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Metabolic
A combined metabolic-research preparation pairing a mitochondrial-derived peptide with a small-molecule NNMT inhibitor.
This blend pairs two compounds that researchers study in metabolic biology, each acting on a different cellular pathway. MOTS-c is a mitochondrial-encoded peptide examined for its role in cellular energy sensing through the AMPK axis and the folate one-carbon cycle. 5-Amino-1MQ is a small-molecule inhibitor of nicotinamide N-methyltransferase (NNMT), an enzyme involved in cellular methyl-group and NAD+ metabolism. The two are studied in preclinical models of energy sensing, adipocyte metabolism, and skeletal-muscle biology, acting on distinct metabolic pathways.
Peptide / small-molecule blend
Molecular formula
C101H152N28O22S2
Molecular weight
~2,175 g/mol
CAS number
1627580-64-6
Sequence
MRWQEMGYIFYPRKLR
Molecular formula
C10H11IN2
Molecular weight
286.11 g/mol
CAS number
42464-96-0
Combines a mitochondrial-derived peptide (MOTS-c) with a small-molecule enzyme inhibitor (5-Amino-1MQ) that act on separate metabolic pathways; no single target applies. MOTS-c is a short cationic peptide encoded by an open reading frame within mitochondrial 12S rRNA (MT-RNR1 locus); mechanistic studies link it to inhibition of the folate-methionine one-carbon cycle, AICAR accumulation, and AMP-activated protein kinase (AMPK) activation, with stress-responsive nuclear translocation. 5-Amino-1MQ is a substrate-site small-molecule inhibitor of nicotinamide N-methyltransferase (NNMT; EC 2.1.1.1), the cytosolic enzyme that transfers a methyl group from S-adenosyl-L-methionine (SAM) to nicotinamide, yielding 1-methylnicotinamide (1-MNA) and S-adenosyl-L-homocysteine; the cationic quinolinium ring occupies the nicotinamide substrate-binding pocket.
Research Focus
Studied in mitochondrial AMPK-axis signaling, NNMT enzymology, and preclinical adipocyte and skeletal-muscle metabolic models.
The two ingredients in this preparation are studied as probes of separate, parallel routes in cellular energy and methyl-group metabolism. MOTS-c is a 16-amino-acid mitochondrial-derived peptide (MDP) encoded within the mitochondrial 12S ribosomal RNA gene (MT-RNR1); mechanistic studies link it to the folate-methionine one-carbon cycle, AICAR accumulation, and activation of AMP-activated protein kinase (AMPK), with stress-responsive translocation to the nucleus. 5-Amino-1MQ is a substrate-site small-molecule inhibitor of nicotinamide N-methyltransferase (NNMT; EC 2.1.1.1), the cytosolic enzyme that methylates nicotinamide using S-adenosyl-L-methionine. Because one component is a mitochondrial-encoded peptide acting through the AMPK axis and the other is a cytosolic-enzyme inhibitor acting on the SAM/NAD+ methylation pathway, no single molecular target describes the pair; the literature treats them as tools for examining complementary nodes of metabolic regulation.
MOTS-c is a peptide whose coding sequence lies within a short open reading frame in the mitochondrial 12S ribosomal RNA gene (MT-RNR1), placing it alongside humanin in the family of mitochondrial-derived peptides. Lee et al. (2015) first characterized the peptide and reported its detection in multiple tissues and in human and rodent plasma, establishing it as a circulating peptide of mitochondrial origin. The foundational mechanistic study (Lee et al., 2015) investigated MOTS-c in HEK293 cells and mouse skeletal muscle, linking it to modulation of the folate-methionine one-carbon cycle and accumulation of AICAR — an endogenous intermediate that activates AMPK. Skeletal muscle was identified as a primary tissue of interest. No specific cell-surface receptor for MOTS-c has been identified, which remains an acknowledged mechanistic gap in the literature.
