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  1. Article ; Online: Keeping the balance in NAD metabolism.

    Strømland, Øyvind / Niere, Marc / Nikiforov, Andrey A / VanLinden, Magali R / Heiland, Ines / Ziegler, Mathias

    Biochemical Society transactions

    2019  Volume 47, Issue 1, Page(s) 119–130

    Abstract: Research over the last few decades has extended our understanding of nicotinamide adenine dinucleotide (NAD) from a vital redox carrier to an important signalling molecule that is involved in the regulation of a multitude of fundamental cellular ... ...

    Abstract Research over the last few decades has extended our understanding of nicotinamide adenine dinucleotide (NAD) from a vital redox carrier to an important signalling molecule that is involved in the regulation of a multitude of fundamental cellular processes. This includes DNA repair, cell cycle regulation, gene expression and calcium signalling, in which NAD is a substrate for several families of regulatory proteins, such as sirtuins and ADP-ribosyltransferases. At the molecular level, NAD-dependent signalling events differ from hydride transfer by cleavage of the dinucleotide into an ADP-ribosyl moiety and nicotinamide. Therefore, non-redox functions of NAD require continuous biosynthesis of the dinucleotide. Maintenance of cellular NAD levels is mainly achieved by nicotinamide salvage, yet a variety of other precursors can be used to sustain cellular NAD levels via different biosynthetic routes. Biosynthesis and consumption of NAD are compartmentalised at the subcellular level, and currently little is known about the generation and role of some of these subcellular NAD pools. Impaired biosynthesis or increased NAD consumption is deleterious and associated with ageing and several pathologies. Insults to neurons lead to depletion of axonal NAD and rapid degeneration, partial rescue can be achieved pharmacologically by administration of specific NAD precursors. Restoring NAD levels by stimulating biosynthesis or through supplementation with precursors also produces beneficial therapeutic effects in several disease models. In this review, we will briefly discuss the most recent achievements and the challenges ahead in this diverse research field.
    MeSH term(s) ADP-Ribosylation/physiology ; Animals ; Humans ; NAD/metabolism ; Signal Transduction/physiology ; Sirtuins/metabolism ; Wallerian Degeneration/metabolism
    Chemical Substances NAD (0U46U6E8UK) ; Sirtuins (EC 3.5.1.-)
    Language English
    Publishing date 2019-01-09
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 184237-7
    ISSN 1470-8752 ; 0300-5127
    ISSN (online) 1470-8752
    ISSN 0300-5127
    DOI 10.1042/BST20180417
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 944: Show issues Location:
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  2. Article ; Online: Compartment-Specific Poly-ADP-Ribose Formation as a Biosensor for Subcellular NAD Pools.

    VanLinden, Magali R / Niere, Marc / Nikiforov, Andrey A / Ziegler, Mathias / Dölle, Christian

    Methods in molecular biology (Clifton, N.J.)

    2017  Volume 1608, Page(s) 45–56

    Abstract: Nicotinamide adenine dinucleotide (NAD) is vital to many cellular processes and is distributed between distinct subcellular pools in the compartmentalized eukaryotic cell. The detection and relative quantification of these individual pools is difficult ... ...

    Abstract Nicotinamide adenine dinucleotide (NAD) is vital to many cellular processes and is distributed between distinct subcellular pools in the compartmentalized eukaryotic cell. The detection and relative quantification of these individual pools is difficult because of the methods usually applied, which require cell disruption and fractionation.Here, we describe an immunochemical method to visualize and relatively quantify subcellular NAD
    MeSH term(s) Animals ; Biosensing Techniques/methods ; Humans ; Immunoblotting ; Immunohistochemistry ; Mitochondria/metabolism ; NAD/metabolism ; Poly (ADP-Ribose) Polymerase-1/metabolism ; Poly Adenosine Diphosphate Ribose/metabolism
    Chemical Substances NAD (0U46U6E8UK) ; Poly Adenosine Diphosphate Ribose (26656-46-2) ; Poly (ADP-Ribose) Polymerase-1 (EC 2.4.2.30)
    Language English
    Publishing date 2017
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 1940-6029
    ISSN (online) 1940-6029
    DOI 10.1007/978-1-4939-6993-7_4
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: NAD biosynthesis in humans--enzymes, metabolites and therapeutic aspects.

