Acyl-CoA-binding domain containing 3 modulates NAD+ metabolism through activating poly(ADP-ribose) polymerase 1

2015 ◽  
Vol 469 (2) ◽  
pp. 189-198 ◽  
Author(s):  
Yong Chen ◽  
Sookhee Bang ◽  
Soohyun Park ◽  
Hanyuan Shi ◽  
Sangwon F. Kim
Keyword(s):  
Nicotinamide Adenine Dinucleotide ◽  
Cell Metabolism ◽  
Living Cells ◽  
Binding Domain ◽  
Nicotinamide Adenine ◽  
Cellular Functions ◽  
Nad Metabolism ◽  
Domain 3 ◽  
And Function

Nicotinamide adenine dinucleotide (NAD) is a coenzyme found in all living cells and plays a fundamental role is basic cellular functions. Our findings revealed that acyl-CoA binding domain 3 (ACBD3) has prominent impacts on the cellular NAD+ metabolism via regulating PARP1 activation-dependent automodification and thus cell metabolism and function.

scholarly journals Pathogen induced subversion of NAD+ metabolism mediating host cell death: a target for development of chemotherapeutics

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Ayushi Chaurasiya ◽  
Swati Garg ◽  
Ashish Khanna ◽  
Chintam Narayana ◽  
Ved Prakash Dwivedi ◽  
...  
Keyword(s):  
Cell Death ◽  
Host Cell ◽  
Nicotinamide Adenine Dinucleotide ◽  
Malaria Parasite ◽  
Host Cells ◽  
Nicotinamide Adenine ◽  
Targeted Therapeutics ◽  
Nad Metabolism ◽  
Host Cell Death ◽  
Nanomolar Range

AbstractHijacking of host metabolic status by a pathogen for its regulated dissemination from the host is prerequisite for the propagation of infection. M. tuberculosis secretes an NAD+-glycohydrolase, TNT, to induce host necroptosis by hydrolyzing Nicotinamide adenine dinucleotide (NAD+). Herein, we expressed TNT in macrophages and erythrocytes; the host cells for M. tuberculosis and the malaria parasite respectively, and found that it reduced the NAD+ levels and thereby induced necroptosis and eryptosis resulting in premature dissemination of pathogen. Targeting TNT in M. tuberculosis or induced eryptosis in malaria parasite interferes with pathogen dissemination and reduction in the propagation of infection. Building upon our discovery that inhibition of pathogen-mediated host NAD+ modulation is a way forward for regulation of infection, we synthesized and screened some novel compounds that showed inhibition of NAD+-glycohydrolase activity and pathogen infection in the nanomolar range. Overall this study highlights the fundamental importance of pathogen-mediated modulation of host NAD+ homeostasis for its infection propagation and novel inhibitors as leads for host-targeted therapeutics.

Regulation and function of ribosomal protein S6 kinase (S6K) within mTOR signalling networks

2011 ◽  
Vol 441 (1) ◽  
pp. 1-21 ◽  
Author(s):  
Brian Magnuson ◽  
Bilgen Ekim ◽  
Diane C. Fingar
Keyword(s):  
Ribosomal Protein ◽  
Cell Metabolism ◽  
Lipid Synthesis ◽  
Cell Physiology ◽  
Cellular Functions ◽  
S6 Kinase ◽  
Glucose Homoeostasis ◽  
Ribosomal Protein S6 ◽  
And Function ◽  
Mtor Signalling

The ribosomal protein S6K (S6 kinase) represents an extensively studied effector of the TORC1 [TOR (target of rapamycin) complex 1], which possesses important yet incompletely defined roles in cellular and organismal physiology. TORC1 functions as an environmental sensor by integrating signals derived from diverse environmental cues to promote anabolic and inhibit catabolic cellular functions. mTORC1 (mammalian TORC1) phosphorylates and activates S6K1 and S6K2, whose first identified substrate was rpS6 (ribosomal protein S6), a component of the 40S ribosome. Studies over the past decade have uncovered a number of additional S6K1 substrates, revealing multiple levels at which the mTORC1–S6K1 axis regulates cell physiology. The results thus far indicate that the mTORC1–S6K1 axis controls fundamental cellular processes, including transcription, translation, protein and lipid synthesis, cell growth/size and cell metabolism. In the present review we summarize the regulation of S6Ks, their cellular substrates and functions, and their integration within rapidly expanding mTOR (mammalian TOR) signalling networks. Although our understanding of the role of mTORC1–S6K1 signalling in physiology remains in its infancy, evidence indicates that this signalling axis controls, at least in part, glucose homoeostasis, insulin sensitivity, adipocyte metabolism, body mass and energy balance, tissue and organ size, learning, memory and aging. As dysregulation of this signalling axis contributes to diverse disease states, improved understanding of S6K regulation and function within mTOR signalling networks may enable the development of novel therapeutics.

