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 the free amino acids dissolved in the body fluids are only a very small proportion of the body's total mass of amino acids, they are very important for the nutritional and metabolic control of the body's proteins. ... Although the plasma compartment is most easily sampled, the concentration of most amino acids is higher in tissue intracellular pools. Typically, large neutral amino acids, such as leucine and phenylalanine, are essentially in equilibrium with the plasma. Others, notably glutamine, glutamic acid, and glycine, are 10- to 50-fold more concentrated in the intracellular pool. Dietary variations or pathological conditions can result in substantial changes in the concentrations of the individual free amino acids in both the plasma and tissue pools.
Table: Comparison of the Pool Sizes of Free and Protein-Bound Amino Acids in Rat Muscle [Table#7489]

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Metabolism / Metabolites
The branched-chain amino acids (BCAA) -- leucine, isoleucine, and valine -- differ from most other indispensable amino acids in that the enzymes initially responsible for their catabolism are found primarily in extrahepatic tissues. Each undergoes reversible transamination, catalyzed by a branched-chain aminotransferase (BCAT), and yields alpha-ketoisocaproate (KIC, from leucine), alpha-keto-beta-methylvalerate (KMV, from isoleucine), and alpha-ketoisovalerate (KIV, from valine). Each of these ketoacids then undergoes an irreversible, oxidative decarboxylation, catalyzed by a branchedchain ketoacid dehydrogenase (BCKAD). The latter is a multienzyme system located in mitochondrial membranes. The products of these oxidation reactions undergo further transformations to yield acetyl CoA, propionyl CoA, acetoacetate, and succinyl CoA; the BCAA are thus keto- and glucogenic.
Once the amino acid deamination products enter the tricarboxylic acid (TCA) cycle (also known as the citric acid cycle or Krebs cycle) or the glycolytic pathway, their carbon skeletons are also available for use in biosynthetic pathways, particularly for glucose and fat. Whether glucose or fat is formed from the carbon skeleton of an amino acid depends on its point of entry into these two pathways. If they enter as acetyl-CoA, then only fat or ketone bodies can be formed. The carbon skeletons of other amino acids can, however, enter the pathways in such a way that their carbons can be used for gluconeogenesis. This is the basis for the classical nutritional description of amino acids as either ketogenic or glucogenic (ie, able to give rise to either ketones [or fat] or glucose). Some amino acids produce both products upon degradation and so are considered both ketogenic and glucogenic. /Amino acids/
Kinetics of leucine and its oxidation were determined in human pregnancy and in the newborn infant, using stable isotopic tracers, to quantify the dynamic aspects of protein metabolism. These data show that in human pregnancy there is a decrease in whole-body rate of leucine turnover compared with nonpregnant women. In addition, data in newborn infants show that leucine turnover expressed as per kg body weight is higher compared with adults. The administering of nutrients resulted in a suppression of the whole-body rate of proteolysis ... The relations among the transamination of leucine, leucine N kinetics, and urea synthesis and glutamine kinetics in human pregnancy and newborn infants /were also examined/. In human pregnancy, early in gestation, there is a significant decrease in urea synthesis in association with a decrease in the rate of transamination of leucine. A linear correlation was evident between the rate of leucine reamination and urea synthesis during fasting in pregnant and nonpregnant women. In healthy-term newborn and growing infants, although the reamination of leucine was positively related to glutamine flux, leucine reamination was negatively related to urea synthesis, suggesting a redirection of amino N toward protein accretion ...
The metabolic disease 3-methylglutaconic aciduria type I (MGA1) is characterized by an abnormal organic acid profile in which there is excessive urinary excretion of 3-methylglutaconic acid, 3-methylglutaric acid and 3-hydroxyisovaleric acid. Affected individuals display variable clinical manifestations ranging from mildly delayed speech development to severe psychomotor retardation with neurological handicap. MGA1 is caused by reduced or absent 3-methylglutaconyl-coenzyme A (3-MG-CoA) hydratase activity within the leucine degradation pathway. The human AUH gene has been reported to encode for a bifunctional enzyme with both RNA-binding and enoyl-CoA-hydratase activity. In addition, it was shown that mutations in the AUH gene are linked to MGA1 ...
For more Metabolism/Metabolites (Complete) data for L-Leucine (8 total), please visit the HSDB record page.

[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.

L-leucine is the L-enantiomer of leucine. It has a role as a plant metabolite, an Escherichia coli metabolite, a Saccharomyces cerevisiae metabolite, a human metabolite, an algal metabolite and a mouse metabolite. It is a pyruvate family amino acid, a proteinogenic amino acid, a leucine and a L-alpha-amino acid. It is a conjugate base of a L-leucinium. It is a conjugate acid of a L-leucinate. It is an enantiomer of a D-leucine. It is a tautomer of a L-leucine zwitterion.
An essential branched-chain amino acid important for hemoglobin formation.
L-Leucine is a metabolite found in or produced by Escherichia coli (strain K12, MG1655).
Leucine has been reported in Microchloropsis, Humulus lupulus, and other organisms with data available.
Leucine is one of nine essential amino acids in humans (provided by food), Leucine is important for protein synthesis and many metabolic functions. Leucine contributes to regulation of blood-sugar levels; growth and repair of muscle and bone tissue; growth hormone production; and wound healing. Leucine also prevents breakdown of muscle proteins after trauma or severe stress and may be beneficial for individuals with phenylketonuria. Leucine is available in many foods and deficiency is rare. (NCI04)
Leucine (abbreviated as Leu or L)[2] is a branched-chain л±-amino acid with the chemical formulaHO2CCH(NH2)CH2CH(CH3)2. Leucine is classified as a hydrophobic amino acid due to its aliphatic isobutyl side chain. It is encoded by six codons (UUA, UUG, CUU, CUC, CUA, and CUG) and is a major component of the subunits in ferritin, astacin, and other 'buffer' proteins. Leucine is an essential amino acid, meaning that the human body cannot synthesize it, and it therefore must be ingested. It is important for hemoglobin formation.
An essential branched-chain amino acid important for hemoglobin formation.
See also: Isoleucine; Leucine (component of) ... View More ...

