L-Norleucine

• Protein synthesis support
• Metabolic regulation

• Potential anticancer properties
• Protein misfolding prevention
• Leucine mimetic

L-Norleucine is a non-proteinogenic amino acid that structurally resembles leucine but with a straight-chain aliphatic side chain instead of the branched chain found in leucine. This structural similarity allows L-Norleucine to interact with many of the same cellular targets and pathways as leucine, though often with different potency or slightly modified effects. One of the primary mechanisms of L-Norleucine is its ability to activate the mammalian target of rapamycin (mTOR) signaling pathway, particularly mTOR complex 1 (mTORC1). Like leucine, L-Norleucine can stimulate mTORC1 activity, which plays a central role in regulating protein synthesis, cell growth, and metabolism.

This activation occurs through multiple mechanisms, including the stimulation of Rag GTPases and inhibition of the TSC1/TSC2 complex, ultimately leading to mTORC1 activation. However, research suggests that L-Norleucine may activate mTORC1 with different kinetics or potency compared to leucine. L-Norleucine can also influence protein synthesis through mechanisms independent of mTOR signaling. It may affect the activity of translation initiation factors and ribosomal proteins, potentially enhancing the efficiency of protein synthesis under certain conditions.

In some experimental models, L-Norleucine has been shown to serve as a leucine substitute in protein synthesis, though this substitution can sometimes lead to altered protein structure and function. Another significant mechanism of L-Norleucine involves its potential to act as a competitive inhibitor of certain enzymes that utilize leucine as a substrate. This includes branched-chain aminotransferase (BCAT) and branched-chain α-keto acid dehydrogenase (BCKDH), enzymes involved in branched-chain amino acid metabolism. By competing with leucine for these enzymes, L-Norleucine may modulate leucine metabolism and its downstream effects.

L-Norleucine has also been investigated for its potential to prevent protein misfolding and aggregation in certain neurodegenerative disease models. The mechanism appears to involve its incorporation into proteins in place of leucine, which may alter protein folding pathways or stability in ways that reduce pathological aggregation. In cancer research, L-Norleucine has been studied for its potential to interfere with tumor metabolism, particularly in cancers that are dependent on specific amino acid metabolic pathways. Some studies suggest it may inhibit certain cancer-associated enzymes or compete with essential amino acids needed for rapid cancer cell proliferation.

It’s important to note that while L-Norleucine shares some mechanisms with leucine, it is not a direct replacement for leucine in all biological functions. The subtle structural differences between these amino acids can lead to significant differences in their interactions with various cellular components and their overall physiological effects.

The effective dosage range for L-Norleucine is not well-established in humans due to limited clinical research. Most information on dosing comes from animal studies and limited experimental research. Based on the available data, research dosages have typically ranged from 100-500 mg per day, though these are not clinically validated doses for specific health outcomes. L-Norleucine is primarily used in research settings rather than as a common dietary supplement.

For research purposes, dosages are often calculated based on body weight, with common ranges being 10-50 mg per kg of body weight in animal studies. Human equivalent dosages would likely be lower when adjusted for body surface area.

L-Norleucine is absorbed from the gastrointestinal tract through amino acid transporters, similar to other amino acids. It primarily uses the L-type amino acid transporter system, which also transports other neutral amino acids like leucine, isoleucine, and valine. While specific pharmacokinetic data for L-Norleucine in humans is limited, it is believed to have relatively good oral bioavailability based on its chemical structure and the observed biological effects following oral administration in research settings. As a small, water-soluble amino acid, L-Norleucine likely reaches peak plasma concentrations within 1-2 hours after ingestion, similar to other amino acids with comparable structures.

L-Norleucine can cross the blood-brain barrier to some extent through the same transporters that carry other large neutral amino acids. The exact half-life in humans has not been well-established in published literature, but based on similar amino acids, it is estimated to be approximately 3-5 hours. Metabolism occurs primarily in the liver, where L-Norleucine undergoes transamination and oxidation processes similar to those of other amino acids. Elimination occurs primarily through renal excretion, with some metabolites also being eliminated through bile.

