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o Glcnac

Hao Zhang, Tihomir Tomašič, Jie Shi, Matjaž Weiss, Rob Ruijtenbeek, Marko Anderluh, Roland J Pieters
O -GlcNAc transferase (OGT) attaches a GlcNAc moiety on specific substrate proteins using UDP-GlcNAc as the sugar donor. This modification can alter protein function by regulating cellular signaling and transcription pathways in response to altered nutrient availability and stress. Specific inhibitors of OGT would be valuable tools for biological studies and lead structures for therapeutics. The existing OGT inhibitors are mainly derived from the sugar donor substrate, but poor cell permeability and off-target effects limit their use...
May 1, 2018: MedChemComm
Pukkavadee Netsirisawan, Parunya Chaiyawat, Daranee Chokchaichamnankit, Kriengsak Lirdprapamongkol, Chantragan Srisomsap, Jisnuson Svasti, Voraratt Champattanachai
O-GlcNAcylation is a dynamic posttranslational modification of nucleoplasmic proteins. Previously, we reported that the O-GlcNAcylation level was increased in primary breast and colorectal cancer tissues. However, its precise roles in cancer development and progression are still largely unexplored. The aim of the present study was to investigate the roles of O-GlcNAcylation in the malignant transformation of cancer cell lines. O-GlcNAcylation level was examined in six cancer cell lines including breast (MCF-7 and MDA-MB-231), colorectal (SW480 and SW620), and liver (SK-Hep1 and HepG2)...
August 1, 2018: Oncology Reports
Caifei Liu, Jing Li
The addition and removal of O-linked N-acetylglucosamine (O-GlcNAc) to and from the Ser and Thr residues of proteins is an emerging post-translational modification. Unlike phosphorylation, which requires a legion of kinases and phosphatases, O-GlcNAc is catalyzed by the sole enzyme in mammals, O-GlcNAc transferase (OGT), and reversed by the sole enzyme, O-GlcNAcase (OGA). With the advent of new technologies, identification of O-GlcNAcylated proteins, followed by pinpointing the modified residues and understanding the underlying molecular function of the modification has become the very heart of the O-GlcNAc biology...
2018: Frontiers in Endocrinology
Zhengliang L Wu, Timothy J Tatge, Alex E Grill, Yonglong Zou
O-GlcNAcylation is a reversible serine/threonine glycosylation for regulating protein activity and availability inside cells. In a given protein, O-GlcNAcylated and unoccupied O-linked β-N-acetylglucosamine (O-GlcNAc) sites are referred to as closed and open sites, respectively. The balance between open and closed sites is believed to be dynamically regulated. In this report, closed sites are detected using in vitro incorporation of GalNAz by B3GALNT2, and open sites are detected by in vitro incorporation of GlcNAz by O-GlcNAc transferase (OGT), via click chemistry...
July 24, 2018: Cell Chemical Biology
Ching-Yu Lai, Hsuan Liu, Kai Xuan Tin, Yi Huang, Kun-Hai Yeh, Hubert W Peng, Huan-Da Chen, Jun-Yu He, Yun-Jung Chiang, Chun-Shan Liu, Shih-Yen Weng, Mi-Hua Tao, Jeffrey Jong-Young Yen, Hsin-Fang Yang-Yen
Aged hepatocyte-specific-Mcl-1 knockout (MKO-hep) mice are prone to develop liver tumors mimicking human hepatocellular carcinoma (HCC). Here we reported that a protein named UDP-N-acetylglucosamine pyrophosphorylase-1-like-1 (Uap1l1) is upregulated in the liver of young MKO-hep mice without any macroscopically detectable tumor nodules and is prominently expressed in the hepatic tumors developed in the aged MKO-hep mice. Intriguingly, human UAP1L1 is also significantly upregulated in a distinct subset of HCC tissues and patients with upregulated expression of UAP1L1 appeared to have poor prognosis...
