Leucine

As a food additive, L-leucine has E number E641 and is classified as a flavor enhancer.^[9]

Requirements

The Food and Nutrition Board (FNB) of the U.S. Institute of Medicine set Recommended Dietary Allowances (RDAs) for essential amino acids in 2002. For leucine, for adults 19 years and older, 42 mg/kg body weight/day.^[10]

Sources

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.^[12] However, results of comparative studies are conflicted. Long-term leucine supplementation does not increase muscle mass or strength in healthy elderly men.^[13] 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 stand-alone, 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.

Both L-leucine and D-leucine protect mice against epileptic seizures.^[14] D-leucine also terminates seizures in mice after the onset of seizure activity, at least as effectively as diazepam and without sedative effects.^[14] Decreased dietary intake of L-leucine lessens adiposity in mice.^[15] High blood levels of leucine are associated with insulin resistance in humans, mice, and rodents.^[16] This might be due to the effect of leucine to stimulate mTOR signaling.^[17] Dietary restriction of leucine and the other BCAAs can reverse diet-induced obesity in wild-type mice by increasing energy expenditure, and can restrict fat mass gain of hyperphagic rats.^[18][19]

Leucine toxicity, as seen in decompensated maple syrup urine disease, causes delirium and neurologic compromise, and can be life-threatening.^[20]

A high intake of leucine may cause or exacerbate symptoms of pellagra in people with low niacin status because it interferes with the conversion of L-tryptophan to niacin.^[21]

Leucine at a dose exceeding 500 mg/kg/d was observed with hyperammonemia.^[22] As such, unofficially, a tolerable upper intake level (UL) for leucine in healthy adult men can be suggested at 500 mg/kg/d or 35 g/d under acute dietary conditions.^[22][23]

Pharmacodynamics

Leucine is a dietary amino acid with the capacity to directly stimulate myofibrillar muscle protein synthesis.^[24] This effect of leucine results from its role as an activator of the mechanistic target of rapamycin (mTOR),^[8] a serine-threonine protein kinase that regulates protein biosynthesis and cell growth. The activation of mTOR by leucine is mediated through Rag GTPases,^[25][26][27] leucine binding to leucyl-tRNA synthetase,^[25][26] leucine binding to sestrin 2,^[28][29][30] and possibly other mechanisms.

Metabolism in humans

Leucine metabolism occurs in many tissues in the human body; however, most dietary leucine is metabolized within the liver, adipose tissue, and muscle tissue.^[36] Adipose and muscle tissue use leucine in the formation of sterols and other compounds.^[36] Combined leucine use in these two tissues is seven times greater than in the liver.^[36]

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).^[37][38][35] Around 40% of dietary L-leucine is converted to acetyl-CoA, which is subsequently used in the synthesis of other compounds.^[35]

The vast majority of L-leucine metabolism is initially catalyzed by the branched-chain amino acid aminotransferase enzyme, producing α-ketoisocaproate (α-KIC).^[37][35] α-KIC is mostly metabolized by the mitochondrial enzyme branched-chain α-ketoacid dehydrogenase, which converts it to isovaleryl-CoA.^[37][35] Isovaleryl-CoA is subsequently metabolized by isovaleryl-CoA dehydrogenase and converted to MC-CoA, which is used in the synthesis of acetyl-CoA and other compounds.^[35] During biotin deficiency, HMB can be synthesized from MC-CoA via enoyl-CoA hydratase and an unknown thioesterase enzyme,^[31][32][39] which convert MC-CoA into HMB-CoA and HMB-CoA into HMB respectively.^[32] 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.^[37][35][40] 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.^[37][35]

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.^[35][41]

The metabolism of HMB is catalyzed by an uncharacterized enzyme which converts it to β-hydroxy β-methylbutyryl-CoA (HMB-CoA).^[31][35] HMB-CoA is metabolized by either enoyl-CoA hydratase or another uncharacterized enzyme, producing β-methylcrotonyl-CoA (MC-CoA) or hydroxymethylglutaryl-CoA (HMG-CoA) respectively.^[37][35] 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.^[37][35][41] HMG-CoA is then cleaved into acetyl-CoA and acetoacetate by HMG-CoA lyase or used in the production of cholesterol via the mevalonate pathway.^[37][35]

Leucine is an essential amino acid in the diet of animals because they lack the complete enzyme pathway to synthesize it de novo from potential precursor compounds. Consequently, they must ingest it, usually as a component of proteins. Plants and microorganisms synthesize leucine from pyruvic acid with a series of enzymes:^[42]

• 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.

Leucine is a branched-chain amino acid (BCAA) since it possesses an aliphatic side chain that is not linear.

Racemic leucine had been^[when?] 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.^[43]

• Leucines, the isomers and derivatives of leucine
• Leucine zipper, a common motif in transcription factor proteins

• Leucine Biosynthesis at the Wayback Machine (archived 2017-05-06)