    Dölle, Christian / Skoge, Renate Hvidsten / Vanlinden, Magali R / Ziegler, Mathias

    Current topics in medicinal chemistry

    2013  Volume 13, Issue 23, Page(s) 2907–2917

    Abstract: NAD plays a major role in all cells as substrate for signal transduction and as cofactor in metabolic redox reactions. Since NAD-dependent signaling involves degradation of the nucleotide, continuous restoration of cellular NAD pools is essential. ... ...

    Abstract NAD plays a major role in all cells as substrate for signal transduction and as cofactor in metabolic redox reactions. Since NAD-dependent signaling involves degradation of the nucleotide, continuous restoration of cellular NAD pools is essential. Moreover, NAD-dependent signaling reactions, which include ADP-ribosylation, protein deacetylation by sirtuins and calcium messenger synthesis, are regulated by NAD availability. Consequently, perturbations of NAD supply can have severe consequences and, in fact, have been associated with major human diseases such as age- and diet-induced disorders, neurodegenerative diseases and cancer. Given the increasing awareness of the biological roles of NAD, the routes, molecular mechanisms and regulation of NAD biosynthesis have been the subject of intense research over the last decade. Impressive progress has been made regarding the molecular identification, functional and structural characterization as well as regulation of the human NAD biosynthetic enzymes. Exciting therapeutic concepts have emerged, which aim at modulation of NAD availability by interfering with the biosynthetic network to prevent, reduce or reverse pathological conditions. Since there are several entry points into NAD synthesis, including the known vitamin B3 precursors nicotinamide and nicotinic acid, targeted nutritional supplementation is likely to have beneficial effects in various diseases. On the other hand, inhibition of NAD synthesis promotes cell death and has emerged as a therapeutic concept for cancer treatment.
    MeSH term(s) Biomedical Research ; Enzymes/metabolism ; Humans ; Models, Molecular ; Molecular Structure ; NAD/antagonists & inhibitors ; NAD/biosynthesis ; NAD/metabolism ; NAD/therapeutic use ; Neoplasms/drug therapy ; Neoplasms/enzymology ; Neoplasms/metabolism
    Chemical Substances Enzymes ; NAD (0U46U6E8UK)
    Language English
    Publishing date 2013-10-26
    Publishing country United Arab Emirates
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2064823-6
    ISSN 1873-4294 ; 1568-0266
    ISSN (online) 1873-4294
    ISSN 1568-0266
    DOI 10.2174/15680266113136660206
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 5572: Show issues Location:
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  4. Article ; Online: Constitutive nuclear localization of an alternatively spliced sirtuin-2 isoform.

    Rack, Johannes G M / VanLinden, Magali R / Lutter, Timo / Aasland, Rein / Ziegler, Mathias

    Journal of molecular biology

    2014  Volume 426, Issue 8, Page(s) 1677–1691

    Abstract: Sirtuin-2 (SIRT2), the cytoplasmic member of the sirtuin family, has been implicated in the deacetylation of nuclear proteins. Although the enzyme has been reported to be located to the nucleus during G2/M phase, its spectrum of targets suggests ... ...

