CSIG-02. NRF2-GUIDED GLUTATHIONE SYNTHESIS IS AN ESSENTIAL METABOLIC PATHWAY IN IN IDH1-MUTATED GLIOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi33-vi33
Author(s):  
Yang Liu ◽  
Di Yu ◽  
Chunzhang Yang
Keyword(s):  
Metabolic Pathway ◽  
Nicotinamide Adenine Dinucleotide ◽  
De Novo ◽  
Redox Homeostasis ◽  
Nicotinamide Adenine ◽  
De Novo Synthesis ◽  
Who Grade ◽  
Glutathione Synthesis ◽  
Synergistic Cytotoxicity ◽  
Idh Mutations

Abstract BACKGROUND Isocitrate dehydrogenase (IDH) mutations are common genetic abnormalities in WHO Grade II/III glioma, which result in the reprogramming of cellular metabolism and redox homeostasis. Many lines of evidence showed that IDH mutations are critical for glioma formation, whereas the therapeutic options for IDH-mutated cancers remain limited. METHODS In the present study, we used the patient-derived glioma cell lines to investigate the role of nuclear factor erythroid 2-related factor 2 (NRF2) governed glutathione de novo synthesis. Further, we evaluated the therapeutic value of NRF2 inhibitors in IDH1-mutated cells and preclinical orthotopic models. RESULTS The neomorphic activity of mutant IDH reprogrammed the metabolic pathways involving enzyme cofactors such as nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). The depletion of NAD(P) in IDH1-mutated cells resulted in elevated oxidative stress and constitutive activation of NRF2-governed cytoprotective pathways through the decoupling of NRF2 from its E3 ligase Kelch-like ECH-associated protein 1 (Keap1). Activation of NRF2 enhanced glutathione synthesis by enhancing the gene transcription of GCLC, GCLM, and SLC7A11, which are the critical for glutathione de novo synthesis. Further, evidence from both in vitro assays and patient cohort indicated that NRF2 governed glutathione synthesis is important for maintaining the redox homeostasis and cell survival, especially in IDH1-mutated glioma. Finally, Blockade of the NRF2/glutathione metabolic pathway exhibited synergistic cytotoxicity with the metabolic stress in IDH1-mutated cells, which results in overwhelming oxidative damage, as well as a substantial reduction in tumor cell proliferation and xenograft expansion. CONCLUSION In this study, we highlighted that NRF2 plays critical roles in the disease progression of IDH1-mutated glioma by prompting glutathione synthesis. Targeting NRF2 governed glutathione metabolism could serve as a valuable synthetic lethality approach for IDH1-mutated malignancies.

scholarly journals EXTH-03. TRIPTOLIDE, A NOVEL THERAPEUTIC AGENT FOR IDH1-MUTATED GLIOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi82-vi83
Author(s):  
Di Yu ◽  
Yang Liu ◽  
Guowang Xu ◽  
Chunzhang Yang
Keyword(s):  
Cancer Cells ◽  
De Novo ◽  
Synthetic Lethality ◽  
Redox Homeostasis ◽  
Glutamate Transporter ◽  
Protective Role ◽  
Related Factor ◽  
De Novo Synthesis ◽  
Ros Scavenging ◽  
Idh Mutations