Taking on an empty stomach: Some evidence suggests that taking L-Norleucine on an empty stomach may improve absorption by reducing competition with other amino acids for intestinal transporters., Avoiding concurrent intake of other large neutral amino acids: Since L-Norleucine competes with other amino acids like leucine, isoleucine, valine, phenylalanine, and tryptophan for the same transporters, limiting concurrent intake of these amino acids might theoretically enhance L-Norleucine absorption., Combining with carbohydrates: Some research on amino acid absorption suggests that carbohydrate intake may enhance amino acid uptake through insulin-mediated mechanisms, though specific data for L-Norleucine is limited., Avoiding high-protein meals when supplementing: Large amounts of dietary amino acids may compete with L-Norleucine for absorption, potentially reducing its bioavailability when taken with high-protein meals.

For research applications, L-Norleucine is typically administered in a fasted state or between meals to minimize competition with dietary amino acids. When used in metabolic research, it is often administered 30-60 minutes before measurements or interventions to allow for absorption and distribution. If multiple daily doses are used in research protocols, spacing them evenly throughout the day (e.g., morning and evening) may help maintain more consistent blood levels. Taking L-Norleucine on an empty stomach or at least 30 minutes before meals may enhance absorption, though this may not be practical for all research protocols.

If gastrointestinal discomfort occurs, taking L-Norleucine with a small amount of food may help mitigate these effects. For specific research applications investigating mTOR activation or protein synthesis, timing may be coordinated with exercise or other interventions based on the specific research question being investigated. It’s important to note that these timing recommendations are based on general principles of amino acid pharmacokinetics and limited research data, rather than extensive clinical studies specifically on L-Norleucine.

• Gastrointestinal discomfort (nausea, stomach pain)
• Potential protein misincorporation (L-Norleucine can be mistakenly incorporated into proteins in place of leucine under certain conditions)
• Headache
• Fatigue
• Potential disruption of normal amino acid metabolism
• Possible interference with leucine-dependent cellular processes

• Pregnancy and breastfeeding (insufficient safety data)
• Children and adolescents under 18 years (insufficient safety data)
• Individuals with liver or kidney disease (due to the role of these organs in amino acid metabolism)
• Individuals with maple syrup urine disease or other disorders of branched-chain amino acid metabolism
• Individuals with known hypersensitivity to L-Norleucine or structurally similar compounds
• Individuals scheduled for surgery within two weeks (due to limited knowledge about interactions with medications and surgical procedures)
• Individuals with neurodegenerative conditions (due to concerns about potential protein misincorporation)

• Leucine-containing medications or supplements (potential competition for transporters and metabolic enzymes)
• Branched-chain amino acid supplements (potential competition and metabolic interactions)
• mTOR inhibitors like rapamycin or everolimus (potential opposing effects on mTOR signaling)
• Medications metabolized by the liver (theoretical potential for interactions, though specific evidence is limited)
• Medications affecting protein synthesis (potential additive or opposing effects)
• Medications used for diabetes or blood sugar control (theoretical interactions due to amino acids’ effects on insulin and glucose metabolism)

No established upper limit by major regulatory bodies. L-Norleucine is primarily used in research settings rather than as a common dietary supplement. Most research protocols use doses between 100-500 mg per day in humans, though these are not clinically validated doses for specific health outcomes. The long-term safety of L-Norleucine supplementation has not been well-established in humans.

One theoretical concern with L-Norleucine is its potential for misincorporation into proteins in place of leucine, which could potentially lead to altered protein structure and function. However, the clinical significance of this at typical research doses is not well-established. Due to limited human safety data, conservative use is recommended, and L-Norleucine should be used primarily in controlled research settings rather than as a general supplement. Individuals considering L-Norleucine for any purpose should consult with healthcare providers knowledgeable about amino acid metabolism and supplementation.