    Abstract Sirtuin-2 (SIRT2), the cytoplasmic member of the sirtuin family, has been implicated in the deacetylation of nuclear proteins. Although the enzyme has been reported to be located to the nucleus during G2/M phase, its spectrum of targets suggests functions in the nucleus throughout the cell cycle. While a nucleocytoplasmic shuttling mechanism has been proposed for SIRT2, recent studies have indicated the presence of a constitutively nuclear isoform. Here we report the identification of a novel splice variant (isoform 5) of SIRT2 that lacks a nuclear export signal and encodes a predominantly nuclear isoform. This novel isoform 5 fails to show deacetylase activity using several assays, both in vitro and in vivo, and we are led to conclude that this isoform is catalytically inactive. Nevertheless, it retains the ability to interact with p300, a known interaction partner. Moreover, changes in intrinsic tryptophan fluorescence upon denaturation indicate that the protein is properly folded. These data, together with computational analyses, confirm the structural integrity of the catalytic domain. Our results suggest an activity-independent nuclear function of the novel isoform.
    MeSH term(s) 5' Untranslated Regions ; Alternative Splicing ; Catalytic Domain/genetics ; Cell Nucleus/enzymology ; HEK293 Cells ; HeLa Cells ; Humans ; Models, Molecular ; Nuclear Export Signals ; Protein Conformation ; Protein Folding ; Protein Isoforms/chemistry ; Protein Isoforms/genetics ; Protein Isoforms/metabolism ; Protein Structure, Tertiary ; RNA Precursors/genetics ; RNA Precursors/metabolism ; Recombinant Proteins/chemistry ; Recombinant Proteins/genetics ; Recombinant Proteins/metabolism ; Sirtuin 2/chemistry ; Sirtuin 2/genetics ; Sirtuin 2/metabolism ; Static Electricity
    Chemical Substances 5' Untranslated Regions ; Nuclear Export Signals ; Protein Isoforms ; RNA Precursors ; Recombinant Proteins ; SIRT2 protein, human (EC 3.5.1.-) ; Sirtuin 2 (EC 3.5.1.-)
    Language English
    Publishing date 2014-04-17
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80229-3
    ISSN 1089-8638 ; 0022-2836
    ISSN (online) 1089-8638
    ISSN 0022-2836
    DOI 10.1016/j.jmb.2013.10.027
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 867: Show issues Location:
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  5. Article: Constitutive Nuclear Localization of an Alternatively Spliced Sirtuin-2 Isoform

    Rack, Johannes G.M / Magali R. VanLinden / Timo Lutter / Rein Aasland / Mathias Ziegler

    Journal of Molecular Biology. 2014 Apr. 17, v. 426

    2014  

    Abstract: Sirtuin-2 (SIRT2), the cytoplasmic member of the sirtuin family, has been implicated in the deacetylation of nuclear proteins. Although the enzyme has been reported to be located to the nucleus during G2/M phase, its spectrum of targets suggests ... ...

    Abstract Sirtuin-2 (SIRT2), the cytoplasmic member of the sirtuin family, has been implicated in the deacetylation of nuclear proteins. Although the enzyme has been reported to be located to the nucleus during G2/M phase, its spectrum of targets suggests functions in the nucleus throughout the cell cycle. While a nucleocytoplasmic shuttling mechanism has been proposed for SIRT2, recent studies have indicated the presence of a constitutively nuclear isoform. Here we report the identification of a novel splice variant (isoform 5) of SIRT2 that lacks a nuclear export signal and encodes a predominantly nuclear isoform. This novel isoform 5 fails to show deacetylase activity using several assays, both in vitro and in vivo, and we are led to conclude that this isoform is catalytically inactive. Nevertheless, it retains the ability to interact with p300, a known interaction partner. Moreover, changes in intrinsic tryptophan fluorescence upon denaturation indicate that the protein is properly folded. These data, together with computational analyses, confirm the structural integrity of the catalytic domain. Our results suggest an activity-independent nuclear function of the novel isoform.
    Keywords active sites ; alternative splicing ; cell cycle ; denaturation ; fluorescence ; nuclear proteins ; protein transport ; tryptophan
    Language English
    Dates of publication 2014-0417
    Size p. 1677-1691.
    Publishing place Elsevier Ltd
    Document type Article
    ZDB-ID 80229-3
    ISSN 1089-8638 ; 0022-2836
    ISSN (online) 1089-8638
    ISSN 0022-2836
    DOI 10.1016/j.jmb.2013.10.027
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  6. Article ; Online: Subcellular Distribution of NAD+ between Cytosol and Mitochondria Determines the Metabolic Profile of Human Cells.

