A small molecule inhibitor of Nicotinamide N-methyltransferase for the treatment of metabolic disorders
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 w...
Gespeichert in:
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
26 February 2018
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| In: |
Scientific reports
Year: 2018, Jahrgang: 8, Heft: 1 |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/s41598-018-22081-7 |
| Online-Zugang: | Verlag, Volltext: https://doi.org/10.1038/s41598-018-22081-7 Verlag, Volltext: https://www.nature.com/articles/s41598-018-22081-7 
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| Verfasserangaben: | Aimo Kannt, Sridharan Rajagopal, Sanjay Venkatachalapathi Kadnur, Juluri Suresh, Ravi Kanth Bhamidipati, Srinivasan Swaminathan, Mahanandeesha Siddappa Hallur, Rajendra Kristam, Ralf Elvert, Jörg Czech, Anja Pfenninger, Christine Rudolph, Herman Schreuder, Devaraj Venkatapura Chandrasekar, Vishal Subhash Mane, Swarnakumari Birudukota, Shama Shaik, Bharat Ravindra Zope, Raghunadha Reddy Burri, Niranjan Naranapura Anand, Manish Kumar Thakur, Manvi Singh, Reejuana Parveen, Saravanan Kandan, Ramesh Mullangi, Takeshi Yura, Ramachandraiah Gosu, Sven Ruf and Saravanakumar Dhakshinamoorthy |
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| 520 | |a 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. | ||
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