“Leucine”的意思、由来-开放百科全书

Leucine (symbol Leu or L)^[2] is an essential amino acid that is used in the biosynthesis of proteins. Leucine is an α-amino acid, meaning 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, and beans and other legumes. It is encoded by the codons UUA, UUG, CUU, CUC, CUA, and CUG.

Like valine and isoleucine, leucine is a branched-chain amino acid. The primary metabolic end products of leucine metabolism are acetyl-CoA and acetoacetate; consequently, it is one of the two exclusively ketogenic amino acids, with lysine being the other.^[3] It is the most important ketogenic amino acid in humans.^[4]^p. 101

Leucine and β-hydroxy β-methylbutyric acid, a minor leucine metabolite, exhibit pharmacological activity in humans and have been demonstrated to promote protein biosynthesis via the phosphorylation of the mechanistic target of rapamycin (mTOR).^[5]^[6]

Dietary leucine

As a food additive, L-leucine has E number E641 and is classified as a flavor enhancer.^[7]

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.^[8]

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.^[10] However, results of comparative studies are conflicted. Long-term leucine supplementation does not increase muscle mass or strength in healthy elderly men.^[11] 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.

Both L-leucine and D-leucine protect mice against seizures.^[12] D-leucine also terminates seizures in mice after the onset of seizure activity, at least as effectively as diazepam and without sedative effects.^[12] Decreased dietary intake of L-leucine promotes adiposity in mice.^[13] High blood levels of leucine are associated with insulin resistance in humans, mice, and rodents.^[14] This might be due to the effect of leucine to stimulate mTOR signaling.^[15] 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.^[16]^[17]

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.^[18]

Leucine at a dose exceeding 500 mg/kg/d was observed with hyperammonemia.^[19] 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.^[19]^[20]

Pharmacology

Pharmacodynamics

Leucine is a dietary amino acid with the capacity to directly stimulate myofibrillar muscle protein synthesis.^[21] This effect of leucine arises results from its role as an activator of the mechanistic target of rapamycin (mTOR),^[6] a serine-threonine protein kinase that regulates protein biosynthesis and cell growth. The activation of mTOR by leucine is mediated through Rag GTPases,^[22]^[23]^[24] leucine binding to leucyl-tRNA synthetase,^[22]^[23] leucine binding to sestrin 2,^[25]^[26]^[27] 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.{{mcn|date=April 2018}} Adipose and muscle tissue use leucine in the formation of sterols and other compounds.{{mcn|date=April 2018}} Combined leucine use in these two tissues is seven times greater than in the liver.^[28]

A small fraction of {{nowrap|{{smallcaps all|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 {{nowrap|β-ketoisocaproate}} (β-KIC), β-ketoisocaproyl-CoA, and then acetyl-CoA by a series of uncharacterized enzymes.

Synthesis in non-human 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:^[29]

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.

