View source for 5yjf


==Co-crystal structure of Human Nicotinamide N-methyltransferase (NNMT) with small molecule analog of Nicotinamide==
<StructureSection load='5yjf' size='340' side='right'caption='[[5yjf]], [[Resolution|resolution]] 2.49&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5yjf]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5YJF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5YJF FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.49&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=8WO:6-methoxy-1-methyl-2H-pyridine-3-carboxamide'>8WO</scene>, <scene name='pdbligand=SAH:S-ADENOSYL-L-HOMOCYSTEINE'>SAH</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5yjf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5yjf OCA], [https://pdbe.org/5yjf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5yjf RCSB], [https://www.ebi.ac.uk/pdbsum/5yjf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5yjf ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/NNMT_HUMAN 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.
<div style="background-color:#fffaf0;">
== 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<ref>PMID:29483571</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5yjf" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Birudukota S]]
[[Category: Dhakshinamoorthy S]]
[[Category: Gosu R]]
[[Category: Hallur MS]]
[[Category: Kandan S]]
[[Category: Kannt A]]
[[Category: Parveen R]]
[[Category: Rajagopal S]]
[[Category: Ruf S]]
[[Category: Swaminathan S]]
[[Category: Thakur MK]]