The AtlasAmino acidsNonpolar, aliphatic

IsoleucineIle · I

The branched-chain amino acid with a second stereocentre: a twin, alloisoleucine, that only maple syrup urine disease piles up; a breakdown that ends half as ketone fuel and half as glucose; and the enzyme an antibiotic jams.

Status Reference · not yet an episodeSources 23Reviewed October 2026

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Skeletal formula — every corner and every line end is a carbon, and the hydrogens on carbon are left implied.

Molecule · Ile · 9 heavy atoms

Isoleucine

C₆H₁₃NO₂131.18 g/mol

Built fromthe charted ones open their own entry

C6CarbonH13Hydrogen N Nitrogen O2Oxygen

Codes: Ile · I
Formula: C₆H₁₃NO₂
Molar mass: 131.18 g/mol
Systematic name: (2S,3S)-2-amino-3-methylpentanoic acid
Side chain: sec-Butyl: four carbons, branched at the β-carbon, which is itself a stereocentre.
Class: Nonpolar, aliphatic
In the diet: Essential
Carbon skeleton: Glucogenic and ketogenic
pKa: α-COOH 2.36 · α-NH₃⁺ 9.68
Isoelectric point: pH 6.02
Hydropathy: +4.5 (Kyte–Doolittle)
Codons: AUU AUC AUA
Main transporters: SLC7A5 (LAT1)

pKa and isoelectric point: Nelson and Cox, Lehninger Principles of Biochemistry, table of amino acid properties (free amino acid, 25 °C). Hydropathy: Kyte and Doolittle, J Mol Biol 1982. Essentiality: Reeds, J Nutr 2000. Formula and mass computed from the structure.

In brief

What it is

One of the three branched-chain amino acids, and the only one with a second stereocentre, in its side chain. Essential: the body cannot make it, and the first two steps of its breakdown are shared with leucine and valine ¹.

Why it matters

Isoleucine is the source of alloisoleucine, the one pathognomonic marker of maple syrup urine disease ^2,3. In mice, cutting isoleucine alone reproduced much of the metabolic benefit of a low-protein diet, and extended life ^4,5. And mupirocin, the ointment used against MRSA, works by blocking the bacterial enzyme that loads isoleucine onto its tRNA ⁶.

Where it runs short

Medical foods for methylmalonic and propionic acidaemia leave isoleucine and valine out; patients on them ran low and had to be given the two back ^7,8.

Where it turns

High isoleucine together with leucine and valine, and above all alloisoleucine above 5 µmol/L, means maple syrup urine disease: the cut-off was exceeded in 2,451 of 2,453 samples from classic patients ⁹.

Healthy adults carry about 1.9 µmol/L of alloisoleucine. It is a normal by-product of isoleucine, not a foreign substance ^9,10.

The molecule

Isoleucine, leucine and valine are the most hydrophobic of the amino acids, and the three help set the structure of globular proteins and the way membrane proteins sit in the lipid bilayer ¹.

It branches at the β-carbon, as valine does, and like valine it prefers β-sheet, where leucine prefers the α-helix. Swapping one branched-chain residue for another is usually conservative, but not always ¹.

The β-carbon is also a stereocentre, which makes isoleucine one of only two standard amino acids, with threonine, to have two. Its natural diastereomer, L-alloisoleucine, differs only at that second centre ¹⁰.

StereochemistryTwo stereocentres, so four stereoisomers; proteins use (2S,3S). L-Alloisoleucine, (2S,3R), is made from it in the body ¹⁰.

Charge · pHIsoleucine carries almost no net charge at the pH of blood.

Move across the chart to read the charge at any pH.

Computed from its pKa values (α-carboxyl 2.36, α-amino 9.68) by the Henderson–Hasselbalch equation, for the free amino acid in water at 25 °C. Inside a folded protein the same groups can shift by a unit or more. The faint lines are the other amino acids.

HydropathyIsoleucine scores +4.5: the most water-avoiding of the twenty.

Kyte–Doolittle hydropathy index: positive values avoid water and tend to be buried inside a folded protein, negative values sit on its surface. Each letter is an amino acid; choose one to open it.

