Isoleucine

In plants and microorganisms, isoleucine is synthesized from pyruvate and alpha-ketobutyrate. This pathway is not present in humans. Enzymes involved in this biosynthesis include:{{Cite book | vauthors = Lehninger AL, Nelson DL, Cox MM |url=https://www.worldcat.org/oclc/42619569 |title=Lehninger principles of biochemistry. |date=2000 |publisher=Worth Publishers |isbn=1-57259-153-6 |edition=3rd |location=New York |oclc=42619569}}

1. Acetolactate synthase (also known as acetohydroxy acid synthase)
2. Acetohydroxy acid isomeroreductase
3. Dihydroxyacid dehydratase
4. Valine aminotransferase

Isoleucine is both a glucogenic and a ketogenic amino acid. After transamination with alpha-ketoglutarate, the carbon skeleton is oxidised and split into propionyl-CoA and acetyl-CoA. Propionyl-CoA is converted into succinyl-CoA, a TCA cycle intermediate which can be converted into oxaloacetate for gluconeogenesis (hence glucogenic). In mammals acetyl-CoA cannot be converted to carbohydrate but can be either fed into the TCA cycle by condensing with oxaloacetate to form citrate or used in the synthesis of ketone bodies (hence ketogenic) or fatty acids.{{Cite book |title=Branched chain amino acids in clinical nutrition

| volume = 1 |date=2015 | vauthors = Rajendram R, Preedy VR, Patel VB |isbn=978-1-4939-1923-9 |location=New York, New York | publisher = Humana |oclc=898999904}}

The degradation of isoleucine is impaired in the following metabolic diseases:

• Combined malonic and methylmalonic aciduria (CMAMMA)
• Maple syrup urine disease (MSUD)
• Methylmalonic acidemia
• Propionic acidemia

Isoleucine, like other branched-chain amino acids, is associated with insulin resistance: higher levels of isoleucine are observed in the blood of diabetic mice, rats, and humans.{{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 = 723–736 | date = December 2014 | pmid = 25287287 | pmc = 4424797 | doi = 10.1038/nrendo.2014.171 }} In diet-induced obese and insulin resistant mice, a diet with decreased levels of isoleucine (with or without the other branched-chain amino acids) results in reduced adiposity and improved insulin sensitivity.{{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 | display-authors = 6 | 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 = February 2018 | pmid = 29266268 | pmc = 5813603 | doi = 10.1113/JP275075 }}{{cite journal | vauthors = Yu D, Richardson NE, Green CL, Spicer AB, Murphy ME, Flores V, Jang C, Kasza I, Nikodemova M, Wakai MH, Tomasiewicz JL, Yang SE, Miller BR, Pak HH, Brinkman JA, Rojas JM, Quinn WJ, Cheng EP, Konon EN, Haider LR, Finke M, Sonsalla M, Alexander CM, Rabinowitz JD, Baur JA, Malecki KC, Lamming DW | display-authors = 6 | title = The adverse metabolic effects of branched-chain amino acids are mediated by isoleucine and valine | journal = Cell Metabolism | volume = 33 | issue = 5 | pages = 905–922.e6 | date = May 2021 | pmid = 33887198 | pmc = 8102360 | doi = 10.1016/j.cmet.2021.03.025 }} Reduced dietary levels of isoleucine are required for the beneficial metabolic effects of a low protein diet. In humans, a protein restricted diet lowers blood levels of isoleucine and decreases fasting blood glucose levels.{{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 | display-authors = 6 | 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 }} Mice fed a low isoleucine diet are leaner, live longer, and are less frail.{{cite journal | vauthors = Green CL, Trautman ME, Chaiyakul K, Jain R, Alam YH, Babygirija R, Pak HH, Sonsalla MM, Calubag MF, Yeh CY, Bleicher A, Novak G, Liu TT, Newman S, Ricke WA, Matkowskyj KA, Ong IM, Jang C, Simcox J, Lamming DW | display-authors = 6 | title = Dietary restriction of isoleucine increases healthspan and lifespan of genetically heterogeneous mice | journal = Cell Metabolism | volume = 35 | issue = 11 | pages = 1976–1995.e6 | date = November 2023 | pmid = 37939658 | pmc = 10655617 | doi = 10.1016/j.cmet.2023.10.005 }} In humans, higher dietary levels of isoleucine are associated with greater body mass index.

The Food and Nutrition Board (FNB) of the U.S. Institute of Medicine has set Recommended Dietary Allowances (RDAs) for essential amino acids in 2002. For adults 19 years and older, 19 mg of isoleucine/kg body weight is required daily.{{Cite book |url=https://www.worldcat.org/oclc/57373786 |title=Dietary reference intakes for energy, carbohydrate, fiber, fat, fatty acids, cholesterol, protein, and amino acids |date=2005 |publisher=National Academies Press | author =Institute of Medicine. Panel on Macronutrients, Institute of Medicine. Standing Committee on the Scientific Evaluation of Dietary Reference Intakes |isbn=0-309-08537-3 |location=Washington, D.C. |oclc=57373786}}

Beside its biological role as a nutrient, isoleucine also participates in regulation of glucose metabolism. Isoleucine is an essential component of many proteins. As an essential amino acid, isoleucine must be ingested or protein production in the cell will be disrupted. Fetal hemoglobin is one of the many proteins that require isoleucine.{{cite journal | vauthors = Honig GR | title = Inhibition of synthesis of fetal hemoglobin by an isoleucine analogue | journal = The Journal of Clinical Investigation | volume = 46 | issue = 11 | pages = 1778–1784 | date = November 1967 | pmid = 4964832 | pmc = 292928 | doi = 10.1172/JCI105668 }} Isoleucine is present in the gamma chain of fetal hemoglobin and must be present for the protein to form.

