Leucine

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Leucine

L-Leucine
File:Leucine Physiological pH.svg
L-Leucine at physiological pH
Names
IUPAC name
Leucine
Other names
2-Amino-4-methylpentanoic acid
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.000.475 Edit this at Wikidata
KEGG
UNII
  • InChI=1S/C6H13NO2/c1-4(2)3-5(7)6(8)9/h4-5H,3,7H2,1-2H3,(H,8,9)/t5-/m0/s1 checkY
    Key: ROHFNLRQFUQHCH-YFKPBYRVSA-N checkY
  • InChI=1/C6H13NO2/c1-4(2)3-5(7)6(8)9/h4-5H,3,7H2,1-2H3,(H,8,9)/t5-/m0/s1
    Key: ROHFNLRQFUQHCH-YFKPBYRVBU
  • CC(C)C[C@@H](C(=O)O)N
Properties
C6H13NO2
Molar mass 131.175 g·mol−1
Acidity (pKa) 2.36 (carboxyl), 9.60 (amino)[1]
-84.9·10−6 cm3/mol
Supplementary data page
Leucine (data page)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Leucine (abbreviated as Leu or L) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH3+ form under biological conditions), an α-carboxylic acid group (which is in the deprotonated −COO− form under biological conditions), and a side chain isobutyl group, making it a non-polar aliphatic amino acid. It is essential in humans, meaning the body cannot synthesize it: it must be obtained from the diet. Human dietary sources are foods that contain protein, such as meats, dairy products, soy products, beans and legumes. In the genetic code it is encoded by the six codons UUA, UUG, CUU, CUC, CUA, and CUG.

Like valine and isoleucine, leucine is a branched-chain amino acid. Because the products of its breakdown are acetyl-CoA and acetoacetate, it is one of the two exclusively ketogenic amino acids, lycine being the other one.[2] It is the most important ketogenic amino acid in humans.[3]p.101

Biology

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.[4]

Leucine is rapidly taken up into the brain where astrocytes convert it to alpha-ketoisocaproate via transamination of alpha-ketoglutarate to glutamate. [reference: Yudoff, Mark. (Feb 01 2017) "Interactions in the Metabolism of Glutamate and the Branched-Chain Amino Acids and ketoacids in the CNS" Neurochem Res. 2017 January; 42(1): 10-18. doi:10.1007/s11064-016-2057-z. ]

Biosynthesis in plants

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:[5]

Synthesis of the small, hydrophobic amino acid valine also includes the initial part of this pathway.

Metabolism in humans

Human metabolic pathway for β-hydroxy β-methylbutyric acid (HMB) and isovaleryl-CoA, relative to L-leucine.[6][7][8] Of the two major pathways, leucine is mostly metabolized into isovaleryl-CoA, while only about 5% is metabolized into HMB.[6][7][8]

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).[7][8][9] Around 40% of dietary L-leucine is converted to acetyl-CoA, which is subsequently used in the synthesis of other compounds.[7]

The vast majority of L-leucine metabolism is initially catalyzed by the branched-chain amino acid aminotransferase enzyme, producing α-ketoisocaproate (α-KIC).[7][8] α-Ketoisocaproate is mostly metabolized by the mitochondrial enzyme branched-chain α-ketoacid dehydrogenase, which converts it to isovaleryl-CoA.[7][8] 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.[7] During biotin deficiency, HMB can be synthesized from MC-CoA via enoyl-CoA hydratase and an unknown thioesterase enzyme,[10][11][12] which convert MC-CoA into β-hydroxy β-methylbutyryl-CoA (HMB-CoA) and HMB-CoA into HMB respectively.[12] 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.[7][8][13] 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.[7][8]

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.[7][14]

The metabolism of HMB is initially catalyzed by an uncharacterized enzyme which converts it to HMB-CoA.[7][8][11] HMB-CoA is metabolized by either enoyl-CoA hydratase or another uncharacterized enzyme, producing MC-CoA or hydroxymethylglutaryl-CoA (HMG-CoA) respectively.[7][8] 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.[7][8][14] 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.[7][8]

Effects

Leucine is an mTOR activator. It is a dietary amino acid with the capacity to directly stimulate muscle protein synthesis.[15] 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.[16] However, results of comparative studies are conflicted. Long-term leucine supplementation does not increase muscle mass or strength in healthy elderly men.[17] 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.[18] 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.[19][20][21]

Both L-leucine and D-leucine protect mice against seizures.[22] D-leucine also terminates seizures in mice after the onset of seizure activity, at least as effectively as diazepam and without sedative effects.[22] Decreased dietary intake of L-leucine promotes adiposity in mice.[23] High blood levels of leucine are associated with insulin resistance in humans, mice, and rodents.[24]

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.[25]

Leucine at a dose exceeding 500 mg/kg/d was observed with hyperammonemia.[26] 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.[26][27]

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.[28]