The genetic codeIsoleucine has 3 codons. The code is redundant, so most single-letter changes at the third position still write isoleucine.

The 64 codons of the standard genetic code. Codons for isoleucine are marked.
1st ↓ 2nd →	U	C	A	G	3rd
U	UUUPhe	UCUSer	UAUTyr	UGUCys	U
	UUCPhe	UCCSer	UACTyr	UGCCys	C
	UUALeu	UCASer	UAAStop	UGAStop	A
	UUGLeu	UCGSer	UAGStop	UGGTrp	G
C	CUULeu	CCUPro	CAUHis	CGUArg	U
	CUCLeu	CCCPro	CACHis	CGCArg	C
	CUALeu	CCAPro	CAAGln	CGAArg	A
	CUGLeu	CCGPro	CAGGln	CGGArg	G
A	AUUIle	ACUThr	AAUAsn	AGUSer	U
	AUCIle	ACCThr	AACAsn	AGCSer	C
	AUAIle	ACAThr	AAALys	AGAArg	A
	AUGMet	ACGThr	AAGLys	AGGArg	G
G	GUUVal	GCUAla	GAUAsp	GGUGly	U
	GUCVal	GCCAla	GACAsp	GGCGly	C
	GUAVal	GCAAla	GAAGlu	GGAGly	A
	GUGVal	GCGAla	GAGGlu	GGGGly	G

The three branched chainsUsually listed together and sold as one product. They are three different molecules.

	Isoleucine	Leucine	Valine
Branch	At the β-carbon, which is a second stereocentre	At the γ-carbon	At the β-carbon
Preferred structure	β-sheet ¹	α-helix ¹	β-sheet ¹
Carbon goes to	Acetyl-CoA and propionyl-CoA ^1,8	Acetyl-CoA and acetoacetate ¹	Propionyl-CoA ⁸
Adult requirement	20 mg/kg/day ¹¹	39 mg/kg/day ¹¹	26 mg/kg/day ¹¹
A disorder of its own pathway	SBCAD, HSD10 and β-ketothiolase deficiency ^12,13	Isovaleric acidaemia ¹⁴	HIBCH and ECHS1 deficiency ¹⁵
Cut from the diet of mice	Better insulin sensitivity, higher energy expenditure ⁴; longer life in both sexes ⁵	No such effect ⁴	Similar, more modest ⁴; longer life in males ¹⁶

All three share their first two breakdown steps and the disease of the second one, maple syrup urine disease ^1,2.

Where it comes from

Humans cannot make it; bacteria and plants do, and industry uses Corynebacterium glutamicum ¹⁷.

Unlike most amino acids, the branched chains largely escape metabolism in the gut and liver on first pass ¹.

EssentialHumans cannot make it. The international adult requirement is 20 mg per kilogram per day ¹¹. Isotope studies measured leucine and valine on their own but not isoleucine; for the three together, young men needed 144 mg/kg/day ¹⁸.

How much

20 mg per kilogram per day for adults, internationally ¹¹: about 1.4 g a day at 70 kg.

Where it is in food

All protein; the branched-chain amino acids are about 20 to 25% of most dietary proteins ¹.

In the bottle · fermentedIndustrial branched-chain amino acids are made mainly by fermentation with Corynebacterium glutamicum, in strains engineered for yield ¹⁷.

What the body does with it

Mostly, it is built into protein. The branched-chain amino acids make up about 20 to 25% of most dietary proteins, and their place in nature is explained by protein structure rather than by their metabolic side roles ¹.

It is also a signal in its own right, at least in mice. A low-isoleucine diet increased the liver’s insulin sensitivity and ketone production and raised energy expenditure through the FGF21–UCP1 axis; low valine did something similar but smaller, and low leucine did not ⁴.

Across people, variation in dietary isoleucine helped explain differences in body mass index, an association rather than a test of cause ⁴.

In three sentences each

Two stereocentres, one twin

L-Isoleucine is (2S,3S); L-alloisoleucine is (2S,3R). Transamination scrambles the side-chain centre of the keto acid as an unavoidable by-product, and re-amination of that keto acid gives a little alloisoleucine ¹⁰.

