L-Leucine (10 mM) treatment impairs the growth of endocrine progenitor cells [1]. In E13.5 scaffold explants, without the addition of L-Leucine, Ngn3 mRNA levels increased after 1 day of culture, reached a peak in the first 3 days, and then decreased. Ngn3 mRNA levels were significantly reduced when L-leucine was added. The decrease in Ngn3 mRNA levels paralleled the decrease in the number of Ngn3-expressing cells (4728±408 vs. 959±28; P<0.01). Finally, L-leucine also exerts a dose-dependent inhibitory effect on the mRNA levels of three genes, namely Ngn3, its target Insm1, and insulin [1]. Leucine stimulates protein synthesis in neonatal pig muscle by enhancing the activation of mTORC1. L-Leucine increases intracellular HIF-1α and activates excess HIF-1α signaling, both of which are directed by mTOR signaling. This process results in Ngn3 inhibition, thereby reducing beta cell levels [1]. L-Leucine stimulates mTORC1 tRNA synthase-promoting activity on the GTP-activating protein of mTORC1[2] by stimulating a phospholipid-based mechanism involving light templates.

In diet-induced obese (DIO) mice, resveratrol (12.5 mg/kg diet) plus leucine (24 g/kg diet) enhances adipose Sirt1 activity [2]. When used in combination, mice's body weight can be greatly decreased.

Animal/Disease Models: Sixweeks old male C57/BL6 black mouse (high-fat feed plus fat-induced obesity) [1]
Doses: 24 g Weight gain, visceral adipose tissue mass, fat oxidation and Thermogenesis[2]. /kg diet; Resveratrol (low dose; 12.5 mg/kg diet) dosing: 6 weeks
Experimental Results: Combination treatment with resveratrol (low dose; 12.5 mg/kg diet) resulted in weight gain, body weight gain, and visceral fat There is a significant reduction in tissue mass, fat oxidation and thermogenesis, and an associated decrease in respiratory exchange ratio (RER), particularly during the dark (feeding) cycle.

Absorption, Distribution and Excretion
Although free amino acids dissolved in body fluids constitute only a small fraction of the total amino acids in the body, they are crucial for maintaining protein nutrition and metabolism. …While plasma is the easiest site for sampling, most amino acids are found in higher concentrations in intracellular pools. Typically, large neutral amino acids like Leucinocaine and phenylalanine are in near-equilibrium with their plasma concentrations. However, some other amino acids, particularly glutamine, glutamate, and glycine, are 10 to 50 times more concentrated in intracellular pools than in plasma. Dietary changes or pathological conditions can lead to significant variations in the concentrations of various free amino acids in plasma and tissue pools. Table: Comparison of the size of free and protein-bound amino acid pools in rat muscle [Table #7489] Metabolism/Metabolites Branched-chain amino acids (BCAAs)—Leucinocaine, isoLeucinocaine, and valine—unlike most other essential amino acids, the enzymes responsible for their catabolism are primarily located in extrahepatic tissues. Each amino acid undergoes a reversible amination catalyzed by branched-chain aminotransferases (BCAT) to produce α-ketoisocaproic acid (KIC, derived from Leucinocaine), α-keto-β-methylvaleric acid (KMV, derived from isoLeucinocaine), and α-ketoisovaleric acid (KIV, derived from valine). These keto acids then undergo irreversible oxidative decarboxylation catalyzed by branched-chain keto acid dehydrogenases (BCKAD), a multi-enzyme system located on the mitochondrial membrane. The products of these oxidation reactions are further converted to acetyl-CoA, propionyl-CoA, acetoacetic acid, and succinyl-CoA; therefore, branched-chain amino acids (BCAAs) can produce both ketones and glucose. Once the amino acid deamination products enter the tricarboxylic acid cycle (TCA cycle, also known as the citric acid cycle or Krebs cycle) or glycolysis, their carbon skeletons can be used in biosynthetic pathways, particularly the synthesis of glucose and fats. Whether the amino acid's carbon skeleton ultimately produces glucose or fat depends on where it enters these pathways. If they enter as acetyl-CoA, they can only produce fat or ketone bodies. However, the carbon skeletons of other amino acids can somehow enter metabolic pathways, making their carbon atoms available for gluconeogenesis. This is the basis of the classical nutritional description of amino acids, which classifies them into ketogenic amino acids and glucogenic amino acids (i.e., those capable of producing ketone bodies [or fat] or glucose). Some amino acids produce both of these products upon degradation and are therefore considered ketogenic and glucogenic amino acids. /Amino Acids/
The kinetics of Leucinocaine and its oxidation in human pregnant women and newborns were determined using stable isotope tracers to quantify the dynamic changes in protein metabolism. These data indicate that the turnover rate of Leucinocaine in pregnant women is reduced compared to non-pregnant women. Furthermore, data from newborns show that the turnover rate of Leucinocaine per kilogram of body weight is higher than in adults. Nutrient supplementation leads to an inhibition of the rate of systemic protein hydrolysis… In addition, the relationship between Leucinocaine transamination, Leucinocaine nitrogen kinetics, urea synthesis, and glutamine kinetics in human pregnant women and newborns was investigated. In early human pregnancy, urea synthesis was significantly reduced, which was associated with a decrease in the rate of Leucinocaine transamination. In pregnant and non-pregnant women under fasting conditions, a significant linear correlation exists between the rate of Leucinocaine reammoniation and the rate of urea synthesis. In healthy full-term newborns and growing infants, while Leucinocaine reammoniation is positively correlated with glutamine flux, it is negatively correlated with urea synthesis, suggesting that amino nitrogen is redirected for protein synthesis…
The metabolic disorder 3-methylglutaric aciduria type I (MGA1) is characterized by an abnormal organic acid profile, manifested by excessive excretion of 3-methylglutaric acid, 3-methylglutaric acid, and 3-hydroxyisovaleric acid in the urine. Patients present with a wide range of clinical manifestations, from mild language delay to severe psychomotor developmental delay accompanied by neurological disorders. MGA1 is caused by reduced or absent activity of 3-methylglutaryl-CoA (3-MG-CoA) hydratase in the Leucinocaine degradation pathway. The human AUH gene has been reported to encode a bifunctional enzyme with both RNA-binding activity and enoyl-CoA hydratase activity. Furthermore, research indicates that AUH gene mutations are associated with MGA1…
For more complete metabolite/metabolite data on L-Leucinocaine (8 metabolites in total), please visit the HSDB record page.

