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

Scientific Reports
Aimo KanntSaravanakumar Dhakshinamoorthy

Abstract

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-tur...Continue Reading

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Citations

Oct 18, 2018·International Journal of Tryptophan Research : IJTR·Adrian C Williams, Lisa J Hill
Dec 19, 2018·Current Opinion in Oncology·Emilie Montellier, Jonathan Gaucher
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Methods Mentioned

BETA
antisense oligonucleotide
enzymatic assay
thermal shift
X-ray
ELISA

Software Mentioned

CCP4 Suite
MOLREP
PyMOL
GraphPad Prism - 5
REFMAC5
PROCHECK
GraphPad Prism
AFITT
COOT

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