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#33937202   2021/04/14 To Up

New Quinolinone O-GlcNAc Transferase Inhibitors Based on Fragment Growth.

O-GlcNAcylation is an important post-translational and metabolic process in cells that must be carefully regulated. O-GlcNAc transferase (OGT) is ubiquitously present in cells and is the only enzyme that catalyzes the transfer of O-GlcNAc to proteins. OGT is a promising target in various pathologies such as cancer, immune system diseases, or nervous impairment. In our previous work we identified the 2-oxo-1,2-dihydroquinoline-4-carboxamide derivatives as promising compounds by a fragment-based drug design approach. Herein, we report the extension of this first series with several new fragments. As the most potent fragment, we identified with an IC value of 116.0 μM. If compared with the most potent inhibitor of the first series, (IC = 117.6 μM), we can conclude that the new fragments did not improve OGT inhibition remarkably. Therefore, was used as the basis for the design of a series of compounds with the elongation toward the O-GlcNAc binding pocket as the free carboxylate allows easy conjugation. Compound with an IC value of 144.5 μM showed the most potent OGT inhibition among the elongated compounds, but it loses inhibition potency when compared to the UDP mimetic . We therefore assume that the binding of the compounds in the O-GlcNAc binding pocket is likely not crucial for OGT inhibition. Furthermore, evaluation of the compounds with two different assays revealed that some inhibitors most likely interfere with the commercially available UDP-Glo™ glycosyltransferase assay, leading to false positive results. This observation calls for caution, when evaluating UDP mimetic as OGT inhibitors with the UDP-Glo™ glycosyltransferase assay, as misinterpretations can occur.
Matjaž Weiss, Elena M Loi, Maša Sterle, Cyril Balsollier, Tihomir Tomašič, Roland J Pieters, Martina Gobec, Marko Anderluh

2057 related Products with: New Quinolinone O-GlcNAc Transferase Inhibitors Based on Fragment Growth.

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#33925313   2021/04/27 To Up

Drosophila -GlcNAcase Mutants Reveal an Expanded Glycoproteome and Novel Growth and Longevity Phenotypes.

The reversible posttranslational -GlcNAc modification of serine or threonine residues of intracellular proteins is involved in many cellular events from signaling cascades to epigenetic and transcriptional regulation. -GlcNAcylation is a conserved nutrient-dependent process involving two enzymes, with -GlcNAc transferase (OGT) adding -GlcNAc and with -GlcNAcase (OGA) removing it in a manner that's protein- and context-dependent. -GlcNAcylation is essential for epigenetic regulation of gene expression through its action on Polycomb and Trithorax and COMPASS complexes. However, the important role of -GlcNAc in adult life and health span has been largely unexplored, mainly due the lack of available model systems. Cataloging the -GlcNAc proteome has proven useful in understanding the biology of this modification in vivo. In this study, we leveraged a recently developed knockout fly mutant to identify the -GlcNAcylated proteins in adult . The adult -GlcNAc proteome revealed many proteins related to cell and organismal growth, development, differentiation, and epigenetics. We identified many -GlcNAcylated proteins that play a role in increased growth and decreased longevity, including HCF, SIN3A, LOLA, KISMET, ATX2, SHOT, and FOXO. Interestingly, mutant flies are larger and have a shorter life span compared to wild type flies, suggesting increased -GlcNAc results in increased growth. Our results suggest that -GlcNAc alters the function of many proteins related to transcription, epigenetic modification and signaling pathways that regulate growth rate and longevity. Therefore, our findings highlight the importance of -GlcNAc in growth and life span in adult .
Ilhan Akan, Adnan Halim, Sergey Y Vakhrushev, Henrik Clausen, John A Hanover

1442 related Products with: Drosophila -GlcNAcase Mutants Reveal an Expanded Glycoproteome and Novel Growth and Longevity Phenotypes.

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#33916244   2021/04/01 To Up

O-GlcNAcylation and O-GlcNAc Cycling Regulate Gene Transcription: Emerging Roles in Cancer.

