Frédéric Van Gool | PubMed Health

PubMed2006

Nicotinamide inhibits B lymphocyte activation by disrupting MAPK signal transduction.

Nicotinamide (NAm) represents both a pharmacological agent known to express cell preserving and anti-inflammatory properties, and a useful investigational tool to elucidate cellular pathways regulating a wide range of cellular functions. We demonstrate in this study that exogenous NAm, when used at pharmacological doses, inhibits activation of primary murine B lymphocytes in response to multiple ligands. NAm appears to affect a membrane proximal event leading to MAPKs activation, a transduction pathway shared by multiple receptors including the antigen-specific B cell receptor, CD38, CD40 and TLR4 receptors. NAm inhibited phospho-ERK accumulation, and only marginally affected phospho-p38 and phospho-JNK induction upon BCR stimulation of naive B lymphocytes. Accordingly, NAm also affected the expression of known targets of the MAPK ERK pathway such as CD69 and cyclin D2. Based on a comparison with well-characterized pharmacological inhibitors, we suggest in this work that NAm may inhibit a post-translational modification mediated by a yet unidentified mono(ADP-ribose)transferase. Collectively, our observations indicate that in addition to its previously described effect on cells of the innate immune system, NAm is able to modulate the activity of B lymphocytes suggesting a potential role of this vitamin in regulating antibody-mediated autoimmune disorders.

3-Iodobenzylguanidine↗

PubMed2003

Reconstructing eukaryotic NAD metabolism.

In addition to its well-known role as a coenzyme in oxidation-reduction reactions, the distinct role of NAD as a precursor for molecules involved in cell regulation has been clearly established. The involvement of NAD in these regulatory processes is based on its ability to function as a donor of ADP-ribose; NAD synthesis is therefore required to avoid depletion of the intracellular pool. The rising interest in the biosynthetic routes leading to NAD formation and the highly conserved nature of the enzymes involved prompted us to reconstruct the NAD biosynthetic routes operating in distinct eukaryotic organisms. The evidence obtained from biochemical and computational analysis provides a good example of how complex metabolic pathways may evolve. In particular, it is proposed that the development of several NAD biosynthetic routes during evolution has led to partial functional redundancy, allowing a given pathway to freely acquire novel functions unrelated to NAD biosynthesis.

Adenosine Diphosphate Ribose↗