Half ketone, half glucose

After the two shared steps, isoleucine has its own pathway, ending in acetyl-CoA, which can make ketone bodies, and propionyl-CoA, which can make glucose ^1,8.

An antibiotic’s target

Mupirocin, made by Pseudomonas fluorescens, inhibits isoleucyl-tRNA synthetase. High-level resistance in Staphylococcus aureus comes from a plasmid carrying a second, more eukaryote-like copy of the enzyme ⁶.

How it is made, moved and broken down

The first two steps are shared with leucine and valine: transamination by BCAT, then oxidative decarboxylation by the branched-chain keto acid dehydrogenase complex, BCKDH ¹.

After that, isoleucine has its own route, through short/branched-chain acyl-CoA dehydrogenase (SBCAD) to tiglyl-CoA, then through HSD10 and β-ketothiolase, two adjacent enzymes, to acetyl-CoA and propionyl-CoA ^12,13.

Most tissues oxidise branched-chain amino acids. In mice the largest amounts went through muscle, brown fat, liver, kidney and heart, and the pancreas took a fifth of its Krebs-cycle carbon from them ¹⁹.

Carbon skeleton · glucogenic and ketogenicIts carbons leave as acetyl-CoA, which is ketogenic, and propionyl-CoA, which becomes succinyl-CoA and can make glucose ^1,8.

Isoleucine’s own routeTwo shared steps, then four of its own ^1,12,13.

Isoleucine
Branched-chain aminotransferaseBCAT1, BCAT2 · vitamin B6
(S)-3-Methyl-2-oxopentanoate
BCKDH complexBCKDHA, BCKDHB, DBT · thiamine, lipoate, NAD⁺
2-Methylbutyryl-CoA
SBCADACADSB · FAD
Tiglyl-CoA
Enoyl-CoA hydrataseECHS1
2-Methyl-3-hydroxybutyryl-CoA
HSD10HSD17B10 · NAD⁺
2-Methylacetoacetyl-CoA
β-KetothiolaseACAT1 · CoA
Acetyl-CoA + propionyl-CoA

Propionyl-CoA into the Krebs cycleThe steps that fail in propionic and methylmalonic acidaemia ^7,8.

Propionyl-CoA
Propionyl-CoA carboxylasePCCA, PCCB · biotin
Methylmalonyl-CoA
Methylmalonyl-CoA mutaseMMUT · vitamin B12
Succinyl-CoA

Where alloisoleucine comes fromA by-product of transamination ¹⁰.

L-Isoleucine (2S,3S)
TransaminationBCAT1, BCAT2 · vitamin B6
(S)- and (R)-3-methyl-2-oxopentanoate
Re-aminationBCAT1, BCAT2 · vitamin B6
L-Alloisoleucine (2S,3R)

How it crosses membranes

SLC7A5 · LAT1the blood–brain barrier — the large neutral amino acid carrier; branched-chain amino acids compete there with tryptophan and tyrosine ²⁰

Where it matters most

Skeletal muscle: The largest share of branched-chain oxidation in mice ¹⁹.
Liver and brown fat: Major oxidisers, and where a low-isoleucine diet changes metabolism ^4,19.
Pancreas: In mice, takes 20% of its Krebs-cycle carbon from the branched chains ¹⁹.
Brain: Entry competes with tryptophan and tyrosine at the blood–brain barrier ²⁰.

When it goes wrong

Inherited

Maple syrup urine disease

BCKDHA, BCKDHB, DBT · autosomal recessive

The shared second step fails, so all three branched-chain amino acids and their keto acids build up, with alloisoleucine the pathognomonic marker and a maple-syrup smell in urine and earwax; untreated, it causes neurological damage and death ². In 184 patients over three decades, strict diet kept levels acceptable but did not fully prevent cognitive and psychiatric disability ²¹.

How it is foundNewborn screening, then alloisoleucine ^3,9.

Inherited

SBCAD deficiency

ACADSB · autosomal recessive

The first isoleucine-only step. Found on newborn screening by a raised C5-carnitine, with 2-methylbutyrylglycine in urine; about 10% of 162 reported patients had symptoms ¹².

How it is foundBlood C5-carnitine, urine 2-methylbutyrylglycine, ACADSB sequencing ¹².