scholarly journals The chemistry of the vitamin B3 metabolome

2018 ◽  
Vol 47 (1) ◽  
pp. 131-147 ◽  
Author(s):  
Mikhail V. Makarov ◽  
Samuel A.J. Trammell ◽  
Marie E. Migaud
Keyword(s):  
Cell Signaling ◽  
Nicotinamide Adenine Dinucleotide ◽  
Cell Metabolism ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Chemical Diversity ◽  
Nicotinamide Adenine ◽  
Vitamin B3 ◽  
Phosphorylated Form ◽  
Reduced Forms ◽  
Therapeutic Avenue

Abstract The functional cofactors derived from vitamin B3 are nicotinamide adenine dinucleotide (NAD+), its phosphorylated form, nicotinamide adenine dinucleotide phosphate (NADP+) and their reduced forms (NAD(P)H). These cofactors, together referred as the NAD(P)(H) pool, are intimately implicated in all essential bioenergetics, anabolic and catabolic pathways in all forms of life. This pool also contributes to post-translational protein modifications and second messenger generation. Since NAD+ seats at the cross-road between cell metabolism and cell signaling, manipulation of NAD+ bioavailability through vitamin B3 supplementation has become a valuable nutritional and therapeutic avenue. Yet, much remains unexplored regarding vitamin B3 metabolism. The present review highlights the chemical diversity of the vitamin B3-derived anabolites and catabolites of NAD+ and offers a chemical perspective on the approaches adopted to identify, modulate and measure the contribution of various precursors to the NAD(P)(H) pool.

Nicotinamide adenine dinucleotide metabolism in plants. I. Intermediates of biosynthesis in wheat leaves and the effect of benzimidazole

1970 ◽  
Vol 48 (12) ◽  
pp. 2267-2278 ◽  
Author(s):  
H. R. Godavari ◽  
E. R. Waygood
Keyword(s):  
Nicotinic Acid ◽  
Nicotinamide Adenine Dinucleotide ◽  
Triticum Aestivum L ◽  
Total Radioactivity ◽  
Significant Loss ◽  
Nicotinamide Adenine ◽  
Nad Metabolism ◽  
Nicotinamide Riboside ◽  
Nicotinamide Mononucleotide ◽  
Wheat Leaves

Leaves of wheat (Triticum aestivum L. var. Selkirk) were incubated with nicotinic acid-7-14C and nicotinamide-7-14C for varying time periods from 5 min to 12 h. Aliquots of alcoholic extracts of leaves were subjected to paper chromatography and radioautography to isolate the intermediates of the synthesis and breakdown of nicotinamide adenine dinucleotide. Nine compounds were isolated quantitatively and identified as intermediates in the pathway of NAD metabolism. All the intermediates were labeled rapidly and the rapidity of labeling became a problem in rigorously proving the sequential operation of the pathway. The results indicate that the Preiss-Handler pathway: nicotinic acid→nicotinic acid mononucleotide→nicotinic acid adenine dinucleotide→NAD operates in wheat leaves. The degradation of NAD proceeded from NAD→nicotinamide mononucleotide→nicotinamide riboside→nicotinamide. Deamidation of the nicotinamide to nicotinic acid initiated a fresh cycle of biosynthesis. The total radioactivity recovered in the intermediates indicates that no measurable amount was lost to other metabolic pathways. Nicotinamide is recovered without significant loss and recycled. The rapid appearance of labeled nicotinamide indicates a possible interconversion of nicotinic acid and nicotinamide. About 80% of the radioactivity accumulated was present in trigonelline which is considered, on the basis of other evidence, to be a non-toxic form of nicotinic acid. Benzimidazole treatment of the leaves increased the incorporation of 14C into NADP.

scholarly journals The synthesis of nicotinamide–adenine dinucleotide and poly(adenosine diphosphate ribose) in various classes of rat liver nuclei

