Kinetic Mechanism of Nicotinamide N-Methyltransferase

Biochemistry
Heather S Loring, Paul R Thompson

Abstract

Nicotinamide N-methyltransferase (NNMT) catalyzes the transfer of a methyl group from S-adenosylmethionine (SAM) to nicotinamide, pyridine, and other structural analogues. Aberrantly increased NNMT activity results in the depletion of SAM, nicotinamide (NAM), and nicotinamide adenine dinucleotide (NAD+); NAM is required for NAD+ biosynthesis. SAM depletion impairs the methylation potential of the cell, resulting in hypomethylated histones and an altered epigenetic profile. In addition, decreased NAD+ levels negatively affect energy metabolism by disrupting oxidative phosphorylation. Because of its impact on epigenetic states and NAD+ levels, NNMT is implicated in cancer, neurodegenerative diseases, and metabolic diseases, making it an appealing target for therapeutic intervention. To gain insights that would guide the design of inhibitors and activity-based probes, we performed detailed kinetic studies of human NNMT. Herein, we report the kinetic mechanism of NNMT. Our initial velocity, product inhibition, and dead-end analogue inhibition studies collectively indicate that NNMT uses a rapid equilibrium ordered mechanism, where NNMT first binds SAM, which is followed by NAM. Methyl transfer occurs, and methylated NAM and S-adeno...Continue Reading

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Citations

Dec 11, 2020·Angewandte Chemie·Ludwig L BengelStephan C Hammer
Jan 28, 2021·International Journal of Molecular Sciences·Faisal HayatMarie E Migaud
May 25, 2021·Drug Discovery Today·Yongzhi GaoMatthijs J van Haren
Oct 8, 2019·Journal of Medicinal Chemistry·Rocco L PolicarpoMatthew D Shair
Aug 31, 2021·RSC Medicinal Chemistry·Iredia D Iyamu, Rong Huang

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