See also

Notes

1. ^Dawson, R.M.C., et al., Data for Biochemical Research, Oxford, Clarendon Press, 1959.
2. ^{{cite web| url = http://www.chem.qmul.ac.uk/iupac/AminoAcid/AA1n2.html | title = Nomenclature and Symbolism for Amino Acids and Peptides | publisher = IUPAC-IUB Joint Commission on Biochemical Nomenclature | year = 1983 | accessdate = 5 March 2018| archiveurl= https://web.archive.org/web/20081009023202/http://www.chem.qmul.ac.uk/iupac/AminoAcid/AA1n2.html| archivedate= 9 October 2008 | deadurl= no}}
3. ^{{Cite book|url=https://books.google.com/books?id=sSyMAwAAQBAJ&pg=PA266|title=Biochemistry|last=Ferrier|first=Denise R.|date=2013-05-24|publisher=Lippincott Williams & Wilkins|isbn=9781451175622|language=en}}
4. ^{{Cite book|url=https://books.google.de/books?id=X3DK4nWybaMC|title=Metabolic & Therapeutic Aspects of Amino Acids in Clinical Nutrition, Second Edition|last=Cynober|first=Luc A.|date=2003-11-13|publisher=CRC Press|isbn=9780203010266|language=en}}
5. ^{{cite journal | vauthors = Silva VR, Belozo FL, Micheletti TO, Conrado M, Stout JR, Pimentel GD, Gonzalez AM | title = β-hydroxy-β-methylbutyrate free acid supplementation may improve recovery and muscle adaptations after resistance training: a systematic review | journal = Nutrition Research | volume = 45 | issue = | pages = 1–9 | date = September 2017 | pmid = 29037326 | doi = 10.1016/j.nutres.2017.07.008 | quote = HMB's mechanisms of action are generally considered to relate to its effect on both muscle protein synthesis and muscle protein breakdown (Figure 1) [2, 3]. HMB appears to stimulate muscle protein synthesis through an up-regulation of the mammalian/mechanistic target of rapamycin complex 1 (mTORC1), a signaling cascade involved in coordination of translation initiation of muscle protein synthesis [2, 4]. Additionally, HMB may have antagonistic effects on the ubiquitin–proteasome pathway, a system that degrades intracellular proteins [5, 6]. Evidence also suggests that HMB promotes myogenic proliferation, differentiation, and cell fusion [7]. ... Exogenous HMB-FA administration has shown to increase intramuscular anabolic signaling, stimulate muscle protein synthesis, and attenuate muscle protein breakdown in humans [2]. }}
6. ^¹{{cite journal | vauthors = Wilkinson DJ, Hossain T, Hill DS, Phillips BE, Crossland H, Williams J, Loughna P, Churchward-Venne TA, Breen L, Phillips SM, Etheridge T, Rathmacher JA, Smith K, Szewczyk NJ, Atherton PJ | title = Effects of leucine and its metabolite β-hydroxy-β-methylbutyrate on human skeletal muscle protein metabolism | journal = The Journal of Physiology | volume = 591 | issue = 11 | pages = 2911–2923 | date = June 2013 | pmid = 23551944 | pmc = 3690694 | doi = 10.1113/jphysiol.2013.253203 | quote = The stimulation of MPS through mTORc1-signalling following HMB exposure is in agreement with pre-clinical studies (Eley et al. 2008). ... Furthermore, there was clear divergence in the amplitude of phosphorylation for 4EBP1 (at Thr37/46 and Ser65/Thr70) and p70S6K (Thr389) in response to both Leu and HMB, with the latter showing more pronounced and sustained phosphorylation. ... Nonetheless, as the overall MPS response was similar, this cellular signalling distinction did not translate into statistically distinguishable anabolic effects in our primary outcome measure of MPS. ... Interestingly, although orally supplied HMB produced no increase in plasma insulin, it caused a depression in MPB (−57%). Normally, postprandial decreases in MPB (of ~50%) are attributed to the nitrogen-sparing effects of insulin since clamping insulin at post-absorptive concentrations (5 μU ml⁻¹) while continuously infusing AAs (18 g h⁻¹) did not suppress MPB (Greenhaff et al. 2008), which is why we chose not to measure MPB in the Leu group, due to an anticipated hyperinsulinaemia (Fig. 3C). Thus, HMB reduces MPB in a fashion similar to, but independent of, insulin. These findings are in-line with reports of the anti-catabolic effects of HMB suppressing MPB in pre-clinical models, via attenuating proteasomal-mediated proteolysis in response to LPS (Eley et al. 2008).}}