August 10, 2018: Oncogene
Mingzuo Jiang, Bing Xu, Xiaowei Li, Yulong Shang, Yi Chu, Weijie Wang, Di Chen, Nan Wu, Sijun Hu, Song Zhang, Mengbin Li, Kaichun Wu, Xiaoyong Yang, Jie Liang, Yongzhan Nie, Daiming Fan
Advanced colorectal cancer (CRC) is one of the deadliest cancers, and the 5-year survival rate of patients with metastasis is extremely low. The epithelial-mesenchymal transition (EMT) is considered essential for metastatic CRC, but the fundamental molecular basis underlying this effect remains unknown. Here, we identified that O-GlcNAcylation, a unique posttranslational modification (PTM) involved in cancer metabolic reprogramming, increased the metastatic capability of CRC. The levels of O-GlcNAcylation were increased in the metastatic CRC tissues and cell lines, which likely promoted the EMT by enhancing EZH2 protein stability and function...
August 9, 2018: Oncogene
Shin-Yi Yu, Cheng-Te Hsiao, Mineko Izawa, Akiko Yusa, Hiroji Ishida, Shigeo Nakamura, Hirokazu Yagi, Reiji Kannagi, Kay-Hooi Khoo
Sulfated glycans are known to be involved in several glycan-mediated cell adhesion and recognition. Our mRNA transcript analyses on the genes involved in synthesizing GlcNAc-6- O -sulfated glycans in human colon cancer tissues indicated that GlcNAc6ST-2 (CHST4) was preferentially expressed in cancer cells compared to non-malignant epithelial cells among the three known major GlcNAc-6- O -sulfotransferases. On the contrary, GlcNAc6ST-3 (CHST5) was only expressed in non-malignant epithelial cells while GlcNAc6ST-1 (CHST2) was expressed equally in both cancerous and non-malignant epithelial cells...
August 9, 2018: Journal of Biological Chemistry
Cesar A De Leon, Geoffrey Lang, Marcos I Saavedra, Matthew R Pratt
The facile synthesis of serine, threonine, and cysteine β-glycosides using commercially available peracetylated β- N-acetylglucosamine (β-Ac4 GlcNAc) and catalytic amounts of indium bromide (InBr3 ) is described. This method involves only inexpensive reagents that require no further modification or special handling. The reagents are simply mixed, dissolved, and refluxed to afford the GlcNAcylated amino acids in great yields (70-80%). This operationally simple procedure should facilitate the study of O-GlcNAcylation without necessitating expertise in synthetic carbohydrate chemistry...
August 8, 2018: Organic Letters
Lingli Lei, Jin Xie, Jie Yu, Yuan Li, Yingshuai Liu
Although a variety of approaches have been developed to analyze protein O-GlcNAcylation, efficient investigations on O-GlcNAcylation of proteins of interest in high-throughput manner are still in high demand to further explore its functionality. In this work, we first develop a powerful microarray platform for a sensitive, specific and high-throughput analysis of protein O-GlcNAcylation. The developed array biochip is then utilized to parallelly analyze the O-GlcNAcylation of three oncogenic transcription factors C-Myc, NF-κB and p53 in normal prostate epithelial cell (RWPE-1) and prostate cancer cell line (PC-3)...
August 4, 2018: Analytical Biochemistry
Linhong Zhao, Junaid Ali Shah, Yong Cai, Jingji Jin
As one of the post-translational modifications, O -linked β- N -acetylglucosamine ( O -GlcNAc) modification ( O -GlcNAcylation) often occurs on serine (Ser) and threonine (Thr) residues of specific substrate cellular proteins via the addition of O -GlcNAc group by O -GlcNAc transferase (OGT). Maintenance of normal intracellular levels of O -GlcNAcylation is controlled by OGT and glycoside hydrolase O -GlcNAcase (OGA). Unbalanced O -GlcNAcylation levels have been involved in many diseases, including diabetes, cancer, and neurodegenerative disease...