Dietary sources

Food sources of leucine[29]
Food g/100g
Whey protein concentrate, dry powder 10.0-12.0
Soy protein concentrate, dry powder 7.5-8.5
Soybeans, mature seeds, roasted, salted 2.87
Hemp seed, hulled 2.16
Beef, round, top round, raw 1.76
Peanuts 1.67
Fish, salmon, pink, raw 1.62
Wheat germ 1.57
Almonds 1.49
Chicken, broilers or fryers, thigh, raw 1.48
Chicken egg, yolk, raw 1.40
Oats 1.28
Edamame (soybeans, green, raw) 0.93
Beans, pinto, cooked 0.78
Lentils, cooked 0.65
Chickpea, cooked 0.63
Corn, yellow 0.35
Cow milk, whole, 3.25% milk fat 0.27
Rice, brown, medium-grain, cooked 0.19
Milk, human, mature, fluid 0.10

Chemical properties

(S)-Leucine (or L-leucine), left; (R)-leucine (or D-leucine), right, in zwitterionic form at neutral pH

Leucine is a branched-chain amino acid (BCAA) since it possesses an aliphatic side-chain that is non-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.[30]

Other uses

As a food additive, L-leucine has E number E641 and is classified as a flavor enhancer.[31]

See also

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

References

  1. ^ Dawson, R.M.C., et al., Data for Biochemical Research, Oxford, Clarendon Press, 1959.
  2. ^ Ferrier, Denise R. (24 May 2013). Biochemistry. Lippincott Williams & Wilkins. ISBN 9781451175622.
  3. ^ Cynober, Luc A. (13 November 2003). Metabolic & Therapeutic Aspects of Amino Acids in Clinical Nutrition, Second Edition. CRC Press. ISBN 9780203010266.
  4. ^ J. Rosenthal, et al. Department of Medicine, University of Toronto, Toronto, Canada. "Metabolic fate of leucine: A significant sterol precursor in adipose tissue and muscle". American Journal of Physiology Vol. 226, No. 2, p. 411-418. Retrieved 25 March 2008.{{cite web}}: CS1 maint: multiple names: authors list (link)
  5. ^ Nelson, D. L.; Cox, M. M. "Lehninger, Principles of Biochemistry" 3rd Ed. Worth Publishing: New York, 2000. ISBN 1-57259-153-6.
  6. ^ a b Wilson JM, Fitschen PJ, Campbell B, Wilson GJ, Zanchi N, Taylor L, Wilborn C, Kalman DS, Stout JR, Hoffman JR, Ziegenfuss TN, Lopez HL, Kreider RB, Smith-Ryan AE, Antonio J (February 2013). "International Society of Sports Nutrition Position Stand: beta-hydroxy-beta-methylbutyrate (HMB)". J. Int. Soc. Sports. Nutr. 10 (1): 6. doi:10.1186/1550-2783-10-6. PMC 3568064. PMID 23374455.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  7. ^ a b c d e f g h i j k l m n Kohlmeier M (2015). "Leucine". Nutrient Metabolism: Structures, Functions, and Genes (2nd ed.). Academic Press. pp. 385–388. ISBN 9780123877840. Retrieved 6 June 2016. Figure 8.57: Metabolism of L-leucine {{cite book}}: External link in |quote= (help)
  8. ^ Brioche T, Pagano AF, Py G, Chopard A (April 2016). "Muscle wasting and aging: Experimental models, fatty infiltrations, and prevention". Mol. Aspects Med. doi:10.1016/j.mam.2016.04.006. PMID 27106402.
  9. ^ "KEGG Reaction: R04137". Kyoto Encyclopedia of Genes and Genomes. Kanehisa Laboratories. Retrieved 24 June 2016.
  10. ^ a b "KEGG Reaction: R10759". Kyoto Encyclopedia of Genes and Genomes. Kanehisa Laboratories. Retrieved 24 June 2016.
  11. ^ a b Mock DM, Stratton SL, Horvath TD, Bogusiewicz A, Matthews NI, Henrich CL, Dawson AM, Spencer HJ, Owen SN, Boysen G, Moran JH (November 2011). "Urinary excretion of 3-hydroxyisovaleric acid and 3-hydroxyisovaleryl carnitine increases in response to a leucine challenge in marginally biotin-deficient humans". J. Nutr. 141 (11): 1925–1930. doi:10.3945/jn.111.146126. PMC 3192457. PMID 21918059.
  12. ^ "Homo sapiens: 4-hydroxyphenylpyruvate dioxygenase reaction". MetaCyc. SRI International. 20 August 2012. Retrieved 6 June 2016.
  13. ^ a b "Leucine metabolism". BRENDA. Technische Universität Braunschweig. Retrieved 8 June 2016.
  14. ^ Etzel MR (2004). "Manufacture and use of dairy protein fractions". The Journal of Nutrition. 134 (4): 996S–1002S. PMID 15051860.
  15. ^ L. Combaret, et al. Human Nutrition Research Centre of Clermont-Ferrand. "A leucine-supplemented diet restores the defective postprandial inhibition of proteasome-dependent proteolysis in aged rat skeletal muscle". Journal of Physiology Volume 569, issue 2, p. 489-499. Retrieved 25 March 2008.
