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Artikel ; Online: Homoharringtonine as a PHGDH inhibitor: Unraveling metabolic dependencies and developing a potent therapeutic strategy for high-risk neuroblastoma.

Hsieh, Chiao-Hui / Huang, Chen-Tsung / Cheng, Yi-Sheng / Hsu, Chun-Hua / Hsu, Wen-Ming / Chung, Yun-Hsien / Liu, Yen-Lin / Yang, Tsai-Shan / Chien, Chia-Yu / Lee, Yu-Hsuan / Huang, Hsuan-Cheng / Juan, Hsueh-Fen

Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie

2023 Band 166, Seite(n) 115429

Abstract: Neuroblastoma, a childhood cancer affecting the sympathetic nervous system, continues to challenge the development of potent treatments due to the limited availability of druggable targets for this aggressive illness. Recent investigations have uncovered ...

Abstract	Neuroblastoma, a childhood cancer affecting the sympathetic nervous system, continues to challenge the development of potent treatments due to the limited availability of druggable targets for this aggressive illness. Recent investigations have uncovered that phosphoglycerate dehydrogenase (PHGDH), an essential enzyme for de novo serine synthesis, serves as a non-oncogene dependency in high-risk neuroblastoma. In this study, we show that homoharringtonine (HHT) acts as a PHGDH inhibitor, inducing intricate alterations in cellular metabolism, and thus providing an efficient treatment for neuroblastoma. We have experimentally verified the reliance of neuroblastoma on PHGDH and employed molecular docking, thermodynamic evaluations, and X-ray crystallography techniques to determine the bond interactions between HHT and PHGDH. Administering HHT to treat neuroblastoma resulted in effective cell elimination in vitro and tumor reduction in vivo. Metabolite and functional assessments additionally disclosed that HHT treatment suppressed de novo serine synthesis, initiating intricate metabolic reconfiguration and oxidative stress in neuroblastoma. Collectively, these discoveries highlight the potential of targeting PHGDH using HHT as a potent approach for managing high-risk neuroblastoma.
Mesh-Begriff(e)	Humans ; Child ; Phosphoglycerate Dehydrogenase ; Homoharringtonine ; Molecular Docking Simulation ; Enzyme Inhibitors ; Neuroblastoma/drug therapy ; Serine
Chemische Substanzen	Phosphoglycerate Dehydrogenase (EC 1.1.1.95) ; Homoharringtonine (6FG8041S5B) ; Enzyme Inhibitors ; Serine (452VLY9402)
Sprache	Englisch
Erscheinungsdatum	2023-09-04
Erscheinungsland	France
Dokumenttyp	Journal Article
ZDB-ID	392415-4
ISSN	1950-6007 ; 0753-3322 ; 0300-0893
ISSN (online)	1950-6007
ISSN	0753-3322 ; 0300-0893
DOI	10.1016/j.biopha.2023.115429
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Structural insights into the role of N-terminal integrity in PhoSL for core-fucosylated N-glycan recognition.

Lou, Yuan-Chao / Tu, Cheng-Fen / Chou, Chun-Chi / Yeh, Hsin-Hong / Chien, Chia-Yu / Sadotra, Sushant / Chen, Chinpan / Yang, Ruey-Bing / Hsu, Chun-Hua

International journal of biological macromolecules

2023 Band 255, Seite(n) 128309

Abstract: PhoSL (Pholiota squarrosa Lectin) has an exceptional binding affinity for biomolecules with core-fucosylated N-glycans. This modification involves the addition of fucose to the inner N-acetylglucosamine within the N-glycan structure and is known to ... ...