1969 ◽  
Vol 115 (5) ◽  
pp. 881-887 ◽  
Author(s):  
M E Haines ◽  
I R Johnston ◽  
A P Mathias ◽  
D. Ridge
Keyword(s):  
Dna Synthesis ◽  
Rat Liver ◽  
Nicotinamide Adenine Dinucleotide ◽  
Adenosine Diphosphate ◽  
Nicotinamide Adenine ◽  
Nad Metabolism ◽  
Rat Liver Nuclei ◽  
Liver Nuclei ◽  
Specific Activities

1. The activities of NMN adenylyltransferase and an enzyme that synthesizes poly (ADP-ribose) from NAD were investigated in the various classes of rat liver nuclei fractionated by zonal centrifugation. 2. The highest specific activities of these two nuclear enzymes occur in different classes of nuclei. In very young and in mature rats it was shown that a correlation exists between DNA synthesis and NMN adenylyltransferase activity, but in rats of intermediate age this correlation is less evident. The highest activities of the enzyme that catalyses formation of poly (ADP-ribose) are in the nuclei involved in the synthesis of RNA. 3. The significance of these results in relation to NAD metabolism is discussed.

Insights from ion mobility-mass spectrometry, infrared spectroscopy, and molecular dynamics simulations on nicotinamide adenine dinucleotide structural dynamics: NAD+vs. NADH

2018 ◽  
Vol 20 (10) ◽  
pp. 7043-7052 ◽  
Author(s):  
Juan Camilo Molano-Arevalo ◽  
Walter Gonzalez ◽  
Kevin Jeanne Dit Fouque ◽  
Jaroslava Miksovska ◽  
Philippe Maitre ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Molecular Dynamics ◽  
Structural Dynamics ◽  
Ion Mobility ◽  
Nicotinamide Adenine Dinucleotide ◽  
Living Cells ◽  
Nicotinamide Adenine ◽  
Ion Mobility Mass Spectrometry ◽  
Enzymatic Reactions ◽  
Dynamics Simulations

Nicotinamide adenine dinucleotide (NAD) is found in all living cells where the oxidized (NAD+) and reduced (NADH) forms play important roles in many enzymatic reactions.

Nicotinamide adenine dinucleotide (NAD+): essential redox metabolite, co-substrate and an anti-cancer and anti-ageing therapeutic target

2020 ◽  
Vol 48 (3) ◽  
pp. 733-744 ◽  
Author(s):  
Hollie B.S. Griffiths ◽  
Courtney Williams ◽  
Sarah J. King ◽  
Simon J. Allison
Keyword(s):  
Nicotinamide Adenine Dinucleotide ◽  
Tumour Microenvironment ◽  
Nicotinamide Adenine ◽  
Reduced Form ◽  
Nad Metabolism ◽  
Growth And Survival ◽  
Cell Functions ◽  
Disease States ◽  
Age Related ◽  
Redox Metabolites

Nicotinamide adenine dinucleotide (NAD+) and its reduced form NADH are essential coupled redox metabolites that primarily promote cellular oxidative (catabolic) metabolic reactions. This enables energy generation through glycolysis and mitochondrial respiration to support cell growth and survival. In addition, many key enzymes that regulate diverse cell functions ranging from gene expression to proteostasis require NAD+ as a co-substrate for their catalytic activity. This includes the NAD+-dependent sirtuin family of protein deacetylases and the PARP family of DNA repair enzymes. Whilst their vital activity consumes NAD+ which is cleaved to nicotinamide, several pathways exist for re-generating NAD+ and sustaining NAD+ homeostasis. However, there is growing evidence of perturbed NAD+ homeostasis and NAD+-regulated processes contributing to multiple disease states. NAD+ levels decline in the human brain and other organs with age and this is associated with neurodegeneration and other age-related diseases. Dietary supplementation with NAD+ precursors is being investigated to counteract this. Paradoxically, many cancers have increased dependency on NAD+. Clinical efforts to exploit this have so far shown limited success. Emerging new opportunities to exploit dysregulation of NAD+ metabolism in cancers are critically discussed. An update is also provided on other key NAD+ research including perturbation of the NAD+ salvage enzyme NAMPT in the context of the tumour microenvironment (TME), methodology to study subcellular NAD+ dynamics in real-time and the regulation of differentiation by competing NAD+ pools.

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