O-linked β-N-acetylglucosamine (O-GlcNAc) is a single sugar post-translational modification (PTM) of intracellular proteins linking nutrient flux through the Hexosamine Biosynthetic Pathway (HBP) to the control of cis-regulatory elements in the genome. Aberrant O-GlcNAcylation is associated with the development, progression, and alterations in gene expression in cancer. O-GlcNAc cycling is defined as the addition and subsequent removal of the modification by O-GlcNAc Transferase (OGT) and O-GlcNAcase (OGA) provides a novel method for cells to regulate various aspects of gene expression, including RNA polymerase function, epigenetic dynamics, and transcription factor activity. We will focus on the complex relationship between phosphorylation and O-GlcNAcylation in the regulation of the RNA Polymerase II (RNAP II) pre-initiation complex and the regulation of the carboxyl-terminal domain of RNAP II via the synchronous actions of OGT, OGA, and kinases. Additionally, we discuss how O-GlcNAcylation of TATA-box binding protein (TBP) alters cellular metabolism. Next, in a non-exhaustive manner, we will discuss the current literature on how O-GlcNAcylation drives gene transcription in cancer through changes in transcription factor or chromatin remodeling complex functions. We conclude with a discussion of the challenges associated with studying O-GlcNAcylation and present several new approaches for studying O-GlcNAc regulated transcription that will advance our understanding of the role of O-GlcNAc in cancer.
Matthew P Parker, Kenneth R Peterson, Chad Slawson

1711 related Products with: O-GlcNAcylation and O-GlcNAc Cycling Regulate Gene Transcription: Emerging Roles in Cancer.



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#33909326   2021/04/28 To Up

The crosstalk network of XIST/miR-424-5p/OGT mediates RAF1 glycosylation and participates in the progression of liver cancer.

Liver cancer is a major public health concern, but the mechanistic actions of bio-markers contributing to liver cancer remain to be determined. In this study, we aimed to investigate the regulatory cascade of microRNA-424-5p (miR-424-5p), X-inactive-specific transcript (XIST), and O-GlcNAc transferase (OGT) in liver cancer.
Deng Ning, Chen Jin, Pengcheng Du, Qiumeng Liu, Qi Cheng, Xue Li, Bixiang Zhang, Xiaoping Chen, Li Jiang

1179 related Products with: The crosstalk network of XIST/miR-424-5p/OGT mediates RAF1 glycosylation and participates in the progression of liver cancer.



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#33888512   2021/04/22 To Up

Modeling transcriptional regulation of model species with deep learning.

To enable large-scale analyses of regulatory logic in model species, we developed DeepArk, a set of deep learning models of the -regulatory codes of four widely-studied species: , , , and DeepArk accurately predicts the presence of thousands of different context-specific regulatory features, including chromatin states, histone marks, and transcription factors. In vivo studies show that DeepArk can predict the regulatory impact of any genomic variant (including rare or not previously observed), and enables the regulatory annotation of understudied model species.
Evan M Cofer, João Raimundo, Alicja Tadych, Yuji Yamazaki, Aaron K Wong, Chandra L Theesfeld, Michael S Levine, Olga G Troyanskaya

1611 related Products with: Modeling transcriptional regulation of model species with deep learning.

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#33871701   2021/04/19 To Up

Effects of turbulence fluctuation intensity in bioreactor of sewage treatment on physical and chemical properties of biofilms.

