Nicotinamide N-methyl transferase (NNMT): An emerging therapeutic target

Gao, Yongzhi; Martin, Nathaniel I.; Haren, Matthijs J. van

doi:10.1016/j.drudis.2021.05.011

Cited by 29 publications

(29 citation statements)

References 55 publications

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“…Taking into account the fact that NNMT inhibition may have a similar suppressive effect on NAD + production as an NAMPT blockade, it might be interesting to consider NNMT as another drug target in IBD. Exploitation of NNMT is especially appealing, as aberrant NNMT expression has been linked with cancer, metabolic diseases, neurodegeneration, and inflammatory conditions [57]. Importantly, multiple classes of NNMT inhibitors were synthesized and are available for testing in IBD models [57].…”

Section: Discussionmentioning

confidence: 99%

Alterations in Kynurenine and NAD+ Salvage Pathways during the Successful Treatment of Inflammatory Bowel Disease Suggest HCAR3 and NNMT as Potential Drug Targets

Wnorowski

Wnorowska

Kurzepa

et al. 2021

IJMS

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A meta-analysis of publicly available transcriptomic datasets was performed to identify metabolic pathways profoundly implicated in the progression and treatment of inflammatory bowel disease (IBD). The analysis revealed that genes involved in tryptophan (Trp) metabolism are upregulated in Crohn’s disease (CD) and ulcerative colitis (UC) and return to baseline after successful treatment with infliximab. Microarray and mRNAseq profiles from multiple experiments confirmed that enzymes responsible for Trp degradation via the kynurenine pathway (IDO1, KYNU, IL4I1, KMO, and TDO2), receptor of Trp metabolites (HCAR3), and enzymes catalyzing NAD+ turnover (NAMPT, NNMT, PARP9, CD38) were synchronously coregulated in IBD, but not in intestinal malignancies. The modeling of Trp metabolite fluxes in IBD indicated that changes in gene expression shifted intestinal Trp metabolism from the synthesis of 5-hydroxytryptamine (5HT, serotonin) towards the kynurenine pathway. Based on pathway modeling, this manifested in a decline in mucosal Trp and elevated kynurenine (Kyn) levels, and fueled the production of downstream metabolites, including quinolinate, a substrate for de novo NAD+ synthesis. Interestingly, IBD-dependent alterations in Trp metabolites were normalized in infliximab responders, but not in non-responders. Transcriptomic reconstruction of the NAD+ pathway revealed an increased salvage biosynthesis and utilization of NAD+ in IBD, which normalized in patients successfully treated with infliximab. Treatment-related changes in NAD+ levels correlated with shifts in nicotinamide N-methyltransferase (NNMT) expression. This enzyme helps to maintain a high level of NAD+-dependent proinflammatory signaling by removing excess inhibitory nicotinamide (Nam) from the system. Our analysis highlights the prevalent deregulation of kynurenine and NAD+ biosynthetic pathways in IBD and gives new impetus for conducting an in-depth examination of uncovered phenomena in clinical studies.

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Section: Discussionmentioning

confidence: 99%

Alterations in Kynurenine and NAD+ Salvage Pathways during the Successful Treatment of Inflammatory Bowel Disease Suggest HCAR3 and NNMT as Potential Drug Targets

Wnorowski

Wnorowska

Kurzepa

et al. 2021

IJMS

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“…However, further studies on larger cohorts of patients are needed to confirm these findings and to explore the biological role of NNMT in HNT. Moreover, this enzyme could be a promising target for cancer therapy, which can be studied in more detail thanks to the development of specific NNMT inhibitors which have shown promising results in preclinical studies [ 46 , 47 , 48 , 49 , 50 , 51 ].…”