In the United States, L-Norleucine exists in a regulatory gray area. It is not explicitly approved as a food additive or dietary ingredient by the FDA. Unlike many amino acids that are common components of the diet, L-Norleucine is a non-proteinogenic amino acid not typically found in significant amounts in the human diet. It does not have GRAS (Generally Recognized as Safe) status.

Companies marketing L-Norleucine as a dietary supplement ingredient would technically be required to submit a New Dietary Ingredient (NDI) notification to the FDA before marketing, though there is little evidence that such notifications have been submitted or approved. The FDA has not issued specific warnings or enforcement actions specifically targeting L-Norleucine, but this does not constitute tacit approval. As with many research compounds that transition to the supplement market, the regulatory status remains ambiguous. L-Norleucine is primarily used in research settings rather than as a common dietary supplement, which may explain the limited regulatory attention it has received.

The European Food Safety Authority (EFSA) has not issued a specific opinion on L-Norleucine as a supplement ingredient. In the European Union, novel food regulations would likely apply to L-Norleucine, requiring authorization before it can be legally marketed as a food or food supplement ingredient. There is no evidence that L-Norleucine has received novel food authorization in the EU. Some research-grade L-Norleucine may be available in the European market for laboratory use, but its status as a supplement ingredient is questionable under current EU regulations.

The regulatory status varies somewhat between individual EU member states, with some countries having more stringent enforcement of novel food regulations than others.

Health Canada has not explicitly approved L-Norleucine as a Natural Health Product (NHP) ingredient. It is not listed in the Natural Health Products Ingredients Database (NHPID) with an approved medicinal role. Products containing L-Norleucine would likely require premarket authorization with supporting safety and efficacy data before they could be legally sold in Canada with a Natural Product Number (NPN). There is little evidence that such authorizations have been sought or granted.

As with other jurisdictions, L-Norleucine is primarily available in Canada as a research chemical rather than as an approved supplement ingredient.

The Therapeutic Goods Administration (TGA) of Australia has not

specifically approved L-Norleucine as an ingredient for listed complementary medicines.

It is not included in the TGA’s list of permitted ingredients for listed medicines. Products containing L-Norleucine would likely require registration rather than listing, which involves a more rigorous premarket evaluation process.

There is little evidence that such registrations have been sought or granted for L-Norleucine-containing supplements in Australia.

Japan: L-Norleucine is not approved as a Food for Specified Health Uses (FOSHU) ingredient. China: Not included in the approved list of health food ingredients. South Korea: Not explicitly approved for use in functional foods. Brazil: Would likely require registration as a novel ingredient through ANVISA.

Russia and Eastern European countries: Often have less stringent regulation of amino acid supplements, and research-grade L-Norleucine may be more readily available. In most jurisdictions globally, L-Norleucine exists in a regulatory gray area rather than having explicit approval or prohibition. The regulatory approach to L-Norleucine varies significantly between countries, with some taking a more permissive approach to novel supplement ingredients while others require substantial premarket safety data.

L-Norleucine is not available as a prescription medication in any major jurisdiction. It is primarily used as a research chemical or experimental compound rather than as an approved therapeutic agent. No medical conditions have approved L-Norleucine as a standard treatment. Some research institutions may use L-Norleucine in experimental protocols under appropriate ethical and regulatory approvals, but this represents research use rather than standard medical practice.

L-Norleucine is primarily available as a research chemical rather than a common dietary supplement, which significantly affects its pricing and availability. Research-grade L-Norleucine typically ranges from $1.00 to $5.00 per gram, with higher purity grades commanding premium prices. For a theoretical supplemental dose of 200 mg per day, this would translate to approximately $0.20-$1.00 per day or $6-$30 per month. However, it’s important to note that research-grade chemicals are not formulated or regulated as dietary supplements and are sold for laboratory use only.

The limited commercial supplement products containing L-Norleucine are typically specialty amino acid formulations or experimental compounds, often priced at a premium compared to common amino acid supplements. These products may cost $30-$100 per month for typical dosages, though pricing varies widely based on formulation, brand, and marketing approach.