Abstract BACKGROUND Isocitrate dehydrogenase (IDH1/2) mutations are common genetic abnormalities in human malignancies, which result in neomorphic enzyme activity that catalyzes 2-hydroxyglutarate (2-HG) production. While IDH mutations are recognized as critical cancer-associated genetic changes, the therapeutic options for IDH-mutated cancers remain limited. METHODS In the present study, we investigated the reactive oxygen species (ROS) scavenging pathways in patient-derived IDH1-mutated cells. Further, we investigated the protective role of glutathione de novo synthesis for IDH1-mutated cancer cells. Finally, we evaluated triptolide, a diterpenoid epoxide derived from Tripterygium wilfordii, as an experimental therapeutic for IDH1-mutated cells and xenografts. RESULTS We discovered that the neomorphic activity of IDH1 mutant enzyme triggers metabolic depletion and a substantial elevated burden of ROS scavenging in cancer cells. The nuclear factor erythroid 2-related factor 2 (NRF2)-guided antioxidant pathway plays a key role in maintaining redox homeostasis for IDH1-mutated cells. Triptolide serves as a potent inhibitor of NRF2 through enhancing the NRF2 ubiquitination and subsequently proteasomal degradation. Additionally, triptolide compromises the de novo synthesis of glutathione via suppression of NRF2-guided transcription of SLC7A11, which encodes cystine/glutamate transporter (xCT). Reduced availability of glutathione results in overwhelming oxidative damage in DNA and lipid, which translates into severe cytotoxicity and reduced xenograft expansion of IDH1-mutated cells. CONCLUSION Overall our findings highlight triptolide as a valuable synthetic lethality approach for IDH1-mutated malignancies by targeting NRF2-guided redox homeostasis.

scholarly journals Differential role of nicotinamide adenine dinucleotide deficiency in acute and chronic kidney disease

2020 ◽  
Vol 36 (1) ◽  
pp. 60-68
Author(s):  
Anna Faivre ◽  
Elena Katsyuba ◽  
Thomas Verissimo ◽  
Maja Lindenmeyer ◽  
Renuga Devi Rajaram ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Nicotinamide Adenine Dinucleotide ◽  
De Novo ◽  
Nicotinamide Adenine ◽  
Sequencing Analysis ◽  
Salvage Pathway ◽  
De Novo Synthesis ◽  
Nad Synthesis ◽  
Ckd Stage

Abstract Background Nicotinamide adenine dinucleotide (NAD+) is a ubiquitous coenzyme involved in electron transport and a co-substrate for sirtuin function. NAD+ deficiency has been demonstrated in the context of acute kidney injury (AKI). Methods We studied the expression of key NAD+ biosynthesis enzymes in kidney biopsies from human allograft patients and patients with chronic kidney disease (CKD) at different stages. We used ischaemia–reperfusion injury (IRI) and cisplatin injection to model AKI, urinary tract obstruction [unilateral ureteral obstruction (UUO)] and tubulointerstitial fibrosis induced by proteinuria to investigate CKD in mice. We assessed the effect of nicotinamide riboside (NR) supplementation on AKI and CKD in animal models. Results RNA sequencing analysis of human kidney allograft biopsies during the reperfusion phase showed that the NAD+de novo synthesis is impaired in the immediate post-transplantation period, whereas the salvage pathway is stimulated. This decrease in de novo NAD+ synthesis was confirmed in two mouse models of IRI where NR supplementation prevented plasma urea and creatinine elevation and tubular injury. In human biopsies from CKD patients, the NAD+de novo synthesis pathway was impaired according to CKD stage, with better preservation of the salvage pathway. Similar alterations in gene expression were observed in mice with UUO or chronic proteinuric glomerular disease. NR supplementation did not prevent CKD progression, in contrast to its efficacy in AKI. Conclusion Impairment of NAD+ synthesis is a hallmark of AKI and CKD. NR supplementation is beneficial in ischaemic AKI but not in CKD models.

scholarly journals Aspects of Tryptophan and Nicotinamide Adenine Dinucleotide in Immunity: A New Twist in an Old Tale

2017 ◽  
Vol 10 ◽  
pp. 117864691771349 ◽  
Author(s):  
Hector Rodriguez Cetina Biefer ◽  
Anju Vasudevan ◽  
Abdallah Elkhal
Keyword(s):  
Immune Responses ◽  
Nicotinamide Adenine Dinucleotide ◽  
Tryptophan Hydroxylase ◽  
De Novo ◽  
Kynurenine Pathway ◽  
Nicotinamide Adenine ◽  
De Novo Synthesis ◽  
Major Pathway ◽  
Adaptive Immune ◽  
Tryptophan Catabolism