Kim et al. (2018) characterized a stress-responsive mechanism in which MOTS-c translocates from the cytoplasm to the nucleus under conditions including glucose restriction, serum withdrawal, and oxidative challenge, with AMPK and reactive oxygen species serving as proximal triggers in cell-based experiments; nuclear MOTS-c was found to associate with antioxidant-response element binding factors including NRF2. Reynolds et al. (2021, Nature Communications) examined MOTS-c expression in treadmill exercise studies across young, middle-aged, and aged mice and measured the peptide in skeletal-muscle biopsies and plasma samples from healthy young men during standardized exercise bouts. D'Souza et al. (2020) characterized MOTS-c content in skeletal muscle of aging men relative to myofiber composition, and Kim SJ et al. (2024, iScience) identified casein kinase 2 alpha (CK2α) as a direct binding partner in skeletal muscle and adipose contexts.
Research on 5-Amino-1MQ centers on its interaction with NNMT, which transfers a methyl group from S-adenosyl-L-methionine to nicotinamide, producing 1-methylnicotinamide and S-adenosyl-L-homocysteine. Neelakantan, Wang, and colleagues (2017) conducted an enzymology and structure-activity relationship study using small-molecule library screening and computational docking against the human NNMT substrate-binding site, identifying N-methylated quinolinium scaffolds. Follow-on work (Neelakantan et al., 2018) examined membrane permeability and selectivity against related SAM-dependent methyltransferases and NAD+ salvage enzymes in vitro, characterized intracellular metabolite changes — including 1-MNA, NAD+, and SAM levels — in cultured adipocytes, and assessed adiposity and white-adipose-tissue endpoints in a diet-induced-obesity mouse model. Sampson, Dimet, and colleagues (2021) profiled adiposity and adipose-tissue metabolomics in a dietary-intervention model in diet-induced-obese mice.
NNMT expression in aged versus young skeletal muscle was a focus of Neelakantan and colleagues (2019), which examined satellite-cell proliferation endpoints, myofiber cross-sectional area, tibialis anterior contractile function, and cellular NAD+/NADH redox state in aged mice, alongside C2C12 myoblast differentiation assays in vitro. A subsequent 8-week study in 22-month-old mice (Dimet-Wiley et al., 2024) examined 5-Amino-1MQ in sedentary or progressive-weighted-wheel-running cohorts, integrating proteomic and metabolomic profiling with functional muscle endpoint measurements in aged mice. A validated LC-MS/MS bioanalytical method in rat plasma and urine was developed and applied to oral bioavailability characterization (Awosemo et al., 2021), and Babula and colleagues (2024) extended pharmacokinetic characterization in mice, reporting tissue distribution measurements in adipose, muscle, and liver tissue.
No peer-reviewed primary study or registered clinical trial has examined the specific MOTS-c plus 5-Amino-1MQ combination; the available literature characterizes each ingredient separately. The rationale for studying a mitochondrial-derived peptide alongside an NNMT inhibitor rests on the observation that the two are examined in overlapping model systems — adipocyte metabolism, skeletal-muscle biology, and cellular NAD+ and energy-sensing endpoints — while acting on distinct pathways: MOTS-c through the AMPK axis and the folate one-carbon cycle, and 5-Amino-1MQ through inhibition of the NNMT-catalyzed SAM-to-nicotinamide methylation step that intersects NAD+ salvage. Any interaction described for the present combination is an extrapolation from these separate bodies of single-compound literature and is not a measurement of this specific pair.
Lyophilized
-20°C
components typically stable ~24 months desiccated and protected from light.
Reconstituted
2-8°C for short-term use
-20°C/-80°C in aliquots for longer storage; carrier protein (0.1% HSA/BSA) recommended for the peptide component.
Avoid freeze-thaw; aliquot; protect from light and moisture. The peptide component carries oxidation-sensitive methionine residues; the small-molecule salt is hygroscopic — keep desiccated.
