L-Leucine at physiological pH
| IUPAC name
| Other names
|3D model (Jmol)||Interactive image|
|Molar mass||131.18 g·mol−1|
|Acidity (pKa)||2.36 (carboxyl), 9.60 (amino)|
|Supplementary data page|
| Refractive index (n),|
Dielectric constant (εr), etc.
| Phase behaviour|
|UV, IR, NMR, MS|
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
|(what is ?)|
Leucine (abbreviated as Leu or L; encoded by the six codons UUA, UUG, CUU, CUC, CUA, and CUG) is an α-amino acid used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH+
3 form under biological conditions), an α-carboxylic acid group (which is in the deprotonated −COO− form under biological conditions), and an isobutyl side chain, classifying it as a nonpolar (at physiological pH) amino acid. It is essential in humans—meaning the body cannot synthesize it and thus must obtain from the diet.
Leucine is used in the liver, adipose tissue, and muscle tissue. Adipose and muscle tissue use leucine in the formation of sterols. Combined leucine use in these two tissues is seven times greater than in the liver.
Biosynthesis in plants
Although it is an essential amino acid, animals cannot synthesize leucine. Consequently, they must ingest it, usually as a component of proteins. Plants and microorganisms synthesize leucine from pyruvic acid with a series of enzymes:
- Acetolactate synthase
- Acetohydroxy acid isomeroreductase
- Dihydroxyacid dehydratase
- α-Isopropylmalate synthase
- α-Isopropylmalate isomerase
- Leucine aminotransferase
Synthesis of the small, hydrophobic amino acid valine also includes the initial part of this pathway.
Metabolism in humans
In healthy individuals, approximately 60% of dietary L-leucine is metabolized after several hours, with roughly 5% (2–10% range) of dietary L-leucine being converted to β-hydroxy β-methylbutyric acid (HMB). Around 40% of dietary L-leucine is converted to acetyl-CoA, which is subsequently used in the synthesis of other compounds.
The vast majority of L-leucine metabolism is initially catalyzed by the branched-chain amino acid aminotransferase enzyme, producing α-ketoisocaproate (α-KIC). α-Ketoisocaproate is mostly metabolized by the mitochondrial enzyme branched-chain α-ketoacid dehydrogenase, which converts it to isovaleryl-CoA. Isovaleryl-CoA is subsequently metabolized by isovaleryl-CoA dehydrogenase and converted to β-methylcrotonoyl-CoA (MC-CoA), which is used in the synthesis of acetyl-CoA and other compounds. During biotin deficiency, HMB can be synthesized from MC-CoA via enoyl-CoA hydratase and an unknown thioesterase enzyme, which convert MC-CoA into β-hydroxy β-methylbutyryl-CoA (HMB-CoA) and HMB-CoA into HMB respectively. A relatively small amount of α-KIC is metabolized in the liver by the cytosolic enzyme 4-hydroxyphenylpyruvate dioxygenase (KIC dioxygenase), which converts α-KIC to HMB. In healthy individuals, this minor pathway – which involves the conversion of L-leucine to α-KIC and then HMB – is the predominant route of HMB synthesis.
A small fraction of L-leucine metabolism – less than 5% in all tissues except the testes where it accounts for about 33% – is initially catalyzed by leucine aminomutase, producing β-leucine, which is subsequently metabolized into β-ketoisocaproate (β-KIC), β-ketoisocaproyl-CoA, and then acetyl-CoA by a series of uncharacterized enzymes. HMB could be produced via certain metabolites that are generated along this pathway, but as of 2015 the associated enzymes and reactions involved are not known.
The metabolism of HMB is initially catalyzed by an uncharacterized enzyme which converts it to HMB-CoA. HMB-CoA is metabolized by either enoyl-CoA hydratase or another uncharacterized enzyme, producing MC-CoA or hydroxymethylglutaryl-CoA (HMG-CoA) respectively. MC-CoA is then converted by the enzyme methylcrotonyl-CoA carboxylase to methylglutaconyl-CoA (MG-CoA), which is subsequently converted to HMG-CoA by methylglutaconyl-CoA hydratase. HMG-CoA is then cleaved into to acetyl-CoA and acetoacetate by HMG-CoA lyase or used in the production of cholesterol via the mevalonate pathway.
Leucine is an mTOR activator. It is a dietary amino acid with the capacity to directly stimulate muscle protein synthesis. As a dietary supplement, leucine has been found to slow the degradation of muscle tissue by increasing the synthesis of muscle proteins in aged rats. However, results of comparative studies are conflicted. Long-term leucine supplementation does not increase muscle mass or strength in healthy elderly men. More studies are needed, preferably ones based on an objective, random sample of society. Factors such as lifestyle choices, age, gender, diet, exercise, etc. must be factored into the analyses to isolate the effects of supplemental leucine as a standalone, or if taken with other branched chain amino acids (BCAAs). Until then, dietary supplemental leucine cannot be associated as the prime reason for muscular growth or optimal maintenance for the entire population.