7. ^{{cite book|last1=Winter|first1=Ruth|title=A consumer's dictionary of food additives|date=2009|publisher=Three Rivers Press|location=New York|isbn=978-0307408921|edition=7th}}
8. ^{{cite book | last1 = Institute of Medicine | title = Dietary Reference Intakes for Energy, Carbohydrates, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids | chapter = Protein and Amino Acids | publisher = The National Academies Press | year = 2002 | location = Washington, DC | pages = 589–768 | chapter-url = https://www.nap.edu/read/10490/chapter/12}}
9. ^{{Cite book|title=National Nutrient Database for Standard Reference |url=http://www.nal.usda.gov/fnic/foodcomp/search/ |publisher=U.S. Department of Agriculture |accessdate=16 September 2009 |deadurl=yes |archiveurl=https://web.archive.org/web/20150303000000/http://www.nal.usda.gov/fnic/foodcomp/search/ |archivedate= 3 March 2015 |df= }}
10. ^{{cite web | author=L. Combaret, et al. Human Nutrition Research Centre of Clermont-Ferrand | title=A leucine-supplemented diet restores the defective postprandial inhibition of proteasome-dependent proteolysis in aged rat skeletal muscle | work=Journal of Physiology Volume 569, issue 2, p. 489-499 | url=http://jp.physoc.org/cgi/reprint/569/2/489 | accessdate=25 March 2008}}
11. ^{{cite journal | vauthors = Verhoeven S, Vanschoonbeek K, Verdijk LB, Koopman R, Wodzig WK, Dendale P, van Loon LJ | title = Long-term leucine supplementation does not increase muscle mass or strength in healthy elderly men | journal = The American Journal of Clinical Nutrition | volume = 89 | issue = 5 | pages = 1468–75 | date = May 2009 | pmid = 19321567 | doi = 10.3945/ajcn.2008.26668 }}
12. ^¹{{cite journal | vauthors = Hartman AL, Santos P, O'Riordan KJ, Stafstrom CE, Marie Hardwick J | title = Potent anti-seizure effects of D-leucine | journal = Neurobiology of Disease | volume = 82 | issue = | pages = 46–53 | date = October 2015 | pmid = 26054437 | pmc = 4640989 | doi = 10.1016/j.nbd.2015.05.013 | url = http://linkinghub.elsevier.com/retrieve/pii/S0969-9961(15)00187-4 }}
13. ^{{cite journal | vauthors = Fontana L, Cummings NE, Arriola Apelo SI, Neuman JC, Kasza I, Schmidt BA, Cava E, Spelta F, Tosti V, Syed FA, Baar EL, Veronese N, Cottrell SE, Fenske RJ, Bertozzi B, Brar HK, Pietka T, Bullock AD, Figenshau RS, Andriole GL, Merrins MJ, Alexander CM, Kimple ME, Lamming DW | title = Decreased Consumption of Branched-Chain Amino Acids Improves Metabolic Health | journal = Cell Reports | volume = 16 | issue = 2 | pages = 520–530 | date = July 2016 | pmid = 27346343 | pmc = 4947548 | doi = 10.1016/j.celrep.2016.05.092 }}
14. ^{{cite journal | vauthors = Lynch CJ, Adams SH | title = Branched-chain amino acids in metabolic signalling and insulin resistance | journal = Nature Reviews. Endocrinology | volume = 10 | issue = 12 | pages = 723–36 | date = December 2014 | pmid = 25287287 | pmc = 4424797 | doi = 10.1038/nrendo.2014.171 }}
15. ^Caron A, Richard D, Laplante M (Jul 2015). "The Roles of mTOR Complexes in Lipid Metabolism". Annual Review of Nutrition. 35: 321–48. doi:10.1146/annurev-nutr-071714-034355. {{PMID|26185979}}.
16. ^{{cite journal | vauthors = Cummings NE, Williams EM, Kasza I, Konon EN, Schaid MD, Schmidt BA, Poudel C, Sherman DS, Yu D, Arriola Apelo SI, Cottrell SE, Geiger G, Barnes ME, Wisinski JA, Fenske RJ, Matkowskyj KA, Kimple ME, Alexander CM, Merrins MJ, Lamming DW | title = Restoration of metabolic health by decreased consumption of branched-chain amino acids | journal = The Journal of Physiology | volume = 596 | issue = 4 | pages = 623–645 | date = December 2017 | pmid = 29266268 | pmc = 5813603 | doi = 10.1113/JP275075 }}
17. ^{{cite journal | vauthors = White PJ, Lapworth AL, An J, Wang L, McGarrah RW, Stevens RD, Ilkayeva O, George T, Muehlbauer MJ, Bain JR, Trimmer JK, Brosnan MJ, Rolph TP, Newgard CB | title = Branched-chain amino acid restriction in Zucker-fatty rats improves muscle insulin sensitivity by enhancing efficiency of fatty acid oxidation and acyl-glycine export | journal = Molecular Metabolism | volume = 5 | issue = 7 | pages = 538–51 | date = July 2016 | pmid = 27408778 | pmc = 4921791 | doi = 10.1016/j.molmet.2016.04.006 }}
