Everything You Need to Know About 5-Amino-1MQ
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Overview
5-amino-1MQ is a small molecule that functions to block the activity of an enzyme called nicotinamide N-methyltransferase (NNMT) [5]. Nicotinamide N-methyltransferase (NNMT) is a cytosolic enzyme that catalyzes the transfer of methyl group from the cofactor S-(5′-adenosyl)-L-methionine (SAM) to substrates such as nicotinamide (NCA), pyridine, and related analogues (e.g., quinoline, isoquinoline, 1,2,3,4-tetrahydroisoquinoline), directly regulating the detoxification of endogenous and exogenous drugs/xenobiotics by the formation of methylated metabolic products (1-methyl nicotinamide [1-MNA], methylated pyridines, and methylated related analogues) [5].
Given its primary metabolizing function, NNMT is predominantly expressed in the liver, but significant levels of the enzyme are also present in other tissues, including adipose tissue, kidney, brain, lung, heart, and muscle [4]. Enhanced expression and enzymatic activity of NNMT has been linked to several chronic disease conditions, making it a significant and relevant target for drug development [4].
For example, several studies have demonstrated a causal relationship between increased NNMT expression and enhanced cell proliferation/progression in a variety of cancer cell lines with potential implications for NNMT as a biomarker for cancer prognosis and a target for anticancer therapeutic development.
NNMT expression has also been reported to be upregulated in patients with Parkinson’s disease, which is suggested to be linked to the production of neurotoxins such as N- methylpyridinium ions that underlie neurodegeneration. SAM-dependent methyltransferases represent a major class of bio transforming enzymes that catalyze the methylation linked to the production of neurotoxins such as N-methylpyridinium ions that underlie neurodegeneration [5].
View the depiction that describes effects of NNMT inhibitor on intracellular levels of NAD+ salvage pathways methionine cycle metabolites [2].
5-Amino-1MQ and Weight Loss
Nicotinamide N-methyltransferase (NNMT) has been implicated in osteoarthritis, metabolic disorders, cardiovascular disease, cancer, kidney disease, and Parkinson’s disease [3]. Higher NNMT expression and MNA concentrations have been associated with obesity and type-2 diabetes [4].
Researchers are currently trying to develop drug candidates that specifically target NNMT and produce targeted reductions in white adipose tissue, leading to significant weight loss and improvements in obesity-linked comorbidities. Importantly, these drug candidates have shown attractive cellular permeability flux when tested in membrane transport assays and in cells.
Studies in both animals and humans have shown that NNMT expression and activity was increased in obesity and related chronic metabolic conditions (for example, type-2 diabetes) [2] [4]. Knockdown of NNMT expression using an antisense oligonucleotide was reported to suppress body weight gain, reduce fat mass, and increases energy expenditure in mice fed high fat diet [2].
While the underlying molecular mechanisms that link decreased NNMT activity to increased adipocyte metabolism are not well understood, NNMT may modulate intracellular metabolite turnover in the methionine−homo-cysteine cycle and/or the nicotinamide adenine dinucleotide (NAD+) synthesis pathway critical for cellular energy expenditure [2].
Therefore, targeted small molecule inhibitors of the NNMT could be significantly beneficial as molecular probes for mechanistic investigations and for the development of therapeutics to treat metabolic and chronic diseases that are characterized by abnormal NNMT activity [2].
NNMT inhibition increases intracellular concentrations of NAD+ and SAM in differentiated adipocytes. Diet-induced obesity (DIO) mice had over a 30% decrease in adipocyte size and over a 40% decrease in adipocyte volume [2]. Plasma lipid-profile measurements showed that the total cholesterol levels were 30% lower in treated DIO mice relative to control DIO mice [2]/ 5-amino-1MQ reduced lipogenesis by 50% and 70%, respectively, compared to control untreated adipocytes [2].