Abstract	PhoSL (Pholiota squarrosa Lectin) has an exceptional binding affinity for biomolecules with core-fucosylated N-glycans. This modification involves the addition of fucose to the inner N-acetylglucosamine within the N-glycan structure and is known to influence many physiological processes. Nevertheless, the molecular interactions underlying high-affinity binding of native PhoSL to core-fucosylated N-glycans remain largely unknown. In this study, we devised a strategy to produce PhoSL with the essential structural characteristics of the native protein (n-PhoSL). To do so, a fusion protein was expressed in E. coli and purified. Then, enzymatic cleavage and incubation with glutathione were utilized to recapitulate the native primary structure and disulfide bonding pattern. Subsequently, we identified the residues crucial for n-PhoSL binding to core-fucosylated chitobiose (N2F) via NMR spectroscopy. Additionally, crystal structures were solved for both apo n-PhoSL and its N2F complex. These analyses suggested a pivotal role of the N-terminal amine in maintaining the integrity of the binding pocket and actively contributing to core-fucose recognition. In support of this idea, the inclusion of additional residues at the N-terminus considerably reduced binding affinity and PhoSL cytotoxicity toward breast cancer cells. Taken together, these findings can facilitate the utilization of PhoSL in basic research, diagnostics and therapeutic strategies.
Mesh-Begriff(e)	Fucose/chemistry ; Escherichia coli/genetics ; Escherichia coli/metabolism ; Polysaccharides/chemistry ; Lectins/chemistry ; Glycosylation
Chemische Substanzen	Fucose (28RYY2IV3F) ; Polysaccharides ; Lectins
Sprache	Englisch
Erscheinungsdatum	2023-11-21
Erscheinungsland	Netherlands
Dokumenttyp	Journal Article
ZDB-ID	282732-3
ISSN	1879-0003 ; 0141-8130
ISSN (online)	1879-0003
ISSN	0141-8130
DOI	10.1016/j.ijbiomac.2023.128309
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Elucidating the tunability of binding behavior for the MERS-CoV macro domain with NAD metabolites.

Lin, Meng-Hsuan / Cho, Chao-Cheng / Chiu, Yi-Chih / Chien, Chia-Yu / Huang, Yi-Ping / Chang, Chi-Fon / Hsu, Chun-Hua

Communications biology

2021 Band 4, Heft 1, Seite(n) 123

Abstract: The macro domain is an ADP-ribose (ADPR) binding module, which is considered to act as a sensor to recognize nicotinamide adenine dinucleotide (NAD) metabolites, including poly ADPR (PAR) and other small molecules. The recognition of macro domains with ... ...

Abstract	The macro domain is an ADP-ribose (ADPR) binding module, which is considered to act as a sensor to recognize nicotinamide adenine dinucleotide (NAD) metabolites, including poly ADPR (PAR) and other small molecules. The recognition of macro domains with various ligands is important for a variety of biological functions involved in NAD metabolism, including DNA repair, chromatin remodeling, maintenance of genomic stability, and response to viral infection. Nevertheless, how the macro domain binds to moieties with such structural obstacles using a simple cleft remains a puzzle. We systematically investigated the Middle East respiratory syndrome-coronavirus (MERS-CoV) macro domain for its ligand selectivity and binding properties by structural and biophysical approaches. Of interest, NAD, which is considered not to interact with macro domains, was co-crystallized with the MERS-CoV macro domain. Further studies at physiological temperature revealed that NAD has similar binding ability with ADPR because of the accommodation of the thermal-tunable binding pocket. This study provides the biochemical and structural bases of the detailed ligand-binding mode of the MERS-CoV macro domain. In addition, our observation of enhanced binding affinity of the MERS-CoV macro domain to NAD at physiological temperature highlights the need for further study to reveal the biological functions.
Mesh-Begriff(e)	Adenosine Diphosphate Ribose/metabolism ; Binding Sites ; Biophysical Phenomena ; Crystallization ; Crystallography, X-Ray ; Humans ; Ligands ; Middle East Respiratory Syndrome Coronavirus/chemistry ; Middle East Respiratory Syndrome Coronavirus/metabolism ; Models, Molecular ; NAD/metabolism ; Nuclear Magnetic Resonance, Biomolecular ; Poly Adenosine Diphosphate Ribose/metabolism ; Protein Binding ; Protein Domains ; Protein Stability ; Thermodynamics ; Viral Proteins/chemistry ; Viral Proteins/metabolism
Chemische Substanzen	Ligands ; Viral Proteins ; NAD (0U46U6E8UK) ; Adenosine Diphosphate Ribose (20762-30-5) ; Poly Adenosine Diphosphate Ribose (26656-46-2)
Sprache	Englisch
Erscheinungsdatum	2021-01-27
Erscheinungsland	England
Dokumenttyp	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2399-3642
ISSN (online)	2399-3642
DOI	10.1038/s42003-020-01633-6
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel: C-terminal Redox Domain of

Chen, Fang-Fang / Chien, Chia-Yu / Cho, Chao-Cheng / Chang, Yu-Yung / Hsu, Chun-Hua

Antioxidants (Basel, Switzerland)

2019 Band 8, Heft 10

Abstract: Sulfur is an essential nutrient that can be converted into utilizable metabolic forms to produce sulfur-containing metabolites in plant. Adenosine 5'-phosphosulfate (APS) reductase (APR) plays a vital role in catalyzing the reduction of activated sulfate ...