Increasing evidence underscores the interesting ability of tryptophan to regulate immune responses. However, the exact mechanisms of tryptophan’s immune regulation remain to be determined. Tryptophan catabolism via the kynurenine pathway is known to play an important role in tryptophan’s involvement in immune responses. Interestingly, quinolinic acid, which is a neurotoxic catabolite of the kynurenine pathway, is the major pathway for the de novo synthesis of nicotinamide adenine dinucleotide (NAD+). Recent studies have shown that NAD+, a natural coenzyme found in all living cells, regulates immune responses and creates homeostasis via a novel signaling pathway. More importantly, the immunoregulatory properties of NAD+ are strongly related to the overexpression of tryptophan hydroxylase 1 (Tph1). This review provides recent knowledge of tryptophan and NAD+ and their specific and intriguing roles in the immune system. Furthermore, it focuses on the mechanisms by which tryptophan regulates NAD+ synthesis as well as innate and adaptive immune responses.

scholarly journals DDRE-08. NRF2/GLUTATHIONE METABOLISM AS A NOVEL THERAPEUTIC TARGET FOR IDH1-MUTATED GLIOMA

2020 ◽  
Vol 3 (Supplement_1) ◽  
pp. i8-i8
Author(s):  
Yang Liu ◽  
Di Yu ◽  
Orieta Celiku ◽  
Aiguo Li ◽  
Mioara Larion ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Tumor Cell ◽  
Cell Lines ◽  
Nicotinamide Adenine Dinucleotide ◽  
Cell Biology ◽  
De Novo ◽  
Nicotinamide Adenine ◽  
Glutathione Metabolism ◽  
De Novo Synthesis ◽  
Cox Regression Analysis

Abstract BACKGROUND IDH1-mutated glioma is a recently defined disease entity with distinctive patterns of tumor cell biology, metabolism, and resistance to therapy. Although IDH1 mutations are highly prevalent in patients with WHO II/III glioma, curative molecular targeting approaches remain unavailable for this disease cluster. METHODS In the present study, we investigated the glutathione de novo synthesis pathway through the TCGA patient cohort and patient-derived cell lines with IDH1 mutation. The biologic function of nuclear factor erythroid 2-related factor 2 (NRF2) was analyzed by biochemistry and cell biology assays. Finally, NRF2 inhibitors were evaluated in IDH1-mutated cell lines and preclinical models as an experimental therapy. RESULTS IDH1 mutant neomorphic activity depletes the cellular pools of enzyme cofactors such as nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). The limitation of NAD(P) not only affects the anabolic reactions, but also results in oxidative stress and damages on DNA and protein. Further, we showed that the reprogrammed redox landscape results in constitutive activation of NRF2-governed cytoprotective pathways through the decoupling of NRF2 from its E3 ligase Kelch-like ECH-associated protein 1. NRF2 mediated the transcriptional activation of GCLC, GCLM, and SLC7A11, which not only strengthens the glutathione de novo synthesis, but also relieves the metabolic burden in IDH1-mutated cells. The importance of the glutathione synthesis is further confirmed through COX regression analysis on lower-grade glioma. Blockade of the NRF2/glutathione metabolic pathway synergizes with the elevated intrinsic oxidative stress, which results in overwhelming oxidative damage, as well as a substantial reduction in tumor cell proliferation and xenograft expansion. CONCLUSION We report that the NRF2-guided cytoprotective pathways play pivotal roles in the disease progression of IDH1-mutated glioma. Targeting NRF2 and glutathione metabolism could be novel targeting strategies for IDH1-mutated glioma.