Reviews
Wan W, et al. (2023). J Transl Med — Review of MOTS-c in stress, metabolism, and aging research contexts
Yoon TK, et al. (2022). Diabetes Metab J — Review integrating MOTS-c into the exercise-mitohormesis framework
Miller B, et al. (2022). J Clin Invest — Review of mitochondrial-derived peptides in aging
Reviews
Frontiers in Pharmacology (2024 review) (2024). Frontiers in Pharmacology — Review of NNMT biology as a research target in metabolic-syndrome models, cataloguing small-molecule inhibitor classes including 5-Amino-1MQ
Roberti A, Fernández AF, Fraga MF. (2021). Mol Metab — Review of NNMT at the crossroads of cellular metabolism and epigenetic gene regulation
Pissios P. (2017). Trends in Endocrinology & Metabolism — Narrative review of NNMT biology and SAM/NAD+ pathway interactions beyond vitamin-B3 clearance
Clinical
Reynolds JC, et al. (2021). Sci Rep — Biomarker study examining circulating MOTS-c in response to aerobic and resistance exercise in breast cancer survivors (RCT; NCT01140282)
Qin Q, et al. (2018). Int J Cardiol — Observational study measuring circulating MOTS-c in coronary endothelial function contexts
Primary research
Kim SJ, et al. (2024). iScience — CK2α direct-binding and kinase-activity study in skeletal muscle and adipose models
Kumagai H, et al. (2021). Am J Physiol Endocrinol Metab — Examination of MOTS-c and myostatin signaling in muscle atrophy model systems
Reynolds JC, et al. (2021). Nat Commun — Exercise-induced expression and physical-capacity study (mouse + human ex vivo)
D'Souza RF, et al. (2020). Aging (Albany NY) — Skeletal-muscle MOTS-c and myofiber composition in aging men (observational)
Lu H, et al. (2019). J Mol Med — Study examining MOTS-c in an ovariectomy model measuring adipose and AMPK pathway endpoints
Kim KH, et al. (2018). Cell Metabolism — Nuclear translocation and gene-regulation study
Lee C, et al. (2015). Cell Metabolism — Foundational metabolic-characterization study via AMPK
Babula JJ, Bui D, Stevenson HL, Watowich SJ, Neelakantan H. (2024). Diabetes, Obesity and Metabolism — 28-day diet-induced-obesity mouse study with metabolic, histopathology, and in vivo PK/tissue distribution endpoints
Dimet-Wiley AL, et al. (2024). Scientific Reports — Proteome/metabolome and muscle-function study in aged sedentary and exercise-trained mice
Awosemo O, Neelakantan H, Watowich S, Ma J, Wu L, Chow DS, Liang D. (2021). Journal of Pharmaceutical and Biomedical Analysis — LC-MS/MS bioanalytical method development and oral-bioavailability study in rat
Sampson CM, Dimet AL, Neelakantan H, Ogunseye KO, Stevenson HL, Hommel JD, Watowich SJ. (2021). Scientific Reports — Diet-induced-obesity mouse study combining NNMT inhibition with dietary substitution; body-composition and adipose-metabolome profiling
Neelakantan H, Brightwell CR, Graber TG, Maroto R, Wang HYL, McHardy SF, Papaconstantinou J, Fry CS, Watowich SJ. (2019). Biochemical Pharmacology — Aged skeletal-muscle stem-cell and post-injury regeneration study examining satellite-cell proliferation, myofiber endpoints, and NAD+/NADH redox state
Neelakantan H, et al. (2018). Biochemical Pharmacology — Membrane permeability, selectivity, and adipocyte metabolite characterization alongside a diet-induced-obesity mouse study
Neelakantan H, Wang HY, Vance V, Hommel JD, McHardy SF, Watowich SJ. (2017). Journal of Medicinal Chemistry — Enzymology and structure-activity relationship study of small-molecule NNMT inhibitors using library screening and computational docking
Kraus D, Yang Q, Kong D, et al. (2014). Nature — Target-validation study of NNMT in white adipose tissue and liver via antisense-oligonucleotide knockdown in diet-induced-obese mice
Also known as: MOTS-c + 5-amino-1-methylquinolinium blend
Research Use Only
These products are intended for research purposes only and are not for human consumption. Not FDA approved. Not intended to diagnose, treat, cure, or prevent any disease.