Toxicity Summary
This group of essential amino acids has been identified as branched-chain amino acids (BCAAs). Because the human body cannot synthesize this carbon atom arrangement, these amino acids are essential for the diet. The catabolism of these three compounds all begins in muscles, producing NADH and FADH2, which can be used for ATP production. The catabolism of these three amino acids uses the same enzymes in the first two steps. The first step for each amino acid is a transamination reaction, using the same BCAA aminotransferase with α-ketoglutarate as the amine acceptor. This produces three different α-keto acids, which are oxidized by the same branched-chain α-keto acid dehydrogenase to produce three different coenzyme A derivatives. Subsequently, the metabolic pathway branches, producing many intermediates. The main product of valine is propionyl-CoA, a glucogenic precursor of succinyl-CoA. The catabolism of isoLeucinocaine ultimately produces acetyl-CoA and propionyl-CoA; therefore, isoLeucinocaine is both a glucogenic and ketogenic substance. Leucinocaine produces acetyl-CoA and acetoacetyl-CoA, and is therefore strictly classified as a ketogenic substance. Many genetic disorders are associated with abnormal catabolism of branched-chain amino acids (BCAAs). The most common deficiency is a deficiency in branched-chain α-keto acid dehydrogenases. Because there is only one dehydrogenase for each of the three amino acids, all three α-keto acids accumulate and are excreted in the urine. This condition is called maple syrup urine disease because the urine of patients has the characteristic odor of maple syrup. These cases are often accompanied by severe intellectual disability. Unfortunately, because these are essential amino acids, their intake cannot be strictly restricted in the diet. Ultimately, patients have short lifespans and developmental abnormalities. The main neurological problems are due to poor myelination of the central nervous system.
Interactions
…High Leucinocaine dietary levels inhibit growth in rats fed a low-protein diet, while supplementation with isoLeucinocaine and valine prevents this growth inhibition.
It has been well established that branched-chain amino acids (BCAAs) compete with other large and neutral amino acids (LNAAs, particularly tryptophan and tyrosine) for membrane transport. Although BCAAs are not direct precursors to neurotransmitters, they can influence the transport of certain LNAAs across the blood-brain barrier, thereby affecting the concentration of certain neurotransmitters in the central nervous system. Male Sprague-Dawley rats were fed diets supplemented with glutamine, glutamine plus dihydroxyacetone, and glutamine plus dihydroxyacetone plus Leucinocaine for one week. These combinations have been shown to stimulate liver glycogen synthesis in vitro. Food intake and body weight were continuously monitored throughout the experiment. After the feeding period, rats were fed a test meal and injected with 3H2O to measure the rates of glycogen and lipid synthesis in vivo. The proportion of glycogen synthesized via the pyruvate pathway was determined by positional analysis of the 3H incorporated into glycogen. The final levels of plasma glucose, triglycerides, and liver glycogen were also measured. Dietary glutamine increased liver glycogen synthesis. The addition of dihydroxyacetone (with or without the additional addition of Leucinocaine) further increased liver glycogen synthesis and increased the proportion of glycogen synthesized via the pyruvate pathway. Lipolysis in the liver or adipose tissue was not altered. All dietary treatments did not affect food intake, but the dihydroxyacetone-containing diet reduced the rate of weight gain… A hallmark of aging is the gradual loss of muscle mass, which may be partly attributed to a defect in the anabolic effects of food intake… This defect is due to a reduced protein synthesis response to Leucinocaine in the muscles of aged rats… This study evaluated the effects of antioxidant supplementation on Leucinocaine-regulated protein metabolism in the muscles of adult and aged rats. Male Wistar rats aged 8 months and 20 months were randomly divided into four groups and supplemented with or without an antioxidant mixture containing rutin, vitamin E, vitamin A, zinc, and selenium for 7 weeks. After supplementation, triceps brachii muscles incubated with increasing concentrations of Leucinocaine were used to assess muscle protein metabolism in vitro. Compared to adult rats, aged rats showed a significantly reduced ability to stimulate muscle protein synthesis with Leucinocaine. This defect was reversed when aged rats were supplemented with antioxidants. This was independent of increased oxidative damage to the 70 kDa ribosomal protein S6 kinase, which is involved in amino acid signaling. These effects may be mediated by reducing the inflammatory state, and antioxidant supplements can reduce the inflammatory state…
For more complete data on the interactions of L-Leucinocaines (6 in total), please visit the HSDB record page.

