NNMTi Chemische Eigenschaften,Einsatz,Produktion Methoden
Beschreibung
NNMTi (CAS 42464-96-0) is a nicotinamide N-methyltransferase (NNMT) inhibitor that promotes myoblast differentiation. NNMT is a fundamental cytosolic biotransforming enzyme that catalyzes the N-methylation of endogenous and exogenous xenobiotics. NNMTi treatment combined with lean diet substitution accelerated improved body weight fat loss, increased whole-body lean mass to body weight ratio, reduced liver epididymal white adipose tissue weights, decreased liver adiposity, improved hepatic steatosis, relative to a lean diet substitution alone.
Chemische Eigenschaften
Brown solid.
Verwenden
NNMTi is an enzyme overexpressed during skeletal muscle aging and is associated with the repair of damage to the NAD+ pathway, dysregulation of sirtuin1 activity, and increased senescence of muscle stem cells.
synthetische
Synthesis of 5-Amino-1-methyl-1-quinolinium Iodide(NNMTi): Iodomethane (0.160 ml, 0.365 g, 2.6 mmol) was added to a solution of 5-aminoquinoline (0.277 g, 1.9 mmol) in tetrahydrofuran (7 ml), and stirred at room temperature for 1 day until a red solid precipitated. After filtration, the filter cake was washed with tetrahydrofuran (2 x 5 ml) and dried under vacuum to give 0.240 g of compound 5-Amino-1-methyl-1-quinolinium Iodide.
Biologische Funktion
The cytosolic enzyme nicotinamide N-methyltransferase (NNMT) has been newly discovered to modulate the levels of nicotinamide precursors required for NAD+ biosynthesis and thus plays a crucial role in regulating the NAD+ salvage pathway and cellular metabolism. NNMT is expressed in skeletal muscle, with progressively greater expression associated with aging in muscle tissues. Importantly, NNMT is a dominant component of the gene expression signature for sarcopenia, overexpression of which could lead to significantly reduced levels of NAD+ and associated declines in muscle mass, strength, and function that accompany aging. Treatment of aged mice with a small molecule NNMT inhibitor (NNMTi) enhanced the proliferation, fusion, and regenerative capacity of muSCs, subsequently increasing the functional performance of skeletal muscle. Similar results were demonstrated in vitro with C2C12 cells that closely mimic muSCs, where NNMTi treatment promoted myoblast differentiation and supported metabolic changes in NAD+ salvage pathway-related cellular metabolites[5].
Einzelnachweise
[1]. Harshini Neelakantan, et al. Small molecule nicotinamide N-methyltransferase inhibitor activates senescent muscle stem cells and improves regenerative capacity of aged skeletal muscle. Biochem Pharmacol. 2019 May;163:481-492. DOI:
10.1016/j.bcp.2019.02.008[2]. Harshini Neelakantan, et al. Structure-Activity Relationship for Small Molecule Inhibitors of Nicotinamide N-Methyltransferase. J Med Chem DOI:
10.1021/acs.jmedchem.7b00389[3]. Mark A Eckert et al. Proteomics reveals NNMT as a master metabolic regulator of cancer-associated fibroblasts. Nature, 569(7758), 723-728 (2019-05-03) DOI:
10.1038/s41586-019-1173-8[4]. SAMPSONCATHERINE M. Combined nicotinamide N-methyltransferase inhibition and reduced-calorie diet normalizes body composition and enhances metabolic benefits in obese mice.[J]. Scientific Reports, 2021: 5637. DOI:
10.1038/s41598-021-85051-6.
[5] Andrea Dimet-Wiley. “Reduced calorie diet combined with NNMT inhibition establishes a distinct microbiome in DIO mice.” Scientific Reports (2022): 484.
[6] Annalisa Roberti. “Nicotinamide N-methyltransferase (NNMT) regulates the glucocorticoid signaling pathway during the early phase of adipogenesis.” Scientific Reports 13 1 (2023): 8293.
NNMTi Upstream-Materialien And Downstream Produkte
Upstream-Materialien
Downstream Produkte
