Enzyme inhibitor
This pseudonucleoside and pro-drug (FW = 253.25 g/mol; CAS 3804827-0; IUPAC Name: (2R,3S,4R,5R)-2-(hydroxymethyl)-5-[6-[[(Z)-4-hydroxy-2- methylbut-2-enyl]amino]purin-9-yl]oxolane-3,4-diol)), also known as norzeatin riboside, is a synthetic nicotinamide riboside analogue that is taken up by human cells and metabolically activated to form benzamide riboside 5’-mono, di- and tri-phosphates as well as benzamide ribosideadenine dinucleotide (or BAD+ ). The latter is a potent inhibitor of IMP dehydrogenase, IC50 = 2 μM. Phosphorylation to BR 5'-P (BRMP) is catalyzed by adenosine kinase, and conversion of the latter to benzamide riboside-adenine dinucleotide (or BAD+ ) is catalyzed by NMN adenylyltransferase. BAD+ is a more potent inhibitor of IMPDH than either BR and BRMP, the cytotoxicity of BR is thus more closely connected with the metabolism to BAD+ . While a weak PARP inhibitor, BAD+ is an extremely potent inhibitor of cell proliferation. Survival-relevant genes (e.g., cdc25A, akt, bcl-2, and transferrin receptor) are repressed by BR, whereas the expression level of the apoptosis enforcing gene c-myc persists. At high BR concentrations, DNA double-strand breaks occur hours before necrosis. There is also a dramatic decrease of intracellular ATP. Restoration of ATP by addition of adenosine or provision of sufficient glucose prevents BR-promoted necrosis and favors apoptosis instead. By inhibiting nicotinamide adenine dinucleotide kinase, BAD+ also reduces cellular pools of NADP+ and NADPH, the lack of which destabilizes dihydrofolate reductase. Likely effects of BAD+ on NAD+ -dependent histone deacetylase have yet to be reported. BAD+ also inhibits cell growth by down-regulating DHFR protein. Supporting this mode of action is the finding that CCRF-CEM/R human T-cell lymphoblasic leukemia cells (which are MTX-resistant as a consequence of DHFR gene amplification and overexpression) are more resistant to BR than are parental cells. BAD+ reduces cellular levels of NADP+ and NADPH by inhibiting nicotinamide adenine dinucleotide kinase (NADK), depleting NADPH, and destabilizing DHFR. NADK inhibition therefore represents another approach for downregulating DHFR and inhibiting cancer cell growth Target(s): IMP dehydrogenase; malate dehydrogenase; dihydrofolate reductase; nicotinamide adenine dinucleotide kinase, or NADK.