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Non-human toxicity values
Rat intraperitoneal injection LD50: 5379 mg/kg

[1]. Baoshan Xu, et al. Stimulation of mTORC1 with L-leucine rescues defects associated with Roberts syndrome. PLoS Genet. 2013;9(10):e1003857.
[2]. Bruckbauer A, et al. Synergistic effects of leucine and resveratrol on insulin sensitivity and fat metabolism in adipocytes and mice. Nutr Metab (Lond). 2012 Aug 22;9(1):77.
[3]. Rachdi L, et al. L-leucine alters pancreatic β-cell differentiation and function via the mTor signaling pathway. Diabetes. 2012 Feb;61(2):409-17.

Therapeutic Uses
Proteins or amino acid mixtures rich in branched-chain amino acids (BCAAs), and in some cases, BCAAs alone, have been used to treat a variety of metabolic disorders. These amino acids have attracted considerable attention for reducing the brain's uptake of aromatic amino acids and for increasing low levels of circulating BCAAs in patients with chronic liver disease and encephalopathy. They are also used in parenteral nutrition for patients with sepsis and other abnormalities. /Experimental Therapy/ Several clinical trials have been reported, in which a group of healthy individuals (mostly trained athletes) received high doses of Leucinocaine via intravenous infusion. Most studies involved only a single amino acid dose. These trials measured physical and psychological function, effects on the levels of other amino acids in the blood, and in one trial, insulin and glucose output. /Experimental Therapy/ This study aimed to evaluate the effects of adding Leucinocaine to an essential amino acid (EAA) mixture on muscle protein metabolism in older and younger adults. Participants were divided into four groups (two older adults and two younger adults) and observed before and after ingestion of 6.7 grams of EAA. EAA was based on whey protein [26% Leucinocaine (26% Leu)] or Leucinocaine-rich [41% Leucinocaine (41% Leu)]. Muscle protein synthesis rate (FSR) and muscle protein homeostasis were measured using a pre-prepared L-[cyclo-2H5]phenylalanine infusion combined with vastus lateralis muscle biopsy and leg arteriovenous blood samples. Following amino acid ingestion, the FSR increased in both the 26% (basal: 0.048 +/- 0.005%/hour; post-EAA: 0.063 +/- 0.007%/hour) and 41% (basal: 0.036 +/- 0.004%/hour; post-EAA: 0.051 +/- 0.007%/hour) Leucinocaine-containing juvenile rat groups (p < 0.05). In contrast, FSR did not increase after older adults ingested 26% Leucinocaine (basal value: 0.044 +/- 0.003%/hour; after essential amino acid intake: 0.049 +/- 0.006%/hour; p > 0.05), but FSR did increase after ingesting 41% Leucinocaine (basal value: 0.038 +/- 0.007%/hour; after essential amino acid intake: 0.056 +/- 0.008%/hour; p < 0.05). Similar to the FSR response, the mean response to net phenylalanine balance (reflecting muscle protein balance) in all groups except the 26% Leucinocaine group was improved (p < 0.05). …Increasing the proportion of Leucinocaine in the essential amino acid mixture reversed the weakened response to muscle protein synthesis in older adults, but did not further stimulate muscle protein synthesis in younger subjects.