Genetic diseases can change the consumption requirements of isoleucine. Amino acids cannot be stored in the body. Buildup of excess amino acids will cause a buildup of toxic molecules so, humans have many pathways to degrade each amino acid when the need for protein synthesis has been met.{{cite journal | vauthors = Korman SH | title = Inborn errors of isoleucine degradation: a review | journal = Molecular Genetics and Metabolism | volume = 89 | issue = 4 | pages = 289–299 | date = December 2006 | pmid = 16950638 | doi = 10.1016/j.ymgme.2006.07.010 }} Mutations in isoleucine-degrading enzymes can lead to dangerous buildup of isoleucine and its toxic derivative. One example is maple syrup urine disease (MSUD), a disorder that leaves people unable to breakdown isoleucine, valine, and leucine.{{cite book | vauthors = Hassan SA, Gupta V | chapter = Maple Syrup Urine Disease |date=2023 | chapter-url = http://www.ncbi.nlm.nih.gov/books/NBK557773/ | title = StatPearls |access-date=2023-04-16 |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=32491705 }} People with MSUD manage their disease by a reduced intake of all three of those amino acids alongside drugs that help excrete built-up toxins. {{cite journal | vauthors = Brunetti-Pierri N, Lanpher B, Erez A, Ananieva EA, Islam M, Marini JC, Sun Q, Yu C, Hegde M, Li J, Wynn RM, Chuang DT, Hutson S, Lee B | display-authors = 6 | title = Phenylbutyrate therapy for maple syrup urine disease | journal = Human Molecular Genetics | volume = 20 | issue = 4 | pages = 631–640 | date = February 2011 | pmid = 21098507 | pmc = 3024040 | doi = 10.1093/hmg/ddq507 }}

Many animals and plants are dietary sources of isoleucine as a component of proteins. Foods that have high amounts of isoleucine include eggs, soy protein, seaweed, turkey, chicken, lamb, cheese, and fish.

Routes to isoleucine are numerous. One common multistep procedure starts from 2-bromobutane and diethylmalonate.{{Cite journal | vauthors = Marvel CS | veditors = Bachmann WE, Holmes DW |date=1941 |title=dl-Isoleucine |url=https://doi.org/10.15227/orgsyn.021.0060 |journal=Organic Syntheses |language=en |volume=21 |pages=60 |doi=10.15227/orgsyn.021.0060 |issn=0078-6209|url-access=subscription }} Synthetic isoleucine was first reported in 1905 by French chemists Bouveault and Locquin.{{Cite journal | vauthors = Bouvealt L, Locquin R |date=1905 |title=Sur la synthése d'une nouvelle leucine |journal=Compt. Rend. |issue=141 |pages=115–117}}

German chemist Felix Ehrlich discovered isoleucine while studying the composition of beet-sugar molasses 1903.{{Cite journal | vauthors = Vickery HB, Schmidt CL |date= October 1931 |title=The History of the Discovery of the Amino Acids. |journal=Chemical Reviews |language=en |volume=9 |issue=2 |pages=169–318 |doi=10.1021/cr60033a001 |issn=0009-2665}} In 1907 Ehrlich carried out further studies on fibrin, egg albumin, gluten, and beef muscle in 1907. These studies verified the natural composition of isoleucine. Ehrlich published his own synthesis of isoleucine in 1908. {{Cite journal | vauthors = Ehrlich F |date=1908 |title=Über eine Synthese des Isoleucins |journal=Chemische Berichte |volume=41 |issue=1 |pages=1453–1458 |doi=10.1002/cber.190804101266 |issn=0365-9496|url=https://zenodo.org/record/2512647 }}

• Alloisoleucine, the diasteromer of isoleucine
• [https://tools.myfooddata.com/nutrient-ranking-tool/protein+isoleucine/beans-and-lentils+dairy-and-egg-products+fish+grains-and-pasta+meats+nuts-and-seeds/highest+lowest/household/common/no Low Isoleucine protein foods]

{{Reflist}}

• [https://metacyc.org/META/NEW-IMAGE?type=PATHWAY&object=ILEUDEG-PWY Isoleucine degradation]
• [https://metacyc.org/META/NEW-IMAGE?type=PATHWAY&object=ILEUSYN-PWY Isoleucine biosynthesis]

{{Amino acids}}

{{Amino acid metabolism intermediates}}

Category:Alpha-Amino acids

Category:Proteinogenic amino acids

Category:Glucogenic amino acids

Category:Ketogenic amino acids

Category:Branched-chain amino acids

Category:Essential amino acids