Nicotinamide N-methyltransferase

Yan L, Otterness DM, Kozak CA, Weinshilboum RM. Mouse nicotinamide N-methyltransferase gene molecular cloning, structural characterization, and chromosomal localization. DNA cell Biol. 1998 17(8) 639—667. 

Epidemiological studies suggest that niacin may be implicated in the pathogenesis of Parkinson s disease via the following process. NAD produced from niacin releases nicotinamide via poly(ADP-ribosyl)ation which is activated in Parkinson s disease. Released excess nicotinamide is methylated to 1-methylnicotinamide (MNA) in the cytoplasm by nicotinamide N-methyltransferase. MNA destroys several subunits of complex I via superoxide formation. This can destroy complex I subunits either directly or indirectly via mitochondrial DNA damage, and stimulates poly(ADP-ribosyl)ation. It has been proposed that this implicates nicotinamide as a potential causal agent in the development of Parkinson s disease (Fukushima et al., 2004). 

Figure 8.3. Metabolites of nicotinamide and nicotinic acid. Nicotinamide deamidase (nicotinamidase), EC 3.5.1.19 nicotinamide N-methyltransferase, EC 2.1.1.1 aldehyde dehydrogenase, EC 1.1.1.1. Relative molecular masses (Mr) nicotinamide, 123.1 nicotinic acid, 122.1 nicotinamide N-oxide, 139.1 iV -methyl nicotinamide, 139.1 trigonelline, 137.1 nicotinuiic acid, 179.2 and methyl pyridone carboxamides, 154.1.

Nicotinamide N-methyltransferase (NNMT) methylates serotonin, tryptophan, and pyridine-containing compounds such as nicotinamide and nicotine. Phenylethanolamine N-methyltransferase (PNMT)... 

As shown in Figure 8.3, the principed metabolites of nicotuicunide cire N -methyl nicotineimide emd methyl pyridone ctuboxamides. A( -Methyl nicotinamide is actively secreted into the urine by the proximal renal tubules. Nicotinamide AT-methyltransferase is em S-adenosyhnethionine-dependent enzyme that is present in most tissues. Very high intakes of nicotinamide may deplete tissue pools of one-carbon fragments - indeed, this was the basis for the use of nicotineimide in the treatment of schizophrenia (Section 8.8). 

A number of methyltransferases are able tc methylate small molecules (46,47). Thus, re. actions of methylation fulfill only two of the three criteria defined above, because the methyl group is small compared with the substrate. The main enzyme responsible for O-methylation is catechol 0-methyltransferas (EC 2.1.1.6 COMT), which is mainly cytosolic but also exists in membrane-bound form. Several enzymes catalyze reactions of xenobiotic N-methylation with different substrate specificities, e.g., nicotinamide iV-methyltrans-ferase (EC 2.1.1.1), histamine methyltrans-ferase (EC 2.1.1.8), phenylethanolamine N-methy 1 transferase (noradrenal ine A-meth-yltransferase EC 2.1.1.28), and nonspecific amine N-methyltransferase (arylamine N-methyltransferase, tryptamine JV-methyl-transferase EC 2.1.1.49) of which some isozymes have been characterized. Reactions of xenobiotic S-methylation are mediated by the membrane-bound thiol methyltransferase (EC 2.1.1.9) and the cytosolic thiopurine methyltransferase (EC 2.1.1.67) (3). 

A/-Methylations are catalysed by several enzymes such as nicotinamide A -methyltransferase, histamine methyltransferase, phenylethanolamine iV-methyltransferase (noradrenaline Af-methyltransferase) and a non-specific amine N-methyltransferase (arylamine iV-methyltransferase, tryptamine iV-methyltransferase). S-Methylations are catalysed by the membrane-bound thiol methyltransferase and the cytosolic thiopurine methyltransferase. 

Nicotinamide iV-methyltransferase 2.1.1.1 N-methylation Nicotinamide, pyridine, drugs, and xenobiotics... 

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