α-Amino-β-carboxymuconate-ε-semialdehyde Decarboxylase (ACMSD) Inhibitors as Novel Modulators of De Novo Nicotinamide Adenine Dinucleotide (NAD+) Biosynthesis

2018 ◽  
Vol 61 (3) ◽  
pp. 745-759 ◽  
Author(s):  
Roberto Pellicciari ◽  
Paride Liscio ◽  
Nicola Giacchè ◽  
Francesca De Franco ◽  
Andrea Carotti ◽  
...  
Keyword(s):  
Nicotinamide Adenine Dinucleotide ◽  
De Novo ◽  
Nicotinamide Adenine ◽  
Nad Biosynthesis

scholarly journals Nicotinamide Phosphoribosyltransferase (Nampt)/Nicotinamide Adenine Dinucleotide (NAD) Axis Suppresses Atrial Fibrillation by Modulating the Calcium Handling Pathway

2020 ◽  
Vol 21 (13) ◽  
pp. 4655
Author(s):  
Duo Feng ◽  
DongZhu Xu ◽  
Nobuyuki Murakoshi ◽  
Kazuko Tajiri ◽  
Rujie Qin ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Nicotinamide Adenine Dinucleotide ◽  
Electrophysiological Study ◽  
Redox Homeostasis ◽  
Calcium Handling ◽  
Nicotinamide Adenine ◽  
Chow Diet ◽  
Nicotinamide Phosphoribosyltransferase ◽  
Nicotinamide Riboside ◽  
Normal Chow

Aging and obesity are the most prominent risk factors for onset of atrial fibrillation (AF). Nicotinamide phosphoribosyltransferase (Nampt) is the rate-limiting enzyme that catalyzes nicotinamide adenine dinucleotide (NAD) activity. Nampt and NAD are essential for maintenance of cellular redox homeostasis and modulation of cellular metabolism, and their expression levels decrease with aging and obesity. However, a role for Nampt in AF is unknown. The present study aims to test whether there is a role of Nampt/NAD axis in the pathogenesis of obesity-induced AF. Male C57BL/6J (WT) mice and heterozygous Nampt knockout (NKO) mice were fed with a normal chow diet (ND) or a high-fat diet (HFD). Electrophysiological study showed that AF inducibility was significantly increased in WT+HFD, NKO+ND, and NKO+HFD mice compared with WT+ND mice. AF duration was significantly longer in WT+HFD and NKO+ND mice and further prolonged in NKO+HFD mice compared with WT+ND mice and the calcium handling pathway was altered on molecular level. Also, treatment with nicotinamide riboside, a NAD precursor, partially restored the HFD-induced AF perpetuation. Overall, this work demonstrates that partially deletion of Nampt facilitated HFD-induced AF through increased diastolic calcium leaks. The Nampt/NAD axis may be a potent therapeutic target for AF.

scholarly journals EXTH-04. BLOCKADE OF NRF2/GLUTATHIONE METABOLISM AS A SYNTHETIC LETHALITY APPROACH FOR IDH1-MUTATED GLIOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi83-vi83
Author(s):  
Yang Liu ◽  
Yanxin Lu ◽  
Orieta Celiku ◽  
Aiguo Li ◽  
Chunzhang Yang
Keyword(s):  
Tumor Cell ◽  
Metabolic Pathway ◽  
De Novo ◽  
Synthetic Lethality ◽  
Substantial Reduction ◽  
Lower Grade ◽  
Related Factor ◽  
De Novo Synthesis ◽  
Antioxidant Genes ◽  
Cox Regression Analysis