Comparing the value of L-Norleucine to other supplements is challenging due to its limited use as a supplement and the lack of established clinical benefits. For protein synthesis support, established supplements like leucine, BCAAs, or whey protein offer better value and stronger evidence bases. Leucine, which shares many mechanisms with L-Norleucine but has far more research support, typically costs $0.10-$0.30 per gram, making it significantly more cost-effective for similar applications. Complete BCAA supplements cost approximately $0.05-$0.15 per gram and provide a spectrum of branched-chain amino acids with established benefits for muscle protein synthesis and recovery.

For research applications, the cost of L-Norleucine may be justified by specific experimental requirements, but for general health or performance enhancement, other supplements offer better established benefits at lower costs. The value proposition of L-Norleucine is primarily in specialized research applications rather than general supplementation for health or performance.

Purchasing research-grade L-Norleucine in bulk (25g-100g) can significantly reduce costs, often bringing the price down to $0.50-$1.00 per gram. This approach is most economical for research institutions conducting studies requiring L-Norleucine. However, proper measurement tools (such as an analytical balance) are necessary when working with research chemicals to ensure accurate dosing. Bulk research chemicals are typically sold with restrictions limiting their use to research purposes only, not for human consumption.

For individuals interested in L-Norleucine for personal use, bulk purchasing options are limited and may not comply with dietary supplement regulations in many jurisdictions.

L-Norleucine supplements or research chemicals are not covered by conventional health insurance plans. Some Health Savings Accounts (HSAs) or Flexible Spending Accounts (FSAs) may cover supplements with a physician’s recommendation, though L-Norleucine would be unlikely to qualify given its limited clinical evidence base and regulatory status. For research institutions, the cost of L-Norleucine for approved studies would typically be covered by research grants or institutional funding rather than health insurance.

Pure L-Norleucine powder typically has a shelf life of 2-3 years

when stored properly under recommended conditions. L-Norleucine in capsule or tablet form generally has a shelf life of 1-2 years, depending on the formulation and presence of other ingredients.

When included in multi-ingredient formulations, the shelf life may be limited by the least stable component in the mixture, typically ranging from 1-2 years. For research-grade L-Norleucine, manufacturers often recommend using opened products within 6-12 months for optimal potency and purity, even if the formal expiration date is further in the future.

Store in a cool, dry place away from direct sunlight, Optimal temperature range: 15-25°C (59-77°F), Keep container tightly closed to protect from moisture, Refrigeration is not necessary but may extend shelf life, For powder forms, use the provided scoop or a clean, dry utensil to prevent moisture introduction, Avoid exposure to heat sources or temperature fluctuations, Keep away from strong oxidizing agents, Store in the original container or in an airtight container if transferred, For research-grade material, some manufacturers recommend storage at 2-8°C (refrigerated)

Exposure to high humidity (can cause clumping and potential degradation of powder forms), Prolonged exposure to high temperatures (>30°C/86°F), Direct sunlight or UV radiation, Oxidation (particularly in solution), Microbial contamination if exposed to moisture, Extreme pH conditions (highly acidic or alkaline environments), Enzymatic degradation in liquid formulations without preservatives, Repeated freeze-thaw cycles, Chemical interactions with other ingredients in multi-component formulations

L-Norleucine is generally stable in aqueous solution at neutral pH for short periods (up to 1 week) when refrigerated. Stability decreases in strongly acidic or alkaline conditions. For maximum stability in solution, a pH range of 6.0-7.5 is optimal. Solutions should be stored in the refrigerator (2-8°C) in a tightly sealed container to prevent microbial growth.

When mixed in beverages, L-Norleucine remains stable for several days when refrigerated, though other ingredients may degrade more quickly. L-Norleucine is relatively resistant to thermal degradation in solution at moderate temperatures, making it suitable for inclusion in warm (but not boiling) beverages. For research applications requiring long-term storage of L-Norleucine solutions, freezing at -20°C in aliquots to avoid repeated freeze-thaw cycles is recommended. Solutions should be prepared fresh when possible, especially for critical applications where precise dosing is important.

