characteristics and survival outcomes. Particularly, high NNMT expression in tumor stroma cells was strongly correlated with metastasis and poor survival in CRC patients. Functional experiments demonstrated that stromal cells with high NNMT expression secreted 1-MAN to promote migration and invasion of CRC cells. Overall, NNMT may serve as a potential prognostic indicator in CRC patients.
Article
Food Science & Technology
Aimei Liu, Mingyue Guo, Lixuan He, Maria-Aranzazu Martinez, Marta Martinez, Bernardo Lopez-Torres, Maria-Rosa Martinez-Larranaga, Xu Wang, Arturo Anadon, Irma Ares
Summary: Deoxynivalenol (DON) is a common contaminant in cereals for infants and can cause growth retardation and inflammation in children. The present research reveals that nicotinamide N-methyltransferase (NNMT) acts as a self-protective factor in DON-exposed cells, alleviating cell growth inhibition by reducing the production of pro-inflammatory cytokines.
FOOD AND CHEMICAL TOXICOLOGY
(2022)
Review
Biochemistry & Molecular Biology
Renata Novak Kujundzic, Marin Prpic, Nikola Dakovic, Nina Dabelic, Marko Tomljanovic, Anamarija Mojzes, Ana Frobe, Koraljka Gall Troselj
Summary: Overexpression and activity of NNMT in cancer can disrupt NAD(+) homeostasis and reduce cellular methylation potential. The inhibitory effect of 2-PY on PARP-1 activity, which cancels out NNMT's positive effect on cellular NAD(+) flux, is often overlooked.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Chemistry, Multidisciplinary
Dylan Coelho, Laurent Le Corre, Karolina Bartosik, Laura Iannazzo, Emmanuelle Braud, Melanie Etheve-Quelquejeu
Summary: RNA methyltransferases (RNA MTases) are enzymes that methylate RNA using S-adenosyl-L-methionine. We developed a new synthesis method for m6A MTases bisubstrate analogues, which enhances the structural diversity of these compounds and allows for exploration of the active site of RNA modification enzymes and development of new inhibitors.
CHEMISTRY-A EUROPEAN JOURNAL
(2023)
Article
Plant Sciences
Enhui Yao, Xiazhen Yang, Xuefeng Huang, Yuchen Mi, Xiaoqian Wu, Meijuan Fang, Jinhua Huang, Yan Qiu, Xiaoting Hong, Lu Peng, Jie Ren, Rui Huang, Caixia Chen, Lichao Yang, Yu Zhou, Rengong Zhuo, Xin Jin, Yun Zhao
Summary: WDL reduces fat mass, suppresses body weight gain, and improves obesity-related metabolic disorders in DIO mice. WDL promotes adipose browning and enhances energy expenditure. WDL reverses obesity through inhibiting NNMT and activating the SIRT1/AMPK/PPAR alpha pathway.
Article
Biochemistry & Molecular Biology
Lucrezia Togni, Marco Mascitti, Davide Sartini, Roberto Campagna, Valentina Pozzi, Eleonora Salvolini, Annamaria Offidani, Andrea Santarelli, Monica Emanuelli
Summary: NNMT is significantly overexpressed in various HNT types and has been associated with cancer cell migration and adverse clinical outcomes. However, its prognostic significance in OSCC remains debated, and further studies on larger patient cohorts are needed to explore its biological role in HNT.
Article
Cell Biology
Alexandra Griffiths, Jun Wang, Qing Song, Iredia D. Iyamu, Lifeng Liu, Jooman Park, Yuwei Jiang, Rong Huang, Zhenyuan Song
Summary: This study revealed that palmitate upregulates NNMT expression through ATF4 activation in hepatocytes, contributing to hepatic lipotoxicity. Inhibition of NNMT provides protection against palmitate-induced hepatotoxicity, with PKA activation partially involved in the protective effect of NNMT inhibition against lipotoxicity. The mTORC1-ATF4 pathway activation leads to NNMT upregulation, which plays a crucial role in the development of hepatic lipotoxicity.
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Iredia D. Iyamu, Ayad A. Al-Hamashi, Rong Huang
Summary: In this study, a potent pan-inhibitor II757 for PRMTs was designed and synthesized, showing high inhibition for various PRMTs and competitively binding at the SAM binding site of PRMT1. II757 also exhibited selectivity for PRMTs over other methyltransferases, serving as a general probe and a lead for further optimization.
Article
Biochemistry & Molecular Biology
Yi-Hsun Ho, Rong Huang
Summary: This study determines the impact of the local chemical environment on the N-terminal SGRGK sequence on NatD-mediated Nα-acetylation of histone H4/H2A and reveals the effects of oncohistone mutations and other PTMs on NatD activity, highlighting the crosstalk between NatD and PTMs.
