title: Neuroprotective effects of nicotinamide N-methyltransferase and its metabolite 1-methylnicotinamide.
abstract: Nicotinamide N-methyltransferase (NNMT, E.C. 2.1.1.1) catalyses the N-methylation of nicotinamide to 1-methylnicotinamide (MeN). We have previously shown that the ectopic expression of NNMT in SH-SY5Y human neuroblastoma cells increased adenosine triphosphate synthesis and complex I activity, effects of which were replicated by the addition of MeN. In this study, we investigated whether NNMT expression in SH-SY5Y conferred protection against mitotoxicity induced by rotenone, potassium cyanide (KCN), 2,4-dinitrophenol, and 6-hydroxydopamine, and whether any effects observed were mediated via increased MeN production. NNMT expression abolished the toxic effects of KCN, 2,4-dinitrophenol, and 6-hydroxydopamine, and reduced that of rotenone. In contrast, although MeN significantly reduced the toxicity of rotenone, it had no effect upon the toxicity of KCN, 2,4-dinitrophenol, and 6-hydroxydopamine. These data show that NNMT is cytoprotective against toxins that inhibit various aspects of mitochondrial function, and that these are not mediated solely via increased MeN production, but in combination with other unidentified mechanisms.
authors.affiliation: Institute of Pharmaceutical Science, King's College London, London, UK.
authors.forename: Zeinab H
authors.initials: ZH
authors.lastname: Milani
authors.forename: David B
authors.initials: DB
authors.lastname: Ramsden
authors.forename: Richard B
authors.initials: RB
authors.lastname: Parsons
mesh_terms: D019297:2,4-Dinitrophenol / Q000633:toxicity; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009447:Neuroblastoma / Q000201:enzymology* / Q000473:pathology; D018696:Neuroprotective Agents / Q000737:chemistry; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000378:metabolism; D050903:Nicotinamide N-Methyltransferase / Q000096:biosynthesis / Q000378:metabolism*; D016627:Oxidopamine / Q000633:toxicity; D011190:Potassium Cyanide / Q000633:toxicity; D012402:Rotenone / Q000633:toxicity
chemical_list: D018696:Neuroprotective Agents; D012402:Rotenone; D009536:Niacinamide; D016627:Oxidopamine; D050903:Nicotinamide N-Methyltransferase; D011190:Potassium Cyanide; D019297:2,4-Dinitrophenol; C024058:N(1)-methylnicotinamide
keywords: 1-Methylnicotinamide; ATP Synthesis; Complex I; Mitochondria; Neuroprotection; Nicotinamide N-methyltransferase