Synthesen von NAD+-Analoga und ihre Anwendungen

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2015
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Based on its diverse functions, nicotinamide adenine dinucleotide (NAD+) is well known to participate in a variety of cellular processes, such as redox metabolism, signaling pathways, and post-translational modifications. In 1963 Chambon et. al. reported for the first time about the formation of a nucleic acid like polymer derived from NAD+, now referring to us as poly(ADP-ribose) (PAR). ADP-ribosylation is a reversible post-translational modification of proteins, catalyzed by a family of enzymes termed ADP-ribosyltransferases (ARTs), formerly known as poly(ADP-ribose) polymerases (PARPs). ARTs play important roles in a wide range of biological processes, including DNA repair, maintenance of genomic stability and transcriptional regulation. ADP-ribosylation comprises the transfer of a single or multiple ADP-ribose moieties from NAD+ to a specific amino acid residues on a target protein, referring to us as mono(ADP-ribosyl)ation or poly(ADP-ribosyl)ation respectively. In this process, the covalent transfer onto glutamic acid, aspartic acid (forming an ester bond) or lysine residues (forming a Schiff base) of target proteins is described. To further investigate the functions of ADP-ribosylation and determine the crosstalk with other post-translational modifications, the identification of ADP-ribose acceptor site is crucial. Mass spectrometry based approaches for the identification of acceptor sites turned at to be a challenging task, because of the complex structure of attached PAR.

Encouraged by current research results, the toolbox of NAD+ analogues were expanded by designing and synthesizing NAD+ analogues. New NAD+ analogues are described in this thesis that are efficiently incorporated by wild-type ARTs and a) bear an affinity tag that will allow subsequent manipulations such as labeling and sample enrichment and b) lead to PAR chain termination owing to a lack of the required hydroxyl group. Since little is known about the substrate scope of ARTs, the five novel NAD+ analogues were successful synthesized and applied in enzymatic studies, and were found to be efficient substrates for ARTD1 and were used to label ADP-ribosylated ARTD1 and H1.2.

Fachgebiet (DDC)
540 Chemie
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NAD+-Analoga, Synthesen, Anwendungen
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ISO 690WANG, Yan, 2015. Synthesen von NAD+-Analoga und ihre Anwendungen [Dissertation]. Konstanz: University of Konstanz
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@phdthesis{Wang2015-08-01Synth-31464,
  year={2015},
  title={Synthesen von NAD<sup>+</sup>-Analoga und ihre Anwendungen},
  author={Wang, Yan},
  address={Konstanz},
  school={Universität Konstanz}
}
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June 25, 2015
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Konstanz, Univ., Diss., 2015
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