A small molecule inhibitor of Nicotinamide N-methyltransferase for the treatment of metabolic disorders

Autor:	Srinivasan Swaminathan, Rajendra Kristam, Manish Kumar Thakur, Anja Pfenninger, Vishal Subhash Mane, Saravanakumar Dhakshinamoorthy, Ralf Elvert, Saravanan Kandan, Niranjan Naranapura Anand, Takeshi Yura, Reejuana Parveen, Ravi Kanth Bhamidipati, Devaraj Venkatapura Chandrasekar, Ramesh Mullangi, Sridharan Rajagopal, Raghunadha Reddy Burri, Herman Schreuder, Mahanandeesha S. Hallur, Sven Ruf, Manvi Singh, Jörg Czech, Juluri Suresh, Ramachandraiah Gosu, Shama Shaik, Sanjay Venkatachalapathi Kadnur, Swarnakumari Birudukota, Bharat Ravindra Zope, Aimo Kannt, Christine Rudolph
Jazyk:	angličtina
Rok vydání:	2018
Předmět:	Male 0301 basic medicine medicine.medical_specialty medicine.medical_treatment lcsh:Medicine 030209 endocrinology & metabolism Nicotinamide N-methyltransferase Substrate analog Diet High-Fat Article Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Metabolic Diseases Internal medicine Diabetes mellitus Nicotinamide N-Methyltransferase medicine Animals Enzyme Inhibitors lcsh:Science Sensitization chemistry.chemical_classification Multidisciplinary Nicotinamide Insulin Body Weight lcsh:R medicine.disease Mice Inbred C57BL 030104 developmental biology Endocrinology medicine.anatomical_structure Enzyme Diabetes Mellitus Type 2 chemistry Knockout mouse lcsh:Q
Zdroj:	Scientific Reports, Vol 8, Iss 1, Pp 1-15 (2018) Scientific Reports
ISSN:	2045-2322
DOI:	10.1038/s41598-018-22081-7
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::5c01f24269126b297e24b498d6f605e4 http://link.springer.com/article/10.1038/s41598-018-22081-7 Zobrazit plný text záznamu Plný text ve formátu PDF Plný text ve formátu HTML
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