The flow velocity plays an important role in the growth and characteristics of biofilm in the bioreactor as well as its treatment efficiency, which has been a hot research topic. In a sewage treatment bioreactor, the type of flow is usually turbulence. According to the methods of Reynolds decomposition, the flow velocity of turbulence consists of the time-mean velocity and fluctuation velocity, which usually exist simultaneously in real flow. However, the current research on the influence of turbulence flow velocity mainly focuses on the time-mean velocity, while the fluctuation velocity has not been reported because of very difficult to control. To this end, in this paper, a laboratory oscillating-grid turbulence (OGT) bioreactor with zero time-mean velocity and only fluctuation velocity was designed. In this bioreactor, the fluctuation velocity could be easily manipulated by varying the operational parameters of the grid. Based on the numerical simulation of Gas-liquid two-phase flow, the distributions of fluctuation velocity and corresponding turbulence fluctuation intensity, gas holdup, and Reynolds stress were obtained. After that, the effects of the turbulent fluctuation intensity on the biofilm thickness, density, and composition of extracellular polymeric substances (EPS) were studied experimentally. The results showed that turbulent fluctuation had a significant effect on the physical and chemical properties of biofilms, and the fluctuation velocity promoted the increase in the biofilm density and the content of protein and carbohydrates in EPS. This study was intended to provide theoretical support for the design and operation optimization of bioreactors.
Chao Luo, Lisha Guo, Shi Zeng, Tianyu Long

1808 related Products with: Effects of turbulence fluctuation intensity in bioreactor of sewage treatment on physical and chemical properties of biofilms.

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#33863881   2021/04/16 To Up

O-linked N-acetylglucosamine transferase is involved in fine regulation of flowering time in winter wheat.

Vernalization genes underlying dramatic differences in flowering time between spring wheat and winter wheat have been studied extensively, but little is known about genes that regulate subtler differences in flowering time among winter wheat cultivars, which account for approximately 75% of wheat grown worldwide. Here, we identify a gene encoding an O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) that differentiates heading date between winter wheat cultivars Duster and Billings. We clone this TaOGT1 gene from a quantitative trait locus (QTL) for heading date in a mapping population derived from these two bread wheat cultivars and analyzed in various environments. Transgenic complementation analysis shows that constitutive overexpression of TaOGT1b from Billings accelerates the heading of transgenic Duster plants. TaOGT1 is able to transfer an O-GlcNAc group to wheat protein TaGRP2. Our findings establish important roles for TaOGT1 in winter wheat in adaptation to global warming in the future climate scenarios.
Min Fan, Fang Miao, Haiyan Jia, Genqiao Li, Carol Powers, Ragupathi Nagarajan, Phillip D Alderman, Brett F Carver, Zhengqiang Ma, Liuling Yan

1547 related Products with: O-linked N-acetylglucosamine transferase is involved in fine regulation of flowering time in winter wheat.

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#33855783   2021/04/15 To Up

O-GlcNAcylation of TDP-43 suppresses proteinopathies and promotes TDP-43's mRNA splicing activity.

Pathological TDP-43 aggregation is characteristic of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP); however, how TDP-43 aggregation and function are regulated remain poorly understood. Here, we show that O-GlcNAc transferase OGT-mediated O-GlcNAcylation of TDP-43 suppresses ALS-associated proteinopathies and promotes TDP-43's splicing function. Biochemical and cell-based assays indicate that OGT's catalytic activity suppresses TDP-43 aggregation and hyperphosphorylation, whereas abolishment of TDP-43 O-GlcNAcylation impairs its RNA splicing activity. We further show that TDP-43 mutations in the O-GlcNAcylation sites improve locomotion defects of larvae and adult flies and extend adult life spans, following TDP-43 overexpression in Drosophila motor neurons. We finally demonstrate that O-GlcNAcylation of TDP-43 promotes proper splicing of many mRNAs, including STMN2, which is required for normal axonal outgrowth and regeneration. Our findings suggest that O-GlcNAcylation might be a target for the treatment of TDP-43-linked pathogenesis.
Meng-Jie Zhao, Xiao Yao, Ping Wei, Chen Zhao, Meng Cheng, Dong Zhang, Wen Xue, Wen-Tian He, Weili Xue, Xinxin Zuo, Lei-Lei Jiang, Zhiyuan Luo, Jiaqi Song, Wen-Jie Shu, Han-Ye Yuan, Yi Liang, Hui Sun, Yan Zhou, Yu Zhou, Ling Zheng, Hong-Yu Hu, Jiwu Wang, Hai-Ning Du

1662 related Products with: O-GlcNAcylation of TDP-43 suppresses proteinopathies and promotes TDP-43's mRNA splicing activity.

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