NNMT Human
Description
Introduction to NNMT Human
NNMT (Nicotinamide N-Methyltransferase) is a cytosolic enzyme catalyzing the N-methylation of nicotinamide and structurally related pyridines using S-adenosylmethionine (SAM) as the methyl donor. The recombinant human variant (ENZ-418) is a His-tagged protein expressed in E. coli, consisting of 284 amino acids (1–264 residues) with a molecular weight of 31.7 kDa . This enzyme plays critical roles in detoxification, NAD+ metabolism, and epigenetic regulation, with significant implications in oncology, neurodegeneration, and metabolic disorders.
Role in Cancer
NNMT is overexpressed in multiple cancers, correlating with poor prognosis and therapeutic resistance:
In pancreatic cancer, NNMT levels correlate with tumor size (>4 cm) and TNM stage III/IV .
Neurodegenerative Diseases
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Alzheimer’s Disease (AD):
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Parkinson’s Disease (PD):
NAD+ and SAM Homeostasis
NNMT depletes SAM and reduces NAD+ levels by consuming nicotinamide, impacting:
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Energy Metabolism: Alters glycolysis, TCA cycle, and oxidative phosphorylation .
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Epigenetic Remodeling: Hypomethylation of repressive histone marks (e.g., H3K27me3) via SAM depletion .
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Autophagy and Stemness: Promotes cancer cell survival and stemness by regulating polyamine flux .
Table: NNMT-Driven Metabolic Pathways
Biomarkers in Cancer
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Serum/Body Fluids:
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Prognostic Value:
Therapeutic Targeting
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Inhibition Strategies:
Research Challenges and Future Directions
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Mechanistic Elucidation:
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Therapeutic Translation:
Product Specs
Q&A
Here’s a structured collection of FAQs tailored for academic researchers studying human Nicotinamide N-Methyltransferase (NNMT), incorporating experimental design considerations, data analysis challenges, and methodological guidance:
Advanced Research Challenges
How to resolve contradictory prognostic data for NNMT across cancer types?
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Case example: Elevated NNMT correlates with poor prognosis in NSCLC but shows no significance in prostate cancer .
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Strategies:
What methodologies validate NNMT as a therapeutic target?
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In vitro: High-throughput screening using FP-based competition assays (IC50 determination for inhibitors like II138 ).
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In vivo: Xenograft models with NNMT-overexpressing cells (e.g., 40% tumor growth reduction with NNMTi-1 ).
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Multi-omics: Integrate RNA-seq (NNMT-linked pathways) with metabolomics (SAM/NAD+ levels).
Table 1: NNMT Expression Levels in Human Cancers
Table 2: NNMT Inhibitors and Efficacy
Methodological Recommendations
How to design studies analyzing NNMT’s role in cancer stem cells (CSCs)?
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Approach:
What statistical methods address NNMT’s variability in clinical cohorts?
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Tools:
Ethical and Technical Caveats
How to mitigate bias in NNMT biomarker studies?
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Blinding: Pathologists should be blinded to clinical outcomes during IHC scoring.
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Validation: Use independent cohorts (e.g., TCGA data for NNMT mRNA ).
Why do NNMT inhibitors show limited efficacy in preclinical models?
Product Science Overview
Nicotinamide N-Methyltransferase (NNMT) is a cytosolic enzyme that plays a crucial role in the methylation of nicotinamide and other pyridines. This enzyme is involved in various biological processes, including the biotransformation and detoxification of xenobiotic compounds. NNMT is found in human fat cells and the liver, where it catalyzes the N-methylation of nicotinamide to form methylnicotinamide .
NNMT is composed of 264 amino acids and is responsible for the N-methylation of nicotinamide, using S-adenosylmethionine (SAM) as a methyl donor. This reaction converts nicotinamide into methylnicotinamide and S-adenosyl-L-homocysteine (SAH). The enzyme’s activity is essential for maintaining cellular methylation potential, impacting DNA and histone epigenetic modifications .
NNMT overexpression has been observed in various solid cancer tissues and body fluids, including serum, urine, and saliva. This overexpression is associated with increased tumorigenesis and chemoresistance. NNMT knockdown has been shown to significantly decrease tumorigenesis and chemoresistance capacity. Additionally, natural NNMT inhibitors, such as yuanhuadine, have demonstrated the ability to reverse resistance to epidermal growth factor receptor tyrosine kinase inhibitors in lung cancer cells .
NNMT activity increases with age and is closely associated with the onset and progression of age-related diseases. The enzyme’s activity depletes nicotinamide, a precursor of nicotinamide adenine dinucleotide (NAD+), and generates SAH, a precursor of homocysteine (Hcy). The reduction in NAD+ levels and the increase in Hcy levels are considered important factors in the aging process and age-related diseases. RNA interference (RNAi) therapies and small-molecule inhibitors targeting NNMT have shown potential in combating aging and its related pathologies .
Given its role in cancer and aging, NNMT has emerged as a promising therapeutic target. The development of more potent and selective NNMT inhibitors could provide new avenues for cancer treatment and anti-aging therapies. However, further research is needed to elucidate the precise mechanisms by which NNMT influences these processes and to develop targeted pharmaceutical interventions .
