L-Aspartate oxidase is present in the anaerobic hyperthermophilic archaeon Pyrococcus horikoshii OT-3: characteristics and role in the de novo biosynthesis of nicotinamide adenine dinucleotide proposed by genome sequencing

Extremophiles ◽  
2002 ◽  
Vol 6 (4) ◽  
pp. 275-281 ◽  
Author(s):  
Haruhiko Sakuraba ◽  
Takenori Satomura ◽  
Ryushi Kawakami ◽  
Sanae Yamamoto ◽  
Yutaka Kawarabayasi ◽  
...  
Keyword(s):  
Genome Sequencing ◽  
Nicotinamide Adenine Dinucleotide ◽  
De Novo ◽  
Nicotinamide Adenine ◽  
Pyrococcus Horikoshii ◽  
Hyperthermophilic Archaeon ◽  
De Novo Biosynthesis

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 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.

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 Impaired Nicotinamide Adenine Dinucleotide Biosynthesis in the Kidney of Chronic Kidney Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Xinhui Liu ◽  
Denggui Luo ◽  
Shiying Huang ◽  
Siqi Liu ◽  
Bing Zhang ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Nicotinamide Adenine Dinucleotide ◽  
De Novo ◽  
Periodic Acid ◽  
Public Health Problem ◽  
Nicotinamide Adenine ◽  
High Morbidity ◽  
Rat Models ◽  
Key Enzymes

Chronic kidney disease (CKD) is a global public health problem with high morbidity and mortality. Decreased nicotinamide adenine dinucleotide (NAD+) levels were found to be associated with aging, cancer, and neurodegenerative and metabolic disorders. However, the alteration of renal NAD+ levels and biosynthesis pathways in CKD is less known. In the present study, we aimed to evaluate renal NAD+ levels and tested the expression of key enzymes in three NAD+ biosynthesis pathways in two different types of CKD rat model. CKD rat models were established by 5/6 nephrectomy (5/6 Nx) and feeding with adenine-containing feed, respectively. Renal function was assessed by serum creatinine (Scr) and blood urea nitrogen (BUN). Renal pathology was evaluated by periodic acid-Schiff (PAS) and Masson’s trichrome staining. The expression of key enzymes in three NAD+ biosynthesis pathways was determined and quantified by Western blot analysis. The results showed CKD rat models were successfully established as evidenced by increased Scr and BUN levels, upregulation of neutrophil gelatinase-associated lipocalin (NGAL), glomerular hypertrophy, and renal fibrosis. Renal NAD+ and NADH content were both declined in two CKD rat models, and NAD+ levels were negatively correlated with Scr and BUN levels in CKD rats. Three key enzymes involved in NAD+ biosynthesis were significantly downregulated in the kidney of both of the two CKD models. They were quinolinate phosphoribosyltransferase (QPRT) in the de novo pathway, nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1), and NMNAT3 in the salvage pathway. Moreover, the expression of NAD+-consuming enzymes sirtuin 3 (SIRT3) and CD38 decreased significantly in CKD rats. In conclusion, NAD+ biosynthesis was significantly impaired in CKD, which may attribute to downregulation of QPRT and NMNAT 1/3.

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.

Effect of Niacin on Mitochondria of Allium Cepa Root Cells

1967 ◽  
Vol 25 ◽  
pp. 78-79
Author(s):  
M. Arif Hayat
Keyword(s):  
Nicotinamide Adenine Dinucleotide ◽  
Hydrogen Transfer ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Nicotinamide Adenine ◽  
Root Tips ◽  
Root Cells ◽  
Transfer Processes ◽  
Standard Procedures ◽  
A Cell ◽  
Critical Interest

Although it is recognized that niacin (pyridine-3-carboxylic acid), incorporated as the amide in nicotinamide adenine dinucleotide (NAD) or in nicotinamide adenine dinucleotide phosphate (NADP), is a cofactor in hydrogen transfer in numerous enzyme reactions in all organisms studied, virtually no information is available on the effect of this vitamin on a cell at the submicroscopic level. Since mitochondria act as sites for many hydrogen transfer processes, the possible response of mitochondria to niacin treatment is, therefore, of critical interest.Onion bulbs were placed on vials filled with double distilled water in the dark at 25°C. After two days the bulbs and newly developed root system were transferred to vials containing 0.1% niacin. Root tips were collected at ¼, ½, 1, 2, 4, and 8 hr. intervals after treatment. The tissues were fixed in glutaraldehyde-OsO4 as well as in 2% KMnO4 according to standard procedures. In both cases, the tissues were dehydrated in an acetone series and embedded in Reynolds' lead citrate for 3-10 minutes.

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