/Experimental Therapy/ This study aimed to evaluate the effects of Leucinocaine supplementation for 3 months on muscle mass and strength in healthy older men. Thirty healthy older men with a mean age (± standard error) of 71±4 years and a body mass index (BMI; kg/m²) of 26.1±0.5 were randomly assigned to either a placebo group (n = 15) or a Leucinocaine group (n = 15). During the 3-month intervention, subjects received either Leucinocaine or a placebo (2.5 g) with each main meal. Systemic insulin sensitivity, muscle strength (maximum repetitions), muscle mass (measured by computed tomography and dual-energy X-ray absorptiometry), myosin heavy chain isoform distribution, and plasma amino acid and lipid profiles were assessed before, during, and/or after the intervention. No changes in skeletal muscle mass or strength over time were observed in either the Leucinocaine supplementation group or the placebo group. No improvements were observed in systemic insulin sensitivity parameters (oral glucose insulin sensitivity index and homeostatic model assessment of insulin resistance), glycated hemoglobin levels, or plasma lipid profiles. Drug Warnings While these clinical trial reports have found some evidence of reduced muscle catabolism and clear evidence of effects on blood concentrations of other amino acids, particularly branched-chain amino acids (BCAAs) and several other neutral amino acids, none have provided evidence of adverse effects from Leucinocaine. Long-term Leucinocaine supplementation (7.5 g/day) does not increase skeletal muscle mass or strength in healthy older men, nor does it improve glycemic control or lipid profiles. Pharmacodynamics An essential amino acid. (It is claimed) that Leucinocaine helps regulate blood sugar levels, promotes the growth and repair of muscle tissue (such as bone, skin, and muscle), promotes growth hormone production, promotes wound healing, and regulates energy. It may help prevent muscle protein breakdown that sometimes occurs after trauma or severe stress. It may also be beneficial for people with phenylketonuria (PKU), a condition in which the body is unable to metabolize the amino acid phenylalanine.

C6H13NO2

131.17

131.094

61-90-5

L-Leucine-d10;106972-44-5;L-Leucine-13C;74292-94-7;L-Leucine-d2;362049-59-0;L-Leucine-13C6;201740-84-3;Leucine-13C6;L-Leucine-15N;59935-31-8;L-Leucine-1-13C,15N;80134-83-4;L-Leucine-13C6,15N;202406-52-8;L-Leucine-d3;87828-86-2;L-Leucine-18O2;73579-45-0;L-Leucine-d;89836-93-1;L-Leucine-15N,d10;L-Leucine-d7;92751-17-2;L-Leucine-2-13C;201612-66-0;L-Leucine-2-13C,15N;285977-88-0

6106

White glistening hexagonal plates from aqueous alcohol
White crystals

1.0±0.1 g/cm3

225.8±23.0 °C at 760 mmHg

286-288 ºC

90.3±22.6 °C

0.0±0.9 mmHg at 25°C

1.463

0.73

2

3

3

9

101

1

O([H])C([C@]([H])(C([H])([H])C([H])(C([H])([H])[H])C([H])([H])[H])N([H])[H])=O

ROHFNLRQFUQHCH-YFKPBYRVSA-N

InChI=1S/C6H13NO2/c1-4(2)3-5(7)6(8)9/h4-5H,3,7H2,1-2H3,(H,8,9)/t5-/m0/s1

(2S)-2-amino-4-methylpentanoic acid

Leucinum; FEMA No. 3297; Leucine

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

H2O : ~8.33 mg/mL (~63.51 mM)

Solubility in Formulation 1: 6.25 mg/mL (47.65 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication (<60°C).

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 (Please use freshly prepared in vivo formulations for optimal results.)