The AtlasAmino acidsNonpolar, aliphatic
ValineVal · V
The smallest of the branched chains: the residue that, put in place of one glutamate, makes sickle hemoglobin; the amino acid penicillin is built from; and a breakdown route through a reactive intermediate that the cell has to clear quickly.
Molecule · Val · 8 heavy atoms
Valine
C5H11NO2117.15 g/mol
The smallest of the branched chains: the residue that, put in place of one glutamate, makes sickle hemoglobin; the amino acid penicillin is built from; and a breakdown route through a reactive intermediate that the cell has to clear quickly.
Built fromthe charted ones open their own entry
- Codes
- Val · V
- Formula
- C5H11NO2
- Molar mass
- 117.15 g/mol
- Systematic name
- (2S)-2-amino-3-methylbutanoic acid
- Side chain
- Isopropyl: three carbons, branched at the β-carbon.
- Class
- Nonpolar, aliphatic
- In the diet
- Essential
- Carbon skeleton
- Glucogenic
- pKa
- α-COOH 2.32 · α-NH3+ 9.62
- Isoelectric point
- pH 5.97
- Hydropathy
- +4.2 (Kyte–Doolittle)
- Codons
GUUGUCGUAGUG- 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, with an isopropyl side chain branched at the β-carbon. Essential; its carbon ends as propionyl-CoA, so it is glucogenic only 1,2.
Why it matters
One valine in place of a glutamate at position 6 of β-globin is sickle cell disease 3,4. Valine’s breakdown passes through methacrylyl-CoA, and when the two enzymes that clear it, ECHS1 and HIBCH, fail, the result is Leigh-like brain disease 5,6. And 3-hydroxyisobutyrate, a valine intermediate, tracks insulin resistance 7,8.
Where it runs short
Medical foods for methylmalonic and propionic acidemia remove valine and add leucine; in 61 patients, weight and height for age fell as the leucine-to-valine intake ratio rose 9.
Where it turns
High valine with the other branched chains means maple syrup urine disease 10. Its intermediate 3-hydroxyisobutyrate rises with blood glucose and in type 2 diabetes 7.
The valine-pathway disorders are found not by valine itself but by what its reactive intermediates leave in urine 5,6.
The molecule
Valine is the smallest of the branched chains, an isopropyl group on the β-carbon. Like isoleucine it prefers β-sheet, where leucine prefers the helix, and the three are the most hydrophobic of the amino acids 1.
Put a nonpolar valine where a charged glutamate belongs, on the surface of β-globin, and you have sickle cell disease: hemoglobin carrying it can polymerize when it gives up its oxygen 3,4.
StereochemistryL-Valine is (S). Penicillin carries D-valine: the L-valine it starts from is inverted while the ACV tripeptide is assembled 11.
Move across the chart to read the charge at any pH.
Computed from its pKa values (α-carboxyl 2.32, α-amino 9.62) 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.
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.
| 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 |
| Sickle: valine | Normal: glutamate | |
|---|---|---|
| Residue 6 of β-globin | Valine 3,12 | Glutamic acid 3,12 |
| Side chain | Nonpolar, uncharged | Acidic, negatively charged |
| Deoxygenated | Can polymerize 4 | Stays in solution |
| Red cell | Sickles and is destroyed early 4 | Flexible, full lifespan |
| One copy | Sickle cell trait, with less severe malaria 12 | No effect |
| Two copies | Sickle cell anemia 12 | Normal hemoglobin |
Counting the initiating methionine, as modern variant names do, the same change is written p.Glu7Val 13.
Where it comes from
Humans cannot make it. Industry ferments it with engineered Escherichia coli and Corynebacterium glutamicum 14,15.
Most of it goes to feed, where adding valine and other essential amino acids lets pig and chicken rations carry less crude protein 15. More is not better there either, and the dose-response has been measured. 960 day-old male broilers were split between diets supplying 100% or 150% of the valine requirement, 24 replicates per treatment, to day 42. At day 14 the high-valine birds had higher plasma valine and nothing else different, including weight. By day 42 they had higher plasma valine and LOWER body weight (p = 0.018), with significantly reduced plasma leucine and isoleucine, a positive correlation between plasma leucine and weight, and raised methylmalonic acid, 2-hydroxyisovaleric acid and α-ketoglutarate — methylmalonic acid and 2-hydroxyisovaleric acid both correlating negatively with weight. γ-Tocopherol fell and tracked inversely with valine 16. The authors read it as branched-chain antagonism followed by catabolic by-products accumulating and the antioxidant defense being used up: the three branched chains compete, so adding one crowds out the other two.
EssentialHumans cannot make it. The 1985 requirement of 10 mg/kg/day came from nitrogen balance and was too low; a 24-hour isotope study in Indian men put the breakpoint at 17 17, and the international adult figure is now 26 18.
How much
26 mg per kilogram per day for adults 18: about 1.8 g a day at 70 kg.
Where it is in food
- All protein; the branched chains are about 20 to 25% of most dietary proteins 1.
In the bottle · fermentedFermented with engineered Escherichia coli and Corynebacterium glutamicum. Used in parenteral nutrition, as a building block for herbicides and antiviral drugs, and increasingly in animal feed 14.
What the body does with it
In protein, valine is mainly structural, as the other branched chains are 1.
Blood-forming stem cells depend on it. Mouse and human hematopoietic stem cells failed to proliferate without valine, and a valine