Inherited

HSD10 disease and β-ketothiolase deficiency

HSD17B10, ACAT1 · X-linked (HSD10); autosomal recessive (ACAT1)

Two adjacent steps, nearly the same urine metabolites, 2-methyl-3-hydroxybutyrate and tiglylglycine, and very different outcomes: in six patients, β-ketothiolase deficiency went far better than HSD10 disease ¹³.

How it is foundUrine organic acids, then DNA, which was what separated them ¹³.

Inherited

Methylmalonic and propionic acidaemia

MMUT, PCCA, PCCB · autosomal recessive

Isoleucine and valine are two of the amino acids that feed propionyl-CoA, so they are restricted. Medical foods that removed them and added leucine left 61 patients short of valine and isoleucine, and growth fell as leucine intake rose relative to valine ⁷; in 71 more, the mixtures lowered isoleucine and valine, which then had to be supplemented ⁸.

How it is foundNewborn screening; plasma amino acids through treatment ⁷.

Drug

Mupirocin

An antibiotic that inhibits bacterial isoleucyl-tRNA synthetase, used since 1985 to help prevent infection with methicillin-resistant Staphylococcus aureus, particularly in hospitals. Resistance was first seen in 1987 ⁶.

How it is measured

Plasma isoleucine is part of the amino acid panel ²². Newborn screening measures leucine, isoleucine and valine by tandem mass spectrometry, and babies on intravenous nutrition can screen falsely high, one reason the second-tier alloisoleucine test exists ³.

For the isoleucine-only disorders, the useful samples are blood acylcarnitines and urine acylglycines and organic acids: 2-methylbutyrylglycine for SBCAD deficiency, and 2-methyl-3-hydroxybutyrate with tiglylglycine for HSD10 and β-ketothiolase deficiency ^12,13.

Plasma alloisoleucineThe pathognomonic marker of maple syrup urine disease ^2,3.Above 5 µmol/L in 2,451 of 2,453 samples from classic MSUD, and not raised in diabetes, ketotic hypoglycaemia, phenylketonuria or carrier parents ⁹.Newborn screening by tandem mass spectrometry cannot see it, because it has the same mass as leucine and isoleucine; a second-tier LC-MS/MS test separates them ³.
Urine 2-methylbutyrylglycineThe hallmark of SBCAD deficiency, the isoleucine-only step after the shared ones; suspected from a raised C5-carnitine on newborn screening ¹².A raised C5-carnitine has to be told apart from isovaleric acidaemia and from pivalic acid exposure ¹².About 10% of 162 reported patients had symptoms, so a positive screen is often a biochemical finding rather than a disease ¹².

Food, supplements and the evidence

Establishedreplicated in people, for a named outcome

In maple syrup urine disease and in methylmalonic and propionic acidaemia, isoleucine is prescribed and measured, and too little is as much a problem as too much ^7,8.

Uncertainsmall, short, mixed, surrogate or preclinical

Eating less isoleucine. In mice it improved metabolic health, reduced frailty and extended life, more in males ⁵; in people there is an association with body mass index, and no trial ⁴.

Sold asthe claim on the label, against the evidence

BCAA powders as muscle builders. Muscle protein needs all the essential amino acids, and no human study had measured muscle protein synthesis after oral BCAAs alone; infused, they lowered both synthesis and breakdown ²³.

What is strange about it

Isoleucine, leucine and alloisoleucine weigh exactly the same, so the mass spectrometer at the heart of newborn screening sees them as one ³.

Its twin is always present. A large oral load of isoleucine, 1,527 µmol per kilogram, raised alloisoleucine in three healthy people by only about 5 µmol/L ⁹.

HSD10 and β-ketothiolase sit next to each other on the isoleucine pathway and leave nearly the same urine pattern, yet HSD10 disease went much worse; the enzyme has other jobs, including neurosteroid metabolism ¹³.

Where it connects

In the Atlas

LeuLeucineNonpolar, aliphatic ValValineNonpolar, aliphatic ThrThreoninePolar, uncharged MetMethionineNonpolar, aliphatic CoCobaltElement

Topics on the map

On the map

A star in The essential amino acids, one of 14. Restricting it alone extends lifespan and improves metabolic health in mice — and it is in every scoop of BCAAs sold for the opposite purpose.