It is important to note that treatment of DIO mice with NNMT inhibitors did not impact food intake, but produced marked reductions in body weight, WAT mass, adipocyte size, and cholesterol levels with negligible toxicity or observable adverse effects [2]. In conclusion, current studies provide evidence for the use of NNMT inhibitors as a therapeutic approach to manage diet-induced obesity and related metabolic comorbidities [2].
5-Amino-1MQ and Muscle Stem Cells
There are no known muscle stem cells (muSC; also termed satellite cells) regenerative small molecules even though regulators of muSC activity can offer novel therapeutics to improve recovery and reduce morbidity among aged adults [1]. MuSCs that proliferate, differentiate to fusion-competent myoblasts, and facilitate muscle regeneration are increasingly dysfunctional upon aging, impairing muscle recovery after injury [1]. The major driving factor for delayed and impaired recovery of aged muscle following injury appears to be a significant decrease in muSC regenerative capacity and function. Therefore, there is a need to investigate a viable pharmacological approach to enhance aged muscle regeneration by rescuing muSC function.
In one study, 24-month-old mice were treated with saline (control), and low and high dose NNMTi (NNMT inhibitor) for 1 week post-injury, or control and high dose NNMTi for 3 weeks post-injury [1]. Mice received 5-ethynyl-2′-deoxyuridine systemically to analyze muSC activity., and all mice underwent an acute muscle injury locally to the tibialis anterior (TA) muscle [1]. Muscle recovery was assessed, in vivo, by measuring contractile function on the injured TA muscle and tissues collected for ex-vivo analyses, including myofiber cross-sectional area (CSA) [1].
Results revealed that muscle stem cell proliferation and subsequent fusion were elevated in NNMTi-treated mice [1]. This result supported almost a 2-fold greater CSA and shifts in fiber size distribution to greater proportions of larger sized myofibers and fewer smaller sized fibers in NNMTi-treated mice compared to controls [1]. Most importantly, improved muSC activity translated not only to larger myofibers after injury but also to greater contractile function, with the peak torque of the TA increased by ~70% in NNMTi-treated mice compared to controls [1].
These events occur independent of sarcopenia, resulting in the formation of dysfunctional senescent muSCs that are no longer activated by muscle injury or turnover stimuli and present compromised ability to proliferate, differentiate, fuse, and promote the repair and replacement of myofibers [6]. Additionally, in some aged skeletal muscle tissues, muSC abundance has been observed to decline as muSCs develop diminished intrinsic capacity for reversible dormancy, which further reduces the population of muSCs supporting the post-injury repair cascade [6].
Researchers will need to further develop and utilize NNMTi as a novel mechanism-of-action therapeutic to improve skeletal muscle regenerative capacity and functional recovery after musculoskeletal injury in older adults.
5-Amino-1MQ and Muscle Mass
Sarcopenia is the loss of muscle mass and strength during aging. It is a degenerative process that brings about a decrease in wellbeing and increased dependency. There have been an increased number of studies indicating that this muscle atrophy is related to chronic inflammation.
Dr. Atonnio Zorzano and his lab have discovered that the inflammatory process that causes muscle atrophy is associated with the accumulation of damaged mitochondria in cells. They have also described how the increase in the levels of BNIP3, a protein related to the clearance of damaged mitochondria, is linked to better muscle aging. On the flip side, if BNIP3 levels are low, at advanced ages, more damaged mitochondria accumulate, and this triggers inflammatory processes which can cause muscle atrophy in turn.
You can view this in the diagram below. It shows the coordination of mitochondrial and lysosomal function by BCL2 interacting protein 3 (BNIP3) is key to limiting muscle inflammation.
5-Amino-1MQ can help build muscle, to prevent the above from happening. Research has shown that lowering NNMT expression can promote the regeneration of aged muscle cells, while also helping in treating muscular disorders such as muscle atrophy. It can also improve neuromuscular function, whether it’s during resistance training or recovering from a muscle injury. Finally, you can repair muscle damage via inhibition of NNMT.
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