NNMTi
Bezeichnung:NNMTi
CAS-Nr42464-96-0
Englisch Name:NNMTi
CBNumberCB05839892
Molgewicht0
MOL-DateiMol file
NNMTi physikalisch-chemischer Eigenschaften
Schmelzpunkt | 213-214 °C |
storage temp. | Store at -20°C |
Löslichkeit | Soluble in DMSO |
Gefahreninformationscode (GHS)
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Bildanzeige (GHS)
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Alarmwort
Warnung
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Gefahrenhinweise
H302:Gesundheitsschädlich bei Verschlucken.
H315:Verursacht Hautreizungen.
H319:Verursacht schwere Augenreizung.
H335:Kann die Atemwege reizen.
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Sicherheit
P261:Einatmen von Staub vermeiden.
P264:Nach Gebrauch gründlich waschen.
P264:Nach Gebrauch gründlich waschen.
P270:Bei Gebrauch nicht essen, trinken oder rauchen.
P271:Nur im Freien oder in gut belüfteten Räumen verwenden.
P280:Schutzhandschuhe/Schutzkleidung/Augenschutz tragen.
P301+P312:BEI VERSCHLUCKEN: Bei Unwohlsein GIFTINFORMATIONSZENTRUM/Arzt/... (geeignete Stelle für medizinische Notfallversorgung vom Hersteller/Lieferanten anzugeben) anrufen.
P302+P352:BEI BERÜHRUNG MIT DER HAUT: Mit viel Wasser/... (Hersteller kann, falls zweckmäßig, ein Reinigungsmittel angeben oder, wenn Wasser eindeutig ungeeignet ist, ein alternatives Mittel empfehlen) waschen.
P304+P340:BEI EINATMEN: Die Person an die frische Luft bringen und für ungehinderte Atmung sorgen.
P305+P351+P338:BEI KONTAKT MIT DEN AUGEN: Einige Minuten lang behutsam mit Wasser spülen. Eventuell vorhandene Kontaktlinsen nach Möglichkeit entfernen. Weiter spülen.
P312:Bei Unwohlsein GIFTINFORMATIONSZENTRUM/Arzt/... (geeignete Stelle für medizinische Notfallversorgung vom Hersteller/Lieferanten anzugeben) anrufen.
P330:Mund ausspülen.
P332+P313:Bei Hautreizung: Ärztlichen Rat einholen/ärztliche Hilfe hinzuziehen.
P337+P313:Bei anhaltender Augenreizung: Ärztlichen Rat einholen/ärztliche Hilfe hinzuziehen.
P362:Kontaminierte Kleidung ausziehen und vor erneutem Tragen waschen.
P403+P233:An einem gut belüfteten Ort aufbewahren. Behälter dicht verschlossen halten.
P405:Unter Verschluss aufbewahren.
P501:Inhalt/Behälter ... (Entsorgungsvorschriften vom Hersteller anzugeben) zuführen.
NNMTi Chemische Eigenschaften,Einsatz,Produktion Methoden
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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. -
benefits
NNMT is a metabolic enzyme that catalyzes the methylation of nicotinamide (NAM) using the universal methyl donor S-adenosyl methionine (SAM), linking the metabolic status of the cell with both methylation balance and intracellular levels of NAD+. NNMT is abundantly expressed in liver and adipose tissue and pathological conditions characterized by increased metabolic demand, such as some cancers, fatty liver disease, and diabetes. NNMT participates in several differentiation processes including naive-to-primed human embryonic stem cell transition, myogenesis, and both epithelial- and neural-mesenchymal transition in several cancers. NNMT expression is regulated in a tissue and context-specific manner rather than by a ubiquitous regulatory pattern[6]. -
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]. -
Biologische Aktivität
NNMTi is a potent nicotinamide N-methyltransferase (NNMT) inhibitor (IC50=1.2 μM), selectively binding to NNMT substrate binding site residues. NNMTi can promote myoblast differentiation in vitro and enhance the fusion and regeneration of muscle stem cells in aged mice. -
in vitro
NNMTi (10-30 μM; 96 hours) produces a concentration-related increase in myoblast differentiation on C2C12 myoblast differentiation. 30 μM NNMTi results in 18% MHC-positive myotube nuclei, representing a 45% increase in the extent of myoblast differentiation compared to untreated differentiating myoblasts (12% MHC-positive myotube nuclei). -
in vivo
NNMTi (subcutaneous (SC) injection; 5 mg/kg and 10 mg/kg; 2 weeks (1 week pre-injury and 1 week post-injury)) has an effect on muscle regeneration after injury, it results in 60% and 75% higher incidence of proliferating/active muSCs at 5 mg/kg and 10 mg/kg, respectively. The relative numbers of fibers with an EdU + myonucleus increased 40% and 48% with NNMTi treatment at 5 mg/kg and 10 mg/kg, respectively. The odds ratio of fused myonuclei for control are 0.58 and 0.53 times the odds at the low and high NNMTi dose, respectively.NNMTi (subcutaneous injection; 10 mg/kg; 1 week) produces no systemic toxicity in mice, the levels of the glucose, cholesterol, plasma proteins, and electrolytes between control and NNMTi-treated samples show no difference in mice. 1-week post-injury daily repeat-dosing of NNMTi is well tolerated with no untoward systemic toxicity or behavioral implications in aged mice. -
Lager
Store at -20°C -
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 Anbieter Lieferant Produzent Hersteller Vertrieb Händler.
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