Leucine

Dietary leucine

As a food additive, L-leucine has the E number E641 and is classified as a flavor enhancer.

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.

Sources {{Anchor|Dietary sources}}

Health effects

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 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. 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 lessens adiposity in mice. High blood levels of leucine are associated with insulin resistance in humans, mice, and rodents. This might be due to the effect of leucine to stimulate mTOR signaling. 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.

Safety

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

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.

Leucine at a dose exceeding 500 mg/kg/d was observed with hyperammonemia. 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.

Pharmacology

Pharmacodynamics

Leucine is a dietary amino acid with the capacity to directly stimulate myofibrillar muscle protein synthesis. This effect of leucine results from its role as an activator of the mechanistic target of rapamycin (mTOR), a serine-threonine protein kinase that regulates protein biosynthesis and cell growth. The activation of mTOR by leucine is mediated through Rag GTPases, leucine binding to leucyl-tRNA synthetase, leucine binding to sestrin 2, 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. Adipose and muscle tissue use leucine in the formation of sterols and other compounds. Combined leucine use in these two tissues is seven times greater than in the liver.

A small fraction of -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.

Synthesis in nonhuman organisms

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:

• 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.

Chemistry

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

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.

Notes

References

References

1. (December 2016). "Accurate hydrogen parameters for the amino acid L-leucine". Acta Crystallographica Section B.
2. Dawson, R.M.C., et al., ''Data for Biochemical Research'', Oxford, Clarendon Press, 1959.
3. (1983). "Nomenclature and Symbolism for Amino Acids and Peptides". IUPAC-IUB Joint Commission on Biochemical Nomenclature.
4. (2014). "Salts of Amino Acids: Crystallization, Structure and Properties". Springer International Publishing.
5. (2013). "Biochemistry". Lippincott Williams & Wilkins.
6. (2003). "Metabolic & Therapeutic Aspects of Amino Acids in Clinical Nutrition". CRC Press.
7. (September 2017). "β-hydroxy-β-methylbutyrate free acid supplementation may improve recovery and muscle adaptations after resistance training: a systematic review". Nutrition Research.
8. (June 2013). "Effects of leucine and its metabolite β-hydroxy-β-methylbutyrate on human skeletal muscle protein metabolism". The Journal of Physiology.
9. (2009). "A consumer's dictionary of food additives". Three Rivers Press.
10. (2002). "Dietary Reference Intakes for Energy, Carbohydrates, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids". The National Academies Press.
11. "National Nutrient Database for Standard Reference". U.S. Department of Agriculture.
12. (December 2005). "A leucine-supplemented diet restores the defective postprandial inhibition of proteasome-dependent proteolysis in aged rat skeletal muscle". The Journal of Physiology.
13. (May 2009). "Long-term leucine supplementation does not increase muscle mass or strength in healthy elderly men". The American Journal of Clinical Nutrition.
14. (October 2015). "Potent anti-seizure effects of D-leucine". Neurobiology of Disease.
15. (July 2016). "Decreased Consumption of Branched-Chain Amino Acids Improves Metabolic Health". Cell Reports.
16. (December 2014). "Branched-chain amino acids in metabolic signalling and insulin resistance". Nature Reviews. Endocrinology.
17. (2015). "The Roles of mTOR Complexes in Lipid Metabolism". Annual Review of Nutrition.
18. (February 2018). "Restoration of metabolic health by decreased consumption of branched-chain amino acids". The Journal of Physiology.
19. (July 2016). "Branched-chain amino acid restriction in Zucker-fatty rats improves muscle insulin sensitivity by enhancing efficiency of fatty acid oxidation and acyl-glycine export". Molecular Metabolism.
20. (2005-06-01). "Brain Amino Acid Requirements and Toxicity: The Example of Leucine". The Journal of Nutrition.
21. (2014). "Mechanisms of the pellagragenic effect of leucine: stimulation of hepatic tryptophan oxidation by administration of branched-chain amino acids to healthy human volunteers and the role of plasma free tryptophan and total kynurenines". International Journal of Tryptophan Research.
22. (October 2012). "Determination of the tolerable upper intake level of leucine in acute dietary studies in young men". The American Journal of Clinical Nutrition.
23. (July 2016). "Determination of the safety of leucine supplementation in healthy elderly men". Amino Acids.
24. (April 2004). "Manufacture and use of dairy protein fractions". The Journal of Nutrition.
25. (September 2017). "Control of leucine-dependent mTORC1 pathway through chemical intervention of leucyl-tRNA synthetase and RagD interaction". Nature Communications.
26. (March 2013). "Amino acid signalling upstream of mTOR". Nature Reviews. Molecular Cell Biology.
27. (June 2008). "The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1". Science.
28. (January 2016). "Sestrin2 is a leucine sensor for the mTORC1 pathway". Science.
29. (January 2016). "Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway". Science.
30. (October 2014). "The Sestrins interact with GATOR2 to negatively regulate the amino-acid-sensing pathway upstream of mTORC1". Cell Reports.
31. (February 1974). "Metabolic fate of leucine: a significant sterol precursor in adipose tissue and muscle". The American Journal of Physiology.
32. (2000). "Lehninger principles of biochemistry.". Worth Publishers.
33. [[Uwe Meierhenrich. Meierhenrich]]: ''Amino acids and the asymmetry of life'', Springer-Verlag, 2008, {{ISBN. 978-3-540-76885-2.