Find it on the map

Sources

23 sources, numbered as they are cited. Every one was checked against PubMed or its publisher before it was cited here; the note under each says what it shows and what it does not.

1
Brosnan JT, Brosnan ME. Branched-chain amino acids: enzyme and substrate regulation.J Nutr · 2006 · 136(1 Suppl):207S–211Sdoi:10.1093/jn/136.1.207S · PMID 16365084
Structure, first-pass escape and the shared first steps of breakdown.
2
Blackburn PR, Gass JM, Vairo FPE, et al. Maple syrup urine disease: mechanisms and management.Appl Clin Genet · 2017 · 10:57–66doi:10.2147/TACG.S125962 · PMID 28919799
Alloisoleucine as the pathognomonic marker.
3
Oglesbee D, Sanders KA, Lacey JM, et al. Second-tier test for quantification of alloisoleucine and branched-chain amino acids in dried blood spots to improve newborn screening for maple syrup urine disease (MSUD).Clin Chem · 2008 · 54(3):542–549doi:10.1373/clinchem.2007.098434 · PMID 18178665
Isobaric amino acids and the second-tier test.
4
Yu D, Richardson NE, Green CL, et al. The adverse metabolic effects of branched-chain amino acids are mediated by isoleucine and valine.Cell Metab · 2021 · 33(5):905–922.e6doi:10.1016/j.cmet.2021.03.025 · PMID 33887198
Each branched chain has distinct effects in mice.
5
Green CL, Trautman ME, Chaiyakul K, et al. Dietary restriction of isoleucine increases healthspan and lifespan of genetically heterogeneous mice.Cell Metab · 2023 · 35(11):1976–1995.e6doi:10.1016/j.cmet.2023.10.005 · PMID 37939658
UM-HET3 mice, both sexes.
6
Gurney R, Thomas CM. Mupirocin: biosynthesis, special features and applications of an antibiotic from a gram-negative bacterium.Appl Microbiol Biotechnol · 2011 · 90(1):11–21doi:10.1007/s00253-011-3128-3 · PMID 21336932
Isoleucyl-tRNA synthetase and resistance.
7
Manoli I, Myles JG, Sloan JL, et al. A critical reappraisal of dietary practices in methylmalonic acidemia raises concerns about the safety of medical foods. Part 1: isolated methylmalonic acidemias.Genet Med · 2016 · 18(4):386–395doi:10.1038/gim.2015.102 · PMID 26270765
Leucine-heavy medical foods and growth.
8
Margoses D, Imbard A, Pontoizeau C, et al. Nutritional management in severe methylmalonic and propionic acidemias: how much medical food is too much?J Inherit Metab Dis · 2026 · 49(1):e70114doi:10.1002/jimd.70114 · PMID 41344680
71 patients; isoleucine and valine fall on amino acid mixtures.
9
Schadewaldt P, Bodner-Leidecker A, Hammen HW, et al. Significance of L-alloisoleucine in plasma for diagnosis of maple syrup urine disease.Clin Chem · 1999 · 45(10):1734–1740PMID 10508118
Reference values and the 5 µmol/L cut-off.
10
Schadewaldt P, Bodner-Leidecker A, Hammen HW, et al. Formation of L-alloisoleucine in vivo: an L-[13C]isoleucine study in man.Pediatr Res · 2000 · 47(2):271–277doi:10.1203/00006450-200002000-00020 · PMID 10674358
Alloisoleucine as a by-product of transamination.
11
Joint WHO/FAO/UNU Expert Consultation. Protein and amino acid requirements in human nutrition.World Health Organ Tech Rep Ser · 2007 · (935):1–265PMID 18330140
The international requirement figures.
12
Porta F, Chiesa N, Martinelli D, et al. Clinical, biochemical, and molecular spectrum of short/branched-chain acyl-CoA dehydrogenase deficiency: two new cases and review of literature.J Pediatr Endocrinol Metab · 2019 · 32(2):101–108doi:10.1515/jpem-2018-0311 · PMID 30730842
162 patients reviewed.
13
Su L, Li X, Lin R, et al. Clinical and molecular analysis of 6 Chinese patients with isoleucine metabolism defects: identification of 3 novel mutations in the HSD17B10 and ACAT1 gene.Metab Brain Dis · 2017 · 32(6):2063–2071doi:10.1007/s11011-017-0097-y · PMID 28875337