In biological buffers commonly used in research (PBS, HEPES, etc.), L-Norleucine maintains good stability when stored properly.

Natural Sources

Synthetic Production Methods

Quality Indicators

Sustainability Considerations

Unlike many other supplements with long histories of traditional use, L-Norleucine does not have a significant history of traditional medicinal applications. As a non-proteinogenic amino acid that is not abundantly found in common food sources, it was not specifically identified or utilized in traditional medicine systems. While various amino acids have been used therapeutically throughout history in different cultural medical traditions, L-Norleucine specifically was not recognized or intentionally employed for health purposes prior to modern scientific investigation. This contrasts with many other supplements that have histories dating back centuries or millennia in traditional Chinese medicine, Ayurveda, or other traditional healing systems.

The absence of traditional use is primarily due to the fact that L-Norleucine was not readily isolated or identified until modern analytical techniques became available, and its specific biological activities were not understood until relatively recent scientific investigations.

L-Norleucine was first identified and characterized as a distinct amino acid in the early 20th century as part of the broader scientific exploration of amino acid chemistry. It was recognized as a structural analog of leucine but with a straight-chain aliphatic side chain instead of the branched chain found in leucine. Early biochemical research in the mid-20th century began to explore the properties of L-Norleucine, particularly its potential to substitute for leucine in certain biological processes. In the 1950s and 1960s, researchers began investigating L-Norleucine’s incorporation into proteins and its effects on protein structure and function.

These studies revealed that L-Norleucine could sometimes be incorporated into proteins in place of leucine, though often with alterations to protein folding and activity. The 1970s and 1980s saw increased interest in L-Norleucine as a tool for studying protein synthesis and amino acid metabolism. Researchers used it as a leucine analog to investigate the specificity of various enzymes and cellular processes. In the 1990s and early 2000s, studies began to explore L-Norleucine’s effects on signaling pathways, particularly those related to protein synthesis and metabolism.

Key research by Lynch et al. in 2002 demonstrated that L-Norleucine, like leucine, could activate the mTOR signaling pathway and stimulate protein synthesis in certain tissues. More recently, L-Norleucine has been investigated for potential applications in various research areas, including protein misfolding diseases, cancer metabolism, and metabolic regulation.

The evolution of L-Norleucine usage has been primarily driven by scientific research rather than traditional practices or widespread supplementation. In the early stages of research, L-Norleucine was primarily used as a biochemical tool to study protein synthesis, amino acid metabolism, and enzyme specificity. It served as a valuable leucine analog that could help researchers understand the structural requirements for various biological processes. As understanding of cellular signaling pathways advanced in the 1990s and 2000s, L-Norleucine began to be studied for its effects on specific pathways, particularly those related to protein synthesis and metabolism.

The discovery that L-Norleucine could activate mTOR signaling, similar to leucine, opened new avenues for research into metabolic regulation and protein synthesis. In the 2000s and 2010s, some sports nutrition researchers began investigating L-Norleucine for potential applications in exercise metabolism and performance. Limited studies explored its effects on substrate utilization during exercise and recovery processes. Concurrently, biomedical researchers began exploring potential therapeutic applications of L-Norleucine in various disease models.

These included investigations into protein misfolding diseases, cancer metabolism, and metabolic disorders. Despite this research interest, L-Norleucine has not become a common dietary supplement or therapeutic agent. It remains primarily a research tool and experimental compound rather than a widely used supplement. Current usage is largely confined to research settings, where it continues to serve as a valuable tool for studying amino acid metabolism, protein synthesis, and related cellular processes.

Unlike many other amino acids that have transitioned from research to widespread supplementation, L-Norleucine has remained primarily in the research domain, with limited commercial availability as a supplement.

Limited information available on ongoing clinical trials specifically focused on L-Norleucine supplementation in humans, Some research groups are investigating non-proteinogenic amino acids, including L-Norleucine, for potential applications in metabolic health, protein synthesis regulation, and disease models, Preclinical research continues to explore the mechanisms and potential applications of L-Norleucine in various biological systems