5u2n | pdb_00005u2n

Crystal structure of human NAMPT with A-1326133

spinqualitylabelsall models 5u2n, resolution 1.73Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5u2n is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 7TA, SO4 Related: 5u2m Gene: NAMPT, PBEF, PBEF1 (HUMAN) Activity: Nicotinamide phosphoribosyltransferase, with EC number 2.4.2.12 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [NAMPT_HUMAN] Catalyzes the condensation of nicotinamide with 5-phosphoribosyl-1-pyrophosphate to yield nicotinamide mononucleotide, an intermediate in the biosynthesis of NAD. It is the rate limiting component in the mammalian NAD biosynthesis pathway (By similarity). Publication Abstract from PubMed Cancer cells are highly reliant on NAD+-dependent processes, including glucose metabolism, calcium signaling, DNA repair, and regulation of gene expression. Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme for NAD+ salvage from nicotinamide, has been investigated as a target for anticancer therapy. Known NAMPT inhibitors with potent cell activity are composed of a nitrogen-containing aromatic group, which is phosphoribosylated by the enzyme. Here, we identified two novel types of NAM-competitive NAMPT inhibitors, only one of which contains a modifiable, aromatic nitrogen that could be a phosphoribosyl acceptor. Both types of compound effectively deplete cellular NAD+, and subsequently ATP, and produce cell death when NAMPT is inhibited in cultured cells for more than 48 hours. Careful characterization of the kinetics of NAMPT inhibition in vivo allowed us to optimize dosing to produce sufficient NAD+ depletion over time that resulted in efficacy in an HCT116 xenograft model. Our data demonstrate that direct phosphoribosylation of competitive inhibitors by the NAMPT enzyme is not required for potent in vitro cellular activity or in vivo antitumor efficacy. Mol Cancer Ther; 16(7); 1236-45. (c)2017 AACR. Discovery and Characterization of Novel Nonsubstrate and Substrate NAMPT Inhibitors.,Wilsbacher JL, Cheng M, Cheng D, Trammell SAJ, Shi Y, Guo J, Koeniger SL, Kovar PJ, He Y, Selvaraju S, Heyman HR, Sorensen BK, Clark RF, Hansen TM, Longenecker KL, Raich D, Korepanova AV, Cepa S, Towne DL, Abraham VC, Tang H, Richardson PL, McLoughlin SM, Badagnani I, Curtin ML, Michaelides MR, Maag D, Buchanan FG, Chiang GG, Gao W, Rosenberg SH, Brenner C, Tse C Mol Cancer Ther. 2017 Jul;16(7):1236-1245. doi: 10.1158/1535-7163.MCT-16-0819., Epub 2017 May 3. PMID:28468779 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Phosphoribosyltransferase

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