HSD10 and β-ketothiolase deficiency compared.
14
Vockley J, Ensenauer R. Isovaleric acidemia: new aspects of genetic and phenotypic heterogeneity.Am J Med Genet C Semin Med Genet · 2006 · 142C(2):95–103doi:10.1002/ajmg.c.30089 · PMID 16602101
The leucine pathway's best-known disorder.
15
Peters H, Ferdinandusse S, Ruiter JP, et al. Metabolite studies in HIBCH and ECHS1 defects: implications for screening.Mol Genet Metab · 2015 · 115(4):168–173doi:10.1016/j.ymgme.2015.06.008 · PMID 26163321
The valine pathway's own disorders.
16
Calubag MF, Ademi I, Green CL, et al. Lifelong restriction of dietary valine has sex-specific benefits for health and lifespan in mice.Nat Aging · 2026 · 6(8):1611–1630doi:10.1038/s43587-026-01169-0 · PMID 42498891
Median male lifespan up 23%.
17
Reifenberg P, Zimmer A. Branched-chain amino acids: physico-chemical properties, industrial synthesis and role in signaling, metabolism and energy production.Amino Acids · 2024 · 56(1):51doi:10.1007/s00726-024-03417-2 · PMID 39198298
Industrial production with Corynebacterium glutamicum.
18
Riazi R, Wykes LJ, Ball RO, et al. The total branched-chain amino acid requirement in young healthy adult men determined by indicator amino acid oxidation by use of L-[1-13C]phenylalanine.J Nutr · 2003 · 133(5):1383–1389doi:10.1093/jn/133.5.1383 · PMID 12730426
144 mg/kg/day for the three together.
19
Neinast MD, Jang C, Hui S, et al. Quantitative analysis of the whole-body metabolic fate of branched-chain amino acids.Cell Metab · 2019 · 29(2):417–429.e4doi:10.1016/j.cmet.2018.10.013 · PMID 30449684
Isotope tracing of oxidation by tissue, in mice.
20
Fernstrom JD. Large neutral amino acids: dietary effects on brain neurochemistry and function.Amino Acids · 2013 · 45(3):419–430doi:10.1007/s00726-012-1330-y · PMID 22677921
Competition at the blood–brain barrier.
21
Strauss KA, Carson VJ, Soltys K, et al. Branched-chain α-ketoacid dehydrogenase deficiency (maple syrup urine disease): treatment, biomarkers, and outcomes.Mol Genet Metab · 2020 · 129(3):193–206doi:10.1016/j.ymgme.2020.01.006 · PMID 31980395
184 patients over three decades.
22
Sharer JD, De Biase I, Matern D, et al. Laboratory analysis of amino acids, 2018 revision: a technical standard of the American College of Medical Genetics and Genomics (ACMG).Genet Med · 2018 · 20(12):1499–1507doi:10.1038/s41436-018-0328-6 · PMID 30459394
Methods for amino acid analysis.
23
Wolfe RR. Branched-chain amino acids and muscle protein synthesis in humans: myth or reality?J Int Soc Sports Nutr · 2017 · 14:30doi:10.1186/s12970-017-0184-9 · PMID 28852372
No human study of oral BCAAs alone.

This is education, not medical advice. Nothing on this page is written with knowledge of your history, your medications or your risks, and nothing here is a dose. Do not start or stop any treatment on the basis of it — talk to your own physician. Read the full medical disclaimer.

In brief

The molecule

Where it comes from

What the body does with it

Two stereocentres, one twin

Half ketone, half glucose

An antibiotic’s target

How it is made, moved and broken down

Where it matters most

When it goes wrong

Maple syrup urine disease

SBCAD deficiency

HSD10 disease and β-ketothiolase deficiency

Methylmalonic and propionic acidaemia

Mupirocin

How it is measured

Food, supplements and the evidence

What is strange about it

Where it connects

Sources

Every source, in your inbox.