Nicotinamide N -Methyltransferase: More Than a Vitamin B3 Clearance Enzyme

Pissios, Pavlos

doi:10.1016/j.tem.2017.02.004

Cited by 194 publications

(202 citation statements)

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“…The NNMT pathway has been linked to lifespan and aging (Calvani et al, 2014;Neelakantan et al, 2019;Schmeisser et al, 2013;Schmeisser and Parker, 2018), to sirtuin protein stabilization in positive a feedback loop to the pathway in Figure 6C involved in energy regulation and obesity (Hong et al, 2015;Kraus et al, 2014;Strom et al, 2018), and to epigenetics in cancer and stem cell status (Jung et al, 2017;Sperber et al, 2015;Ulanovskaya et al, 2013;Xie et al, 2014) (reviewed by (Pissios, 2017)). We show that PGRMC1 Y180 modulates this system.…”

Section: Discussionmentioning

confidence: 99%

PGRMC1 phosphorylation and cell plasticity 2: genomic integrity and CpG methylation

et al. 2019

Preprint

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SUMMARYProgesterone receptor membrane component 1 (PGRMC1) is often elevated in cancers, and exists in alternative states of phosphorylation. A motif centered on PGRMC1 Y180 was evolutionarily acquired concurrently with the embryological gastrulation organizer that orchestrates vertebrate tissue differentiation. Here, we show that mutagenic manipulation of PGRMC1 phosphorylation alters cell metabolism, genomic stability, and CpG methylation. Each of several mutants elicited distinct patterns of genomic CpG methylation. Mutation of S57A/Y180/S181A led to increased net hypermethylation, reminiscent of embryonic stem cells. Pathways enrichment analysis suggested modulation of processes related to animal cell differentiation status and tissue identity, as well as cell cycle control and ATM/ATR DNA damage repair regulation. We detected different genomic mutation rates in culture. A companion manuscript shows that these cell states dramatically affect protein abundances, cell and mitochondrial morphology, and glycolytic metabolism. We propose that PGRMC1 phosphorylation status modulates cellular plasticity mechanisms relevant to early embryological tissue differentiation.

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Section: Discussionmentioning

confidence: 99%

PGRMC1 phosphorylation and cell plasticity 2: genomic integrity and CpG methylation

et al. 2019

Preprint

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“…In addition to the NO metabolism, increased levels of PGI2 have been reported in response to MNAM administration (Chlopicki et al, ; KaŸmierczak et al, ; Mateuszuk et al, ; Pissios, ). It is well known that PGI2 is mainly produced by endothelial cell when phospholipase A2 (PLA2) releases arachidonic acid (AA) from endoplasmic reticulum (ER) or nuclear envelope (NE) followed by activation of cyclooxygenases (COXs) and PGI2 synthase (PGIS) (Chu, Liou, & Wu, ; McAdam et al, ;).…”

Section: Mnam and Endothelial Functionmentioning

confidence: 99%

“…In addition to the NO metabolism, increased levels of PGI2 have been reported in response to MNAM administration (Chlopicki et al, 2007;KaŸmierczak et al, 2008;Mateuszuk et al, 2016;Pissios, 2017).…”

Section: Mnam No and Pgimentioning

confidence: 99%

N1‐methylnicotinamide (MNAM) as a guardian of cardiovascular system

Nejabati

Mihanfar

Pezeshkian

et al. 2018

Journal Cellular Physiology

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Atherosclerosis is identified as the formation of atherosclerotic plaques, which could initiate the formation of a blood clot in which its growth to coronary artery can lead to a heart attack. N-methyltransferase (NNMT) is an enzyme that converts the NAM (nicotinamide) to its methylated form, N1-methylnicotinamide (MNAM). Higher levels of MNAM have been reported in cases with coronary artery disease (CAD). Further, MNAM increases endothelial prostacyclin (PGI2) and nitric oxide (NO) and thereby causes vasorelaxation. The vasoprotective, anti-inflammatory and anti-thrombotic roles of MNAM have been well documented; however, the exact underlying mechanisms remain to be clarified. Due to potential role of MNAM in the formation of lipid droplets (LDs), it might exert its function in coordination with lipids, and their targets. In this study, we summarized the roles of MNAM in cardiovascular system and highlighted its possible mode of actions.

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“…NAM, a form of vitamin B3, is the most studied endogenous substrate of NNMT and is converted to N1-methylnicotinamide (MNAM) after methylation. NAM is also a precursor of salvage pathways to produce NAD + , an important coenzyme involved in redox metabolism and sirtuins-catalyzed deacetylation reaction [2,3]. In addition, NNMT also methylates 4-phenylpyridine to generate the neurotoxin 1-methyl-4phenylpyridinium ion, which interferes with complex I and is implicated in idiopathic Parkinson's disease [4].…”

Section: Introductionmentioning

confidence: 99%

“…The reaction mixture was warmed to rt and stirred for 6 h. The solution was concentrated under reduced pressure, dissolved in water and purified by reverse HPLC to get the corresponding bisubstrate compound. ((3aR,4R,6R,6aR)-6-(6-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol(2). To a suspension of 1 (1.0 g, 3.4 mmol) in dry acetone (200 mL) was added p-TsOH monohydrate (6.6 g, 34.0 mmol) in one portion.…”

mentioning

confidence: 99%

Development of fluorescence polarization-based competition assay for nicotinamideN-methyltransferase

Iyamu

Huang

2020

Preprint

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Methylation-mediated pathways play an important role in the progression of cancer. Inhibitors of several key methyltransferases including DNA methyltransferases and histone methyltransferases have proven to be instrumental for both understanding the function of the respective enzymes activites and translational applications in cancer epigenetic therapy. Nicotinamide Nmethyltransferase (NNMT) is a major metabolic enzyme involved in epigenetic regulation through catalysis of methyl transfer from the cofactor S-adenosyl-L-methionine, onto nicotinamide and other pyridines, to form S-adenosyl homocysteine and 1-methyl-nicotinamide or the corresponding pyridinium ions. Accumulating evidence infers that NNMT is a novel therapeutic target for a variety of diseases such as cancer, diabetes, obesity, cardiovascular and neurodegenerative diseases. Therefore, there is an urgent need to discover potent and specific inhibitors for NNMT. Herein, we reported the design and synthesis of a fluorescent probe II138, and established a fluorescence polarization (FP)-based competition assay for evaluation of NNMT inhibitors. Importantly, the unique feature of this FP competition assay is its capability to identify inhibitors that interfere with the interaction of the NNMT active site directly or allosterically. In addition, this assay performane is robust with a Z factor of 0.76, and applicable in high-throughput screening for inhibitors for NNMT.

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Nicotinamide N -Methyltransferase: More Than a Vitamin B3 Clearance Enzyme

Cited by 194 publications

References 91 publications

PGRMC1 phosphorylation and cell plasticity 2: genomic integrity and CpG methylation

PGRMC1 phosphorylation and cell plasticity 2: genomic integrity and CpG methylation

N1‐methylnicotinamide (MNAM) as a guardian of cardiovascular system

Development of fluorescence polarization-based competition assay for nicotinamideN-methyltransferase

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