Leucine potently activates the mammalian target of rapamycin kinase that regulates cell growth. Infusion of leucine into the rat brain has been shown to decrease food intake and body weight via activation of the mTOR pathway. Several sensing mechanisms have been proposed; most recently, it has been demonstrated that sestrin 2 can directly bind to leucine and activate mTORC1 activity by promoting its localization to the lysosome.
Both L-leucine and D-leucine protect mice against seizures. D-leucine also terminates seizures in mice after the onset of seizure activity, at least as effectively as diazepam and without sedative effects. Decreased dietary intake of L-leucine promotes adiposity in mice. High blood levels of leucine are associated with insulin resistance in humans, mice, and rodents.
Excess leucine may be a cause of pellagra, whose main symptoms are "the four D's": diarrhea, dermatitis, dementia and death, though the relationship is unclear.
Leucine at a dose exceeding 500 mg/kg/d was observed with hyperammonemia. As such, the UL for leucine in healthy adult men can be suggested at 500 mg/kg/d or 35 g/d under acute dietary conditions.
|Soybeans, mature seeds, roasted, salted||2.868|
|Hemp seed, hulled||2.163|
|Beef, round, top round, separable lean and fat, trimmed to 3 mm (1⁄8 in) fat, select, raw||1.76|
|Fish, salmon, pink, raw||1.62|
|Chicken, broilers or fryers, thigh, meat only, raw||1.48|
|Chicken egg, yolk, raw, fresh||1.40|
|soybeans, Edamame, green, raw||0.926|
|Beans, pinto, cooked||0.765|
|Cow milk, whole, 3.25% milk fat||0.27|
|Rice, brown, medium-grain, cooked||0.191|
|Milk, human, mature, fluid||0.10|
Racemic leucine had been subjected to circularly polarized synchrotron radiation to better understand the origin of biomolecular asymmetry. An enantiomeric enhancement of 2.6% had been induced, indicating a possible photochemical origin of biomolecules' homochirality.
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In conclusion, HMB treatment clearly appears to be a safe potent strategy against sarcopenia, and more generally against muscle wasting, because HMB improves muscle mass, muscle strength, and physical performance. It seems that HMB is able to act on three of the four major mechanisms involved in muscle deconditioning (protein turnover, apoptosis, and the regenerative process), whereas it is hypothesized to strongly affect the fourth (mitochondrial dynamics and functions). Moreover, HMB is cheap (~30– 50 US dollars per month at 3 g per day) and may prevent osteopenia (Bruckbauer and Zemel, 2013; Tatara, 2009; Tatara et al., 2007, 2008, 2012) and decrease cardiovascular risks (Nissen et al., 2000). For all these reasons, HMB should be routinely used in muscle-wasting conditions especially in aged people. ... 3 g of CaHMB taken three times a day (1 g each time) is the optimal posology, which allows for continual bioavailability of HMB in the body (Wilson et al., 2013).
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Reduced activity of MCC impairs catalysis of an essential step in the mitochondrial catabolism of the BCAA leucine. Metabolic impairment diverts methylcrotonyl CoA to 3-hydroxyisovaleryl CoA in a reaction catalyzed by enoyl-CoA hydratase (22, 23). 3-Hydroxyisovaleryl CoA accumulation can inhibit cellular respiration either directly or via effects on the ratios of acyl CoA:free CoA if further metabolism and detoxification of 3-hydroxyisovaleryl CoA does not occur (22). The transfer to carnitine by 4 carnitine acyl-CoA transferases distributed in subcellular compartments likely serves as an important reservoir for acyl moieties (39–41). 3-Hydroxyisovaleryl CoA is likely detoxified by carnitine acetyltransferase producing 3HIA-carnitine, which is transported across the inner mitochondrial membrane (and hence effectively out of the mitochondria) via carnitine-acylcarnitine translocase (39). 3HIA-carnitine is thought to be either directly deacylated by a hydrolase to 3HIA or to undergo a second CoA exchange to again form 3-hydroxyisovaleryl CoA followed by release of 3HIA and free CoA by a thioesterase.
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A significant increase in blood ammonia concentrations above normal values, plasma leucine concentrations, and urinary leucine excretion were observed with leucine intakes >500 mg · kg⁻¹ · d⁻¹. The oxidation of l-[1-¹³C]-leucine expressed as label tracer oxidation in breath (F¹³CO₂), leucine oxidation, and α-ketoisocaproic acid (KIC) oxidation led to different results: a plateau in F¹³CO₂ observed after 500 mg · kg⁻¹ · d⁻¹, no clear plateau observed in leucine oxidation, and KIC oxidation appearing to plateau after 750 mg · kg⁻¹ · d⁻¹. On the basis of plasma and urinary variables, the UL for leucine in healthy adult men can be suggested at 500 mg · kg⁻¹ · d⁻¹ or ~35 g/d as a cautious estimate under acute dietary conditions.
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the upper limit for leucine intake in healthy elderly could be set similar to young men at 500 mg kg-1 day-1 or ~35 g/day for an individual weighing 70 kg
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- Leucine biosynthesis
- Combined ingestion of protein and free leucine with carbohydrate increases postexercise muscle protein synthesis in vivo in male subjects