  16. ^ Verhoeven, Suzanne; Vanschoonbeek, Kristof; Verdijk, Lex B.; Koopman, René; Wodzig, Will K.W.H.; Dendale, Paul; van Loon, Luc JC (May 2009). "Long-term leucine supplementation does not increase muscle mass or strength in healthy elderly men". Am J Clin Nutr. 89 (5): 1468–75. doi:10.3945/ajcn.2008.26668. PMID 19321567.
  17. ^ Cota D, Proulx K, Smith KA, Kozma SC, Thomas G, Woods SC, Seeley RJ (2006). "Hypothalamic mTOR signaling regulates food intake". Science. 312 (5775): 927–930. doi:10.1126/science.1124147. PMID 16690869.
  18. ^ Wolfson, Rachel L.; Chantranupong, Lynne; Saxton, Robert A.; Shen, Kuang; Scaria, Sonia M.; Cantor, Jason R.; Sabatini, David M. (1 January 2016). "Sestrin2 is a leucine sensor for the mTORC1 pathway". Science. 351 (6268): 43–48. doi:10.1126/science.aab2674. ISSN 1095-9203. PMC 4698017. PMID 26449471.
  19. ^ Saxton, Robert A.; Knockenhauer, Kevin E.; Wolfson, Rachel L.; Chantranupong, Lynne; Pacold, Michael E.; Wang, Tim; Schwartz, Thomas U.; Sabatini, David M. (1 January 2016). "Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway". Science. 351 (6268): 53–58. doi:10.1126/science.aad2087. ISSN 1095-9203. PMC 4698039. PMID 26586190.
  20. ^ Chantranupong, Lynne; Wolfson, Rachel L.; Orozco, Jose M.; Saxton, Robert A.; Scaria, Sonia M.; Bar-Peled, Liron; Spooner, Eric; Isasa, Marta; Gygi, Steven P. (9 October 2014). "The Sestrins interact with GATOR2 to negatively regulate the amino-acid-sensing pathway upstream of mTORC1". Cell Reports. 9 (1): 1–8. doi:10.1016/j.celrep.2014.09.014. ISSN 2211-1247. PMC 4223866. PMID 25263562.
  21. ^ a b Hartman AL, Santos P, O'Riordan KJ, Stafstrom CE, Marie Hardwick J (2015). "Potent anti-seizure effects of D-leucine". Neurobiology of Disease. 82: 46–53. doi:10.1016/j.nbd.2015.05.013. PMID 26054437. Retrieved 26 November 2015.
  22. ^ Fontana, Luigi; Cummings, Nicole E.; Arriola Apelo, Sebastian I.; Neuman, Joshua C.; Kasza, Ildiko; Schmidt, Brian A.; Cava, Edda; Spelta, Francesco; Tosti, Valeria (21 June 2016). "Decreased Consumption of Branched-Chain Amino Acids Improves Metabolic Health". Cell Reports. 16: 520–30. doi:10.1016/j.celrep.2016.05.092. ISSN 2211-1247. PMC 4947548. PMID 27346343.
  23. ^ Lynch, Christopher J.; Adams, Sean H. (1 December 2014). "Branched-chain amino acids in metabolic signalling and insulin resistance". Nature Reviews. Endocrinology. 10 (12): 723–736. doi:10.1038/nrendo.2014.171. ISSN 1759-5037. PMC 4424797. PMID 25287287.
  24. ^ Badawy AA, Lake SL, Dougherty DM (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". Int J Tryptophan Res. 7: 23–32. doi:10.4137/IJTR.S18231. PMC 4259507. PMID 25520560.
  25. ^ a b Elango R, Chapman K, Rafii M, Ball RO, Pencharz PB (2012). "Determination of the tolerable upper intake level of leucine in acute dietary studies in young men". The American Journal of Clinical Nutrition. 96 (4): 759–67. doi:10.3945/ajcn.111.024471. PMID 22952178. Retrieved 7 December 2015. 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.
  26. ^ Rasmussen B, Gilbert E, Turki A, Madden K, Elango R (2016). "Determination of the safety of leucine supplementation in healthy elderly men". Amino Acids. 48: 1707–16. doi:10.1007/s00726-016-2241-0. PMID 27138628. Retrieved 6 May 2016. 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
  27. ^ Institute of Medicine (2002). "Protein and Amino Acids". Dietary Reference Intakes for Energy, Carbohydrates, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids. Washington, DC: The National Academies Press. pp. 589–768.
  28. ^ National Nutrient Database for Standard Reference. U.S. Department of Agriculture. Archived from the original on 3 March 2015. Retrieved 16 September 2009. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
  29. ^ Meierhenrich: Amino acids and the asymmetry of life, Springer-Verlag, 2008, ISBN 978-3-540-76885-2.
  30. ^ Winter, Ruth (2009). A consumer's dictionary of food additives (7th ed.). New York: Three Rivers Press. ISBN 0307408922.

External links

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