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Drug Indication
Indicated to assist in the prevention of the breakdown of muscle proteins that sometimes occur after trauma or severe stress.

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Mechanism of Action
This group of essential amino acids are identified as the branched-chain amino acids, BCAAs. Because this arrangement of carbon atoms cannot be made by humans, these amino acids are an essential element in the diet. The catabolism of all three compounds initiates in muscle and yields NADH and FADH2 which can be utilized for ATP generation. The catabolism of all three of these amino acids uses the same enzymes in the first two steps. The first step in each case is a transamination using a single BCAA aminotransferase, with a-ketoglutarate as amine acceptor. As a result, three different a-keto acids are produced and are oxidized using a common branched-chain a-keto acid dehydrogenase, yielding the three different CoA derivatives. Subsequently the metabolic pathways diverge, producing many intermediates. The principal product from valine is propionylCoA, the glucogenic precursor of succinyl-CoA. Isoleucine catabolism terminates with production of acetylCoA and propionylCoA; thus isoleucine is both glucogenic and ketogenic. Leucine gives rise to acetylCoA and acetoacetylCoA, and is thus classified as strictly ketogenic. There are a number of genetic diseases associated with faulty catabolism of the BCAAs. The most common defect is in the branched-chain a-keto acid dehydrogenase. Since there is only one dehydrogenase enzyme for all three amino acids, all three a-keto acids accumulate and are excreted in the urine. The disease is known as Maple syrup urine disease because of the characteristic odor of the urine in afflicted individuals. Mental retardation in these cases is extensive. Unfortunately, since these are essential amino acids, they cannot be heavily restricted in the diet; ultimately, the life of afflicted individuals is short and development is abnormal The main neurological problems are due to poor formation of myelin in the CNS.
The mechanism of intracellular protein degradation, by which protein is hydrolyzed to free amino acids, is more complex and is not as well characterized at the mechanistic level as that of synthesis. A wide variety of different enzymes that are capable of splitting peptide bonds are present in cells. However, the bulk of cellular proteolysis seems to be shared between two multienzyme systems: the lysosomal and proteasomal systems. The lysosome is a membrane-enclosed vesicle inside the cell that contains a variety of proteolytic enzymes and operates mostly at acid pH. Volumes of the cytoplasm are engulfed (autophagy) and are then subjected to the action of the protease enzymes at high concentration. This system is thought to be relatively unselective in most cases, although it can also degrade specific intracellular proteins. The system is highly regulated by hormones such as insulin and glucocorticoids, and by amino acids. The second system is the ATP-dependent ubiquitin-proteasome system, which is present in the cytoplasm. The first step is to join molecules of ubiquitin, a basic 76-amino acid peptide, to lysine residues in the target protein. Several enzymes are involved in this process, which selectively targets proteins for degradation by a second component, the proteasome.
Dietary leucine transported into the brain parenchyma serves several functions. Most prominent is the role of leucine as a metabolic precursor of fuel molecules, alpha-ketoisocaproate and ketone bodies. As alternatives to glucose, these compounds are forwarded by the producing astrocytes to the adjacent neural cells. Leucine furthermore participates in the maintenance of the nitrogen balance in the glutamate/glutamine cycle pertinent to the neurotransmitter glutamate. Leucine also serves as a regulator of the activity of some enzymes important for brain energy metabolism. Another role of leucine as an informational molecule is in mTOR signaling that participates in the regulation of food ingestion. The importance of leucine for brain function is stressed by the fact that inborn errors in its metabolism cause metabolic diseases often associated with neuropathological symptoms. In this overview, the current knowledge on the metabolic and regulatory roles of this essential amino acid in neural cells are briefly summarized.
Ingestion of a leucine-enriched essential amino acid nutrient solution rapidly and potently activates the mammalian target of rapamycin signalling pathway and protein synthesis in human skeletal muscle. Further, mTOR signalling and muscle protein synthesis are enhanced when leucine-enriched nutrients are ingested following resistance exercise. The addition of leucine to regular meals may improve the ability of feeding to stimulate protein synthesis in old human muscle. ... Leucine and essential amino acids appear to stimulate human muscle protein synthesis primarily by activating the mammalian target of rapamycin signalling pathway. How human muscle cells sense an increase in leucine and/or essential amino acids to activate mammalian target of rapamycin signalling is currently unknown. Recent work, however, suggests that the kinases hVps34 and MAP43K may be involved. Leucine-enriched essential amino acid ingestion, in combination with resistance exercise in some cases, may be a useful intervention to promote mTOR signalling and protein synthesis in an effort to counteract a variety of muscle wasting conditions (e.g. sarcopenia, cachexia, AIDS, inactivity/bed rest, sepsis, kidney failure, and trauma).
One of the amino acids most affected by exercise is the branched-chain amino acid leucine. ... Leucine appears to exert a synergistic role with insulin as a regulatory factor in the insulin/ phosphatidylinositol-3 kinase (PI3-K) signal cascade. Insulin serves to activate the signal pathway, while leucine is essential to enhance or amplify the signal for protein synthesis at the level of peptide initiation. Studies feeding amino acids or leucine soon after exercise suggest that post-exercise consumption of amino acids stimulates recovery of muscle protein synthesis via translation regulations ...
For more Mechanism of Action (Complete) data for L-Leucine (12 total), please visit the HSDB record page.

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.)