18. ^{{cite journal | vauthors = Badawy AA, Lake SL, Dougherty DM | title = 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 | journal = International Journal of Tryptophan Research | volume = 7 | issue = | pages = 23–32 | year = 2014 | pmid = 25520560 | pmc = 4259507 | doi = 10.4137/IJTR.S18231 }}
19. ^¹{{cite journal | vauthors = Elango R, Chapman K, Rafii M, Ball RO, Pencharz PB | title = Determination of the tolerable upper intake level of leucine in acute dietary studies in young men | journal = The American Journal of Clinical Nutrition | volume = 96 | issue = 4 | pages = 759–67 | date = October 2012 | pmid = 22952178 | doi = 10.3945/ajcn.111.024471 | url = http://www.ajcn.org/cgi/pmidlookup?view=long&pmid=22952178 | quote = 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. }}
20. ^{{cite journal | vauthors = Rasmussen B, Gilbert E, Turki A, Madden K, Elango R | title = Determination of the safety of leucine supplementation in healthy elderly men | journal = Amino Acids | volume = 48 | issue = 7 | pages = 1707–16 | date = July 2016 | pmid = 27138628 | doi = 10.1007/s00726-016-2241-0 | quote = 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 }}
21. ^{{cite journal | vauthors = Etzel MR | title = Manufacture and use of dairy protein fractions | journal = The Journal of Nutrition | volume = 134 | issue = 4 | pages = 996S–1002S | date = April 2004 | pmid = 15051860 | url = http://jn.nutrition.org/content/134/4/996S.long | doi = 10.1093/jn/134.4.996S }}
22. ^¹{{cite journal | vauthors = Kim JH, Lee C, Lee M, Wang H, Kim K, Park SJ, Yoon I, Jang J, Zhao H, Kim HK, Kwon NH, Jeong SJ, Yoo HC, Kim JH, Yang JS, Lee MY, Lee CW, Yun J, Oh SJ, Kang JS, Martinis SA, Hwang KY, Guo M, Han G, Han JM, Kim S | title = Control of leucine-dependent mTORC1 pathway through chemical intervention of leucyl-tRNA synthetase and RagD interaction | journal = Nature Communications | volume = 8 | issue = 1 | pages = 732 | date = September 2017 | pmid = 28963468 | pmc = 5622079 | doi = 10.1038/s41467-017-00785-0 | url = }}
23. ^¹{{cite journal | vauthors = Jewell JL, Russell RC, Guan KL | title = Amino acid signalling upstream of mTOR | journal = Nature Reviews Molecular Cell Biology | volume = 14 | issue = 3 | pages = 133–9 | date = Mar 2013 | pmid = 23361334 | doi = 10.1038/nrm3522 | pmc=3988467}}
24. ^{{cite journal | vauthors = Sancak Y, Peterson TR, Shaul YD, Lindquist RA, Thoreen CC, Bar-Peled L, Sabatini DM | title = The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1 | journal = Science | volume = 320 | issue = 5882 | pages = 1496–501 | date = Jun 2008 | pmid = 18497260 | pmc = 2475333 | doi = 10.1126/science.1157535 }}
25. ^{{cite journal | vauthors = Wolfson RL, Chantranupong L, Saxton RA, Shen K, Scaria SM, Cantor JR, Sabatini DM | title = Sestrin2 is a leucine sensor for the mTORC1 pathway | journal = Science | volume = 351 | issue = 6268 | pages = 43–8 | date = January 2016 | pmid = 26449471 | pmc = 4698017 | doi = 10.1126/science.aab2674 }}
26. ^{{cite journal | vauthors = Saxton RA, Knockenhauer KE, Wolfson RL, Chantranupong L, Pacold ME, Wang T, Schwartz TU, Sabatini DM | title = Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway | journal = Science | volume = 351 | issue = 6268 | pages = 53–8 | date = January 2016 | pmid = 26586190 | pmc = 4698039 | doi = 10.1126/science.aad2087 }}
27. ^{{cite journal | vauthors = Chantranupong L, Wolfson RL, Orozco JM, Saxton RA, Scaria SM, Bar-Peled L, Spooner E, Isasa M, Gygi SP, Sabatini DM | title = The Sestrins interact with GATOR2 to negatively regulate the amino-acid-sensing pathway upstream of mTORC1 | journal = Cell Reports | volume = 9 | issue = 1 | pages = 1–8 | date = October 2014 | pmid = 25263562 | pmc = 4223866 | doi = 10.1016/j.celrep.2014.09.014 }}
28. ^{{cite journal | vauthors = Rosenthal J, Angel A, Farkas J | title = Metabolic fate of leucine: a significant sterol precursor in adipose tissue and muscle | journal = Am. J. Physiol. | volume = 226 | issue = 2 | pages = 411–8 | date = February 1974 | pmid = 4855772 | doi = 10.1152/ajplegacy.1974.226.2.411 }}
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