ACS CHEMICAL BIOLOGY
(2022)
Article
Chemistry, Multidisciplinary
Iredia D. Iyamu, Jonah Z. Vilseck, Ravi Yadav, Nicholas Noinaj, Rong Huang
Summary: The study reports the first cell-potent NNMT bisubstrate inhibitor II399, which demonstrates strong binding affinity and selectivity for NNMT. The inhibition mechanism and crystal structure analysis reveal the interactions between II399 and both the substrate and cofactor binding pockets. This research provides a valuable probe for studying NNMT biology and introduces a strategy for developing cell-potent inhibitors for SAM-dependent methyltransferases.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2022)
Article
Biochemistry & Molecular Biology
Guangping Dong, Iredia D. Iyamu, Jonah Z. Vilseck, Dongxing Chen, Rong Huang
Summary: A new peptidomimetic inhibitor named GD562 was discovered with enhanced inhibitory activity against N-terminal methylation mediated by NTMT1, particularly showing improved inhibition on SET protein in human colorectal cancer cells. GD562 also exhibited over 100-fold selectivity for NTMT1 compared to other methyltransferases, providing a valuable probe for investigating the biological functions of NTMT1.
Article
Biochemistry & Molecular Biology
Iredia D. D. Iyamu, Yingzhao Zhao, Prakash T. T. Parvatkar, Bracken F. F. Roberts, Debora R. R. Casandra, Lukasz Wojtas, Dennis E. E. Kyle, Debopam Chakrabarti, Roman Manetsch
Summary: A compound with promising antimalarial activity against chloroquine-resistant and chloroquine-sensitive strains of the parasite was identified through screening and structure-activity relationship studies. The essential features necessary for its activity and properties were determined through extensive research.
BIOORGANIC & MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Ye Han, Iredia D. Iyamu, Matthew R. Clutter, Rama K. Mishra, Kyle A. Lyman, Chengwen Zhou, Ioannis Michailidis, Maya Y. Xia, Horrick Sharma, Chi-Hao Luan, Gary E. Schiltz, Dane M. Chetkovich
Summary: Major depressive disorder is a critical public health problem with a high prevalence in the United States. Researchers have discovered that disrupting the interaction between HCN channels and TRIP8b could be a potential therapeutic target for treating cognitive impairment caused by chronic stress.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Linjie Li, Mingbo Su, Weiwei Lu, Hongzhi Song, Jiaxiang Liu, Xin Wen, Yanrui Suo, Jingjing Qi, Xiaomin Luo, Yu-Bo Zhou, Xin-Hua Liao, Jia Li, Xiaojie Lu
Summary: This study reports the design of a covalent DNA-encoded library (DEL) and its selection method for discovering covalent inhibitors for target proteins. The triazine-based covalent DELs yielded potent compounds after covalent selection against target proteins, which is of significant importance for the discovery of covalent drugs.
ACS MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Chemistry, Medicinal
Youchao Deng, Guangping Dong, Ying Meng, Nicholas Noinaj, Rong Huang
Summary: We discovered the first in vivo chemical probe GD433 for NTMT1, which was optimized from our previously reported lead compound venglustat. GD433 showed improved potency and selectivity compared to venglustat across biochemical, biophysical, and cellular assays. We also identified an inactive analogue YD2160 against NTMT1. These compounds will serve as valuable tools to study the physiological and pharmacological functions of NTMT1 catalytic activity.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Emma K. Seipp, Rong Huang
Summary: A Proteolysis Targeting Chimera (PROTAC) is a bivalent molecule that promotes the degradation of specific proteins. In this study, a fluorescent probe ES148 with a binding affinity of 1.6 +/- 0.1 μM for FEM1C was designed and synthesized. A robust fluorescence polarization (FP) based competition assay was established to characterize FEM1C ligands, and the binding affinities were validated using isothermal titration calorimetry. This study offers new tools for PROTAC development by accelerating the discovery of FEM1C ligands.
BIOORGANIC & MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Manish K. Yadav, Jagannath Maharana, Ravi Yadav, Shirsha Saha, Parishmita Sarma, Chahat Soni, Vinay Singh, Sayantan Saha, Manisankar Ganguly, Xaria X. Li, Samanwita Mohapatra, Sudha Mishra, Htet A. Khant, Mohamed Chami, Trent M. Woodruff, Ramanuj Banerjee, Arun K. Shukla, Cornelius Gati
Summary: This study elucidates the structure and activation mechanism of complement anaphylatoxin receptors, providing clues for structure-guided drug discovery.
Article
Pharmacology & Pharmacy
Youchao Deng, Xiaosheng Song, Iredia D. Iyamu, Aiping Dong, Jinrong Min, Rong Huang
Summary: In this study, we reported the discovery of a noncanonical SAH surrogate YD1113 that selectively inhibits PRMT3/4/5. Crystal structures revealed a unique hydrophobic binding pocket induced by YD1113 in PRMT3/4. Furthermore, YD1113 could be modified to form a bisubstrate analogue YD1290, which exhibited potent and selective inhibition to type I PRMTs.
ACTA PHARMACEUTICA SINICA B
(2023)