5yjf

Co-crystal structure of Human Nicotinamide N-methyltransferase (NNMT) with small molecule analog of Nicotinamide

spinqualitylabelsall models 5yjf, resolution 2.49Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5yjf is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.49Å Ligands: 8WO, SAH Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function NNMT_HUMAN Catalyzes the N-methylation of nicotinamide and other pyridines to form pyridinium ions. This activity is important for biotransformation of many drugs and xenobiotic compounds. Publication Abstract from PubMed Nicotinamide N-methyltransferase (NNMT) is a cytosolic enzyme that catalyzes the transfer of a methyl group from the co-factor S-adenosyl-L-methionine (SAM) onto the substrate, nicotinamide (NA) to form 1-methyl-nicotinamide (MNA). Higher NNMT expression and MNA concentrations have been associated with obesity and type-2 diabetes. Here we report a small molecule analog of NA, JBSNF-000088, that inhibits NNMT activity, reduces MNA levels and drives insulin sensitization, glucose modulation and body weight reduction in animal models of metabolic disease. In mice with high fat diet (HFD)-induced obesity, JBSNF-000088 treatment caused a reduction in body weight, improved insulin sensitivity and normalized glucose tolerance to the level of lean control mice. These effects were not seen in NNMT knockout mice on HFD, confirming specificity of JBSNF-000088. The compound also improved glucose handling in ob/ob and db/db mice albeit to a lesser extent and in the absence of weight loss. Co-crystal structure analysis revealed the presence of the N-methylated product of JBSNF-000088 bound to the NNMT protein. The N-methylated product was also detected in the plasma of mice treated with JBSNF-000088. Hence, JBSNF-000088 may act as a slow-turnover substrate analog, driving the observed metabolic benefits. A small molecule inhibitor of Nicotinamide N-methyltransferase for the treatment of metabolic disorders.,Kannt A, Rajagopal S, Kadnur SV, Suresh J, Bhamidipati RK, Swaminathan S, Hallur MS, Kristam R, Elvert R, Czech J, Pfenninger A, Rudolph C, Schreuder H, Chandrasekar DV, Mane VS, Birudukota S, Shaik S, Zope BR, Burri RR, Anand NN, Thakur MK, Singh M, Parveen R, Kandan S, Mullangi R, Yura T, Gosu R, Ruf S, Dhakshinamoorthy S Sci Rep. 2018 Feb 26;8(1):3660. doi: 10.1038/s41598-018-22081-7. PMID:29483571 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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