Abstract	Sulfur is an essential nutrient that can be converted into utilizable metabolic forms to produce sulfur-containing metabolites in plant. Adenosine 5'-phosphosulfate (APS) reductase (APR) plays a vital role in catalyzing the reduction of activated sulfate to sulfite, which requires glutathione. Previous studies have shown that the C-terminal domain of APR acts as a glutathione-dependent reductase. The crystal structure of the C-terminal redox domain of
Sprache	Englisch
Erscheinungsdatum	2019-10-08
Erscheinungsland	Switzerland
Dokumenttyp	Journal Article
ZDB-ID	2704216-9
ISSN	2076-3921
ISSN	2076-3921
DOI	10.3390/antiox8100461
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Structural and biochemical evidence supporting poly ADP-ribosylation in the bacterium Deinococcus radiodurans.

Cho, Chao-Cheng / Chien, Chia-Yu / Chiu, Yi-Chih / Lin, Meng-Hsuan / Hsu, Chun-Hua

Nature communications

2019 Band 10, Heft 1, Seite(n) 1491

Abstract: Poly-ADP-ribosylation, a post-translational modification involved in various cellular processes, is well characterized in eukaryotes but thought to be devoid in bacteria. Here, we solve crystal structures of ADP-ribose-bound poly(ADP-ribose) ... ...

Abstract	Poly-ADP-ribosylation, a post-translational modification involved in various cellular processes, is well characterized in eukaryotes but thought to be devoid in bacteria. Here, we solve crystal structures of ADP-ribose-bound poly(ADP-ribose)glycohydrolase from the radioresistant bacterium Deinococcus radiodurans (DrPARG), revealing a solvent-accessible 2'-hydroxy group of ADP-ribose, which suggests that DrPARG may possess endo-glycohydrolase activity toward poly-ADP-ribose (PAR). We confirm the existence of PAR in D. radiodurans and show that disruption of DrPARG expression causes accumulation of endogenous PAR and compromises recovery from UV radiation damage. Moreover, endogenous PAR levels in D. radiodurans are elevated after UV irradiation, indicating that PARylation may be involved in resistance to genotoxic stresses. These findings provide structural insights into a bacterial-type PARG and suggest the existence of a prokaryotic PARylation machinery that may be involved in stress responses.
Mesh-Begriff(e)	Adenosine Diphosphate Ribose/chemistry ; Adenosine Diphosphate Ribose/metabolism ; Bacterial Proteins/chemistry ; Bacterial Proteins/genetics ; Bacterial Proteins/metabolism ; Biocatalysis ; Deinococcus/enzymology ; Deinococcus/genetics ; Deinococcus/metabolism ; Deinococcus/radiation effects ; Glycoside Hydrolases/chemistry ; Glycoside Hydrolases/genetics ; Glycoside Hydrolases/metabolism ; Poly ADP Ribosylation/radiation effects ; Poly Adenosine Diphosphate Ribose/chemistry ; Poly Adenosine Diphosphate Ribose/metabolism ; Substrate Specificity ; Ultraviolet Rays
Chemische Substanzen	Bacterial Proteins ; Adenosine Diphosphate Ribose (20762-30-5) ; Poly Adenosine Diphosphate Ribose (26656-46-2) ; Glycoside Hydrolases (EC 3.2.1.-) ; poly ADP-ribose glycohydrolase (EC 3.2.1.143)
Sprache	Englisch
Erscheinungsdatum	2019-04-02
Erscheinungsland	England
Dokumenttyp	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-019-09153-6
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel: C-Terminal Redox Domain of <i>Arabidopsis</i> APR1 Is a Non-Canonical Thioredoxin Domain with Glutaredoxin Function

Chen, Fang-Fang / Chien, Chia-Yu / Cho, Chao-Cheng / Chang, Yu-Yung / Hsu, Chun-Hua

Antioxidants. 2019 Oct. 08, v. 8, no. 10

2019

Abstract: Sulfur is an essential nutrient that can be converted into utilizable metabolic forms to produce sulfur-containing metabolites in plant. Adenosine 5′-phosphosulfate (APS) reductase (APR) plays a vital role in catalyzing the reduction of activated sulfate ...