Section: Discussionmentioning

confidence: 99%

Nicotinamide N-Methyltransferase in Head and Neck Tumors: A Comprehensive Review

et al. 2021

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The head and neck tumors (HNT) are a heterogeneous group of diseases ranging from benign to malignant lesions, with distinctive molecular and clinical behaviors. Several studies have highlighted the presence of an altered metabolic phenotype in HNT, such as the upregulation of nicotinamide N-methyltransferase (NNMT). However, its biological effects have not been completely disclosed and the role of NNMT in cancer cell metabolism remains unclear. Therefore, this comprehensive review aims to evaluate the available literature regarding the biological, diagnostic, and prognostic role of NNMT in HNT. NNMT was shown to be significantly overexpressed in all of the evaluated HNT types. Moreover, its upregulation has been correlated with cancer cell migration and adverse clinical outcomes, such as high-pathological stage, lymph node metastasis, and locoregional recurrences. However, in oral squamous cell carcinoma (OSCC) these associations are still debated, and several studies have failed to demonstrate the prognostic significance of NNMT. The shRNA-mediated gene silencing efficiently suppressed the NNMT gene expression and exhibited a clear inhibitory effect on cell proliferation, promoting the expression of apoptosis-related proteins and modulating the cell cycle. NNMT could represent a new molecular biomarker and a new target of molecular-based therapy, although further studies on larger patient cohorts are needed to explore its biological role in HNT.

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“…Many research groups, including our own, are now actively developing inhibitors of NNMT as anti-cancer therapies (for a comprehensive review of the current state of NNMT inhibitor development, see [198]). The first description of an NNMT inhibitor which was not S-adenosylhomocysteine (SAH) or MNA identified S-adenosylethionine as a potent inhibitor, although this was significantly less effective than SAH [199].…”

Section: Small-molecule Inhibitors Of Nnmt Activitymentioning

confidence: 99%

“…The first description of an NNMT inhibitor which was not S-adenosylhomocysteine (SAH) or MNA identified S-adenosylethionine as a potent inhibitor, although this was significantly less effective than SAH [199]. In recent years, rapid progress in inhibitor design has been made in a relatively short amount of time due to our increased understanding of the interactions between nicotinamide, SAM and the NNMT active site [30,198]. The key to unlocking this understanding was the first publication of the crystal structure of NNMT co-crystalised with nicotinamide and SAH by Peng and colleagues [200].…”

Section: Small-molecule Inhibitors Of Nnmt Activitymentioning

confidence: 99%

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Nicotinamide N-Methyltransferase: An Emerging Protagonist in Cancer Macro(r)evolution

Parsons

Facey

2021

Biomolecules

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Nicotinamide N-methyltransferase (NNMT) has progressed from being considered merely a Phase II metabolic enzyme to one with a central role in cell function and energy metabolism. Over the last three decades, a significant body of evidence has accumulated which clearly demonstrates a central role for NNMT in cancer survival, metastasis, and drug resistance. In this review, we discuss the evidence supporting a role for NNMT in the progression of the cancer phenotype and how it achieves this by driving the activity of pro-oncogenic NAD+-consuming enzymes. We also describe how increased NNMT activity supports the Warburg effect and how it promotes oncogenic changes in gene expression. We discuss the regulation of NNMT activity in cancer cells by both post-translational modification of the enzyme and transcription factor binding to the NNMT gene, and describe for the first time three long non-coding RNAs which may play a role in the regulation of NNMT transcription. We complete the review by discussing the development of novel anti-cancer therapeutics which target NNMT and provide insight into how NNMT-based therapies may be best employed clinically.

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Nicotinamide N-methyl transferase (NNMT): An emerging therapeutic target

Cited by 29 publications

References 55 publications

Alterations in Kynurenine and NAD+ Salvage Pathways during the Successful Treatment of Inflammatory Bowel Disease Suggest HCAR3 and NNMT as Potential Drug Targets

Alterations in Kynurenine and NAD+ Salvage Pathways during the Successful Treatment of Inflammatory Bowel Disease Suggest HCAR3 and NNMT as Potential Drug Targets

Nicotinamide N-Methyltransferase in Head and Neck Tumors: A Comprehensive Review

Nicotinamide N-Methyltransferase: An Emerging Protagonist in Cancer Macro(r)evolution

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