    VanLinden, Magali R / Dölle, Christian / Pettersen, Ina K N / Kulikova, Veronika A / Niere, Marc / Agrimi, Gennaro / Dyrstad, Sissel E / Palmieri, Ferdinando / Nikiforov, Andrey A / Tronstad, Karl Johan / Ziegler, Mathias

    The Journal of biological chemistry

    2015  Volume 290, Issue 46, Page(s) 27644–27659

    Abstract: The mitochondrial NAD pool is particularly important for the maintenance of vital cellular functions. Although at least in some fungi and plants, mitochondrial NAD is imported from the cytosol by carrier proteins, in mammals, the mechanism of how this ... ...

    Abstract The mitochondrial NAD pool is particularly important for the maintenance of vital cellular functions. Although at least in some fungi and plants, mitochondrial NAD is imported from the cytosol by carrier proteins, in mammals, the mechanism of how this organellar pool is generated has remained obscure. A transporter mediating NAD import into mammalian mitochondria has not been identified. In contrast, human recombinant NMNAT3 localizes to the mitochondrial matrix and is able to catalyze NAD(+) biosynthesis in vitro. However, whether the endogenous NMNAT3 protein is functionally effective at generating NAD(+) in mitochondria of intact human cells still remains to be demonstrated. To modulate mitochondrial NAD(+) content, we have expressed plant and yeast mitochondrial NAD(+) carriers in human cells and observed a profound increase in mitochondrial NAD(+). None of the closest human homologs of these carriers had any detectable effect on mitochondrial NAD(+) content. Surprisingly, constitutive redistribution of NAD(+) from the cytosol to the mitochondria by stable expression of the Arabidopsis thaliana mitochondrial NAD(+) transporter NDT2 in HEK293 cells resulted in dramatic growth retardation and a metabolic shift from oxidative phosphorylation to glycolysis, despite the elevated mitochondrial NAD(+) levels. These results suggest that a mitochondrial NAD(+) transporter, similar to the known one from A. thaliana, is likely absent and could even be harmful in human cells. We provide further support for the alternative possibility, namely intramitochondrial NAD(+) synthesis, by demonstrating the presence of endogenous NMNAT3 in the mitochondria of human cells.
    MeSH term(s) Amino Acid Sequence ; Arabidopsis Proteins/chemistry ; Arabidopsis Proteins/genetics ; Arabidopsis Proteins/metabolism ; Biological Transport ; Carrier Proteins/chemistry ; Carrier Proteins/genetics ; Carrier Proteins/metabolism ; Cytosol/metabolism ; Glycolysis ; HEK293 Cells ; Humans ; Metabolome ; Mitochondria/metabolism ; Mitochondrial Proteins ; Molecular Sequence Data ; NAD/metabolism ; Nicotinamide-Nucleotide Adenylyltransferase/chemistry ; Nicotinamide-Nucleotide Adenylyltransferase/genetics ; Nicotinamide-Nucleotide Adenylyltransferase/metabolism ; Nucleotide Transport Proteins ; Organic Cation Transport Proteins/chemistry ; Organic Cation Transport Proteins/genetics ; Organic Cation Transport Proteins/metabolism ; Recombinant Proteins/chemistry ; Recombinant Proteins/genetics ; Recombinant Proteins/metabolism ; Saccharomyces cerevisiae Proteins/chemistry ; Saccharomyces cerevisiae Proteins/genetics ; Saccharomyces cerevisiae Proteins/metabolism
    Chemical Substances Arabidopsis Proteins ; Carrier Proteins ; Mitochondrial Proteins ; Ndt1 protein, S cerevisiae ; Nucleotide Transport Proteins ; Organic Cation Transport Proteins ; Recombinant Proteins ; Saccharomyces cerevisiae Proteins ; NAD (0U46U6E8UK) ; NMNAT3 protein, human (EC 2.7.7.1) ; Nicotinamide-Nucleotide Adenylyltransferase (EC 2.7.7.1)
    Language English
    Publishing date 2015-10-02
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1074/jbc.M115.654129
    Database MEDical Literature Analysis and Retrieval System OnLINE

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