Abstract	Sulfur is an essential nutrient that can be converted into utilizable metabolic forms to produce sulfur-containing metabolites in plant. Adenosine 5′-phosphosulfate (APS) reductase (APR) plays a vital role in catalyzing the reduction of activated sulfate to sulfite, which requires glutathione. Previous studies have shown that the C-terminal domain of APR acts as a glutathione-dependent reductase. The crystal structure of the C-terminal redox domain of Arabidopsis APR1 (AtAPR1) shows a conserved α/β thioredoxin fold, but not a glutaredoxin fold. Further biochemical studies of the redox domain from AtAPR1 provided evidence to support the structural observation. Collectively, our results provide structural and biochemical information to explain how the thioredoxin fold exerts the glutaredoxin function in APR.
Schlagwörter	Arabidopsis ; adenosine ; amino acid sequences ; crystal structure ; glutathione ; metabolites ; sulfates ; sulfites ; sulfur ; thioredoxins
Sprache	Englisch
Erscheinungsverlauf	2019-1008
Erscheinungsort	Multidisciplinary Digital Publishing Institute
Dokumenttyp	Artikel
ZDB-ID	2704216-9
ISSN	2076-3921
ISSN	2076-3921
DOI	10.3390/antiox8100461
Datenquelle	NAL Katalog (AGRICOLA)

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Artikel ; Online: Structural basis for -35 element recognition by σ

Lou, Yuan-Chao / Chou, Chun-Chi / Yeh, Hsin-Hong / Chien, Chia-Yu / Sadotra, Sushant / Hsu, Chun-Hua / Chen, Chinpan

Proteins

2019 Band 88, Heft 1, Seite(n) 69–81

Abstract: In class II transcription activation, the transcription factor normally binds to the promoter near the -35 position and contacts the domain 4 of σ factors ( ... ...

Abstract	In class II transcription activation, the transcription factor normally binds to the promoter near the -35 position and contacts the domain 4 of σ factors (σ
Mesh-Begriff(e)	Bacterial Proteins/chemistry ; Bacterial Proteins/genetics ; Bacterial Proteins/metabolism ; Crystallography, X-Ray ; DNA, Bacterial/genetics ; DNA, Bacterial/metabolism ; DNA-Directed RNA Polymerases/chemistry ; DNA-Directed RNA Polymerases/genetics ; DNA-Directed RNA Polymerases/metabolism ; Gene Expression Regulation, Bacterial ; Klebsiella pneumoniae/chemistry ; Klebsiella pneumoniae/genetics ; Klebsiella pneumoniae/metabolism ; Models, Molecular ; Promoter Regions, Genetic ; Protein Binding ; Protein Interaction Maps ; Sigma Factor/chemistry ; Sigma Factor/genetics ; Sigma Factor/metabolism ; Transcriptional Activation
Chemische Substanzen	Bacterial Proteins ; DNA, Bacterial ; Sigma Factor ; sigma factor KatF protein, Bacteria ; RNA polymerase sigma 70 (EC 2.7.7.-) ; DNA-Directed RNA Polymerases (EC 2.7.7.6)
Sprache	Englisch
Erscheinungsdatum	2019-07-22
Erscheinungsland	United States
Dokumenttyp	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	806683-8
ISSN	1097-0134 ; 0887-3585
ISSN (online)	1097-0134
ISSN	0887-3585
DOI	10.1002/prot.25768
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Plant Cytosolic Ascorbate Peroxidase with Dual Catalytic Activity Modulates Abiotic Stress Tolerances.

Chin, Dan-Chu / Senthil Kumar, Rajendran / Suen, Ching-Shu / Chien, Chia-Yu / Hwang, Ming-Jing / Hsu, Chun-Hua / Xuhan, Xu / Lai, Zhong Xiong / Yeh, Kai-Wun

iScience

2019 Band 16, Seite(n) 31–49

Abstract: Ascorbic acid-glutathione (AsA-GSH) cycle represents important antioxidant defense system in planta. Here we utilized Oncidium cytosolic ascorbate peroxidase (OgCytAPX) as a model to demonstrate that CytAPX of several plants possess dual catalytic ... ...

Abstract	Ascorbic acid-glutathione (AsA-GSH) cycle represents important antioxidant defense system in planta. Here we utilized Oncidium cytosolic ascorbate peroxidase (OgCytAPX) as a model to demonstrate that CytAPX of several plants possess dual catalytic activity of both AsA and GSH, compared with the monocatalytic activity of Arabidopsis APX (AtCytAPX). Structural modeling and site-directed mutagenesis identified that three amino acid residues, Pro
Sprache	Englisch
Erscheinungsdatum	2019-05-15
Erscheinungsland	United States
Dokumenttyp	Journal Article
ISSN	2589-0042
ISSN (online)	2589-0042
DOI	10.1016/j.isci.2019.05.014
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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