August 6, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Abhishek Asthana, Parameswaran Ramakrishnan, Yorleny Vicioso, Keman Zhang, Reshmi Parameswaran
Treatment for Acute myeloid leukemia (AML) has remained unchanged for past 40 years. Targeting cell metabolism is a promising avenue for future cancer therapy. We found that enzymes involved in metabolic hexosamine biosynthetic pathway (HBP) are increased in AML patients. Inhibiting GFAT (the rate limiting enzyme of HBP) induced differentiation and apoptosis in AML cells, sparing normal cells. UDP-GlcNAc, the end product of HBP, is the substrate for O-GlcNAcylation, a post-translational modification. O-GlcNAc transferase (OGT) is the enzyme which transfers GlcNAc from UDP-GlcNAc to target proteins...
August 6, 2018: Molecular Cancer Therapeutics
Jéssica S G Miguez, Vanessa D Justina, Alecsander F M Bressan, Patrícia G F Marchi, Adenilda C Honorio-França, Fernando S Carneiro, R Clinton Webb, Rita C Tostes, Fernanda R Giachini, Victor V Lima
AIMS: The interleukin-10 (IL-10) is an immuno-regulatory cytokine that plays a protective effect in the vasculature. IL-10 binding to its receptor, activating the IL-10/JAK1/STAT3 cascade to exert its effects. Therefore, STAT3 phosphorylation is essential for IL-10 actions. O-Glycosylation with linked β-N-acetylglucosamine (O-GlcNAc) is a post-translational modification able to regulate many proteins by interfering with protein on a phosphorylation level. Our aim was to determine whether O-GlcNAc promotes the inhibition of IL-10-pathway (JAK1/STAT3/IL-10), inactivationg its action in the vasculature...
July 31, 2018: Life Sciences
Dandan Wang, Xiaoyue Hu, Seung Hee Lee, Feng Chen, Kai Jiang, Zizhuo Tu, Zejian Liu, Jing Du, Li Wang, Chaoying Yin, Yu Liao, Hongcai Shang, Kathleen A Martin, Raimund I Herzog, Lawrence H Young, Li Qian, John Hwa, Yaozu Xiang
Management for patients with diabetes experiencing myocardial infarction remains a challenge. Here the authors show that hyperglycemia- and hyperinsulinemia-induced microRNA-24 (miR-24) reduction and O-GlcNAcylation in the diabetic heart contribute to poor survival and increased infarct size in diabetic myocardial ischemia/reperfusion (I/R). In a mouse model of myocardial I/R, pharmacological or genetic overexpression of miR-24 in hearts significantly reduced myocardial infarct size. Experimental validation revealed that miR-24 targets multiple key proteins, including O-GlcNac transferase, ATG4A, and BIM, to coordinately protect the myocardium from I/R injury...
June 2018: JACC. Basic to Translational Science
Ke Qin, Yuntao Zhu, Wei Qin, Jinjun Gao, Xuan Shao, Yan-Ling Wang, Wen Zhou, Chu Wang, Xing Chen
Large-scale quantification of protein O-linked β- N-acetylglucosamine (O-GlcNAc) modification in a site-specific manner remains a key challenge in studying O-GlcNAc biology. Herein, we developed an isotope-tagged cleavable linker (isoTCL) strategy, which enabled isotopic labeling of O-GlcNAc through bioorthogonal conjugation of affinity tags. We demonstrated the application of the isoTCL in mapping and quantification of O-GlcNAcylation sites in HeLa cells. Furthermore, we investigated the O-GlcNAcylation sensitivity to the sugar donor by quantifying the levels of modification under different concentrations of the O-GlcNAc labeling probe in a site-specific manner...
August 17, 2018: ACS Chemical Biology
Jie Gao, Yang Yang, Rongfang Qiu, Kai Zhang, Xu Teng, Ruiqiong Liu, Yan Wang
The role of O-GlcNAc transferase (OGT) in gene regulation and tumor invasion is poorly understood. Here, we have identified several previously undiscovered OGT-interacting proteins, including the PRMT5/WDR77 complex, the PRC2 complex, the TET family, the CRL4B complex and the NuRD complex. Genome-wide analysis of target genes responsive to OGT resulted in identification of a cohort of genes including SNAI1 and ING4 that are critically involved in cell epithelial-to-mesenchymal transition (EMT) and invasion/metastasis...