Abstract BACKGROUND Mutations in isocitrate dehydrogenase (IDH1/2) are frequent genetic abnormalities in human malignancies. IDH1/2-mutated cancers are a recently defined disease entity with distinctive patterns of tumor cell biology, metabolism and resistance to therapy. Molecular targeting approaches against this disease cluster remain limited. METHODS We investigated the redox homeostasis in IDH1 mutant-transduced cells and patient-derived brain tumor initiating cells. The importance of antioxidant genes was confirmed through COX regression analysis on a large cohort of lower grade glioma. We investigated the biologic impact of Nuclear factor erythroid 2-related factor 2 (NRF2) on the glutathione de novo synthesis in IDH1-mutated cells. Finally, we evaluated the value of targeting NRF2/glutathione metabolic pathway as a potential synthetic lethality approach for IDH1-mutated cell in vitro and in vivo. RESULTS We discovered that acquisition of cancer-associated IDH1 mutants results in constitutive activation of NRF2-governed cytoprotective pathways through decoupling of NRF2 from its E3 ligase Kelch-like ECH-associated protein 1. NRF2 mediated the transcriptional activation of GCLC, GCLM and SLC7A11, which strengthens the glutathione de novo synthesis, and relieves the metabolic burden derived from IDH1 mutant neomorphic activity. Blockade of the NRF2/glutathione metabolic pathway synergizes with the elevated intrinsic reactive oxygen species, which results in overwhelming oxidative damage in IDH1-mutated cells, as well as a substantial reduction in tumor cell proliferation and xenograft expansion. CONCLUSION Our findings suggest that blockade of the NRF2/glutathione synthetic pathway is a novel targeting strategy for IDH1-mutated malignancies.

scholarly journals Versatile selective evolutionary pressure using synthetic defect in universal metabolism

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Lara Sellés Vidal ◽  
James W. Murray ◽  
John T. Heap
Keyword(s):  
Artificial Selection ◽  
Nicotinamide Adenine Dinucleotide ◽  
De Novo ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Industrial Applications ◽  
Nicotinamide Adenine ◽  
Growth Defect ◽  
Limited Information ◽  
High Performing ◽  
Structures And Properties

AbstractThe non-natural needs of industrial applications often require new or improved enzymes. The structures and properties of enzymes are difficult to predict or design de novo. Instead, semi-rational approaches mimicking evolution entail diversification of parent enzymes followed by evaluation of isolated variants. Artificial selection pressures coupling desired enzyme properties to cell growth could overcome this key bottleneck, but are usually narrow in scope. Here we show diverse enzymes using the ubiquitous cofactors nicotinamide adenine dinucleotide (NAD) or nicotinamide adenine dinucleotide phosphate (NADP) can substitute for defective NAD regeneration, representing a very broadly-applicable artificial selection. Inactivation of Escherichia coli genes required for anaerobic NAD regeneration causes a conditional growth defect. Cells are rescued by foreign enzymes connected to the metabolic network only via NAD or NADP, but only when their substrates are supplied. Using this principle, alcohol dehydrogenase, imine reductase and nitroreductase variants with desired selectivity modifications, and a high-performing isopropanol metabolic pathway, are isolated from libraries of millions of variants in single-round experiments with typical limited information to guide design.

Effect of Interferon-γ and LPS on Tetrahydrobiopterin in Rat PC 12 and Human KNA Cells

Pteridines ◽  
2001 ◽  
Vol 12 (4) ◽  
pp. 167-171
Author(s):  
Karoline Vrecko ◽  
Roswitha Pfragner ◽  
Veronika Siegl ◽  
Konrad Schauenstein ◽  
Gilbert Reibnegger
Keyword(s):  
Cell Line ◽  
Nicotinamide Adenine Dinucleotide ◽  
De Novo ◽  
Interferon Γ ◽  
De Novo Synthesis ◽  
Gtp Cyclohydrolase I ◽  
Dopamine Biosynthesis ◽  
Recycling Pathway ◽  
Stimulation Of

Abstract The first human phaeochromocytorna cell line KNA was tested with regard to stimulation of dopamine biosynthesis by nicotinamide adenine dinucleotide (NADH). Differently from rat phaeochromocytoma cells - clone PC12, where NADH increased dopamine biosynthesis significantly, no stimulation in KNA cells was found. NADH is effective on speeding up the formation of the active cofactor tetrahydrobiopterin by a recycling pathway via the dihydropteridinreductase system. Another way of formation of tetrahydrobiopterin is the induction of de novo synthesis by cytokines such as interferon-y or by lipopolysaccharide via activation of GTP cyclohydrolase I, as shown in rnacrophages. Neither rat PC12 nor human KNA cells showed in vitro a stimulation of tetrahydrobiopterin de novo synthesis by interferon-y and/or lipopolysaccharide.

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