July 23, 2018: Carcinogenesis
Su Jin Lee, Min Jung Nam, Da Eun Lee, Jeen-Woo Park, Beom Sik Kang, Dong-Seok Lee, Hyun-Shik Lee, Oh-Shin Kwon
The mechanisms underlying the progression to non-alcoholic steatohepatitis (NASH) remain to be elucidated. In the present study, we aimed to identify the proteins involved in the pathogenesis of liver tissue inflammation and to investigate the effects of silibinin, a natural polyphenolic flavonoid, on steatohepatitis. We performed comparative proteomic analysis using methionine and choline-deficient (MCD) diet-induced NASH model mice. Eighteen proteins were identified from the two-dimensional proteomic analysis, which are not only differentially expressed, but also significantly improved, by silibinin treatment...
July 24, 2018: International Journal of Molecular Sciences
Kevin Qian, Simeng Wang, Minnie Fu, Jinfeng Zhou, Jay Prakash Singh, Min-Dian Li, Yunfan Yang, Kaisi Zhang, Jing Wu, Yongzhan Nie, Hai-Bin Ruan, Xiaoyong Yang
Many intracellular proteins are reversibly modified by O -linked N -acetylglucosamine ( O -GlcNAc), a post-translational modification that dynamically regulates fundamental cellular processes in response to diverse environmental cues. Accumulating evidence indicates that both excess and deficiency of protein O -GlcNAcylation can have deleterious effects on the cell, suggesting that maintenance of O -GlcNAc homeostasis is essential for proper cellular function. However, the mechanisms through which O -GlcNAc homeostasis is maintained in the physiologic state and altered in the disease state have not yet been investigated...
July 23, 2018: Journal of Biological Chemistry
Antonella Tramutola, Nidhi Sharma, Eugenio Barone, Chiara Lanzillotta, Andrea Castellani, Federica Iavarone, Federica Vincenzoni, Massimo Castagnola, D Allan Butterfield, Silvana Gaetani, Tommaso Cassano, Marzia Perluigi, Fabio Di Domenico
PET scan analysis demonstrated the early reduction of cerebral glucose metabolism in Alzheimer disease (AD) patients that can make neurons vulnerable to damage via the alteration of the hexosamine biosynthetic pathway (HBP). Defective HBP leads to flawed protein O-GlcNAcylation coupled, by a mutual inverse relationship, with increased protein phosphorylation on Ser/Thr residues. Altered O-GlcNAcylation of Tau and APP have been reported in AD and is closely related with pathology onset and progression. In addition, type 2 diabetes patients show an altered O-GlcNAcylation/phosphorylation that might represent a link between metabolic defects and AD progression...
July 18, 2018: Biochimica et Biophysica Acta
Shoichi Naito, Tatsuya Takahashi, Junji Onoda, Shoko Uemura, Naoki Ohyabu, Hiroshi Takemoto, Shoji Yamane, Ikuo Fujii, Shin-Ichiro Nishimura, Yoshito Numata
Numerous anti-mucin 1 (anti-MUC1) antibodies that recognize O -glycan core structures have already been developed. However, most of them show low specificities toward O -glycan structures and/or low affinity toward a monovalent epitope. In this study, using an MUC1 glycopeptide library, we established two novel anti-MUC1 monoclonal antibodies (1B2 and 12D10) with designed carbohydrate specificities. Compared with previously reported anti-MUC1 antibodies, 1B2 and 12D10 showed quite different features regarding their specificities, affinities, and reactivity profiles to various cell lines...
November 30, 2017: ACS Omega
Mitsutaka Ogawa, Yuya Senoo, Kazutaka Ikeda, Hideyuki Takeuchi, Tetsuya Okajima
Extracellular O -GlcNAc is a novel class of modification catalyzed by epidermal growth factor-like (EGF)-domain specific O -GlcNAc transferase (EOGT). In mammals, EOGT is required for ligand-mediated Notch signaling for vascular development. Previous studies have revealed that O -GlcNAc in mammalian cultured cells is subject to subsequent glycosylation, which may impose additional layers of regulation. This study aimed to analyze the O -GlcNAc glycans of Drosophila EGF20 as model substrates and mouse Notch1 EGF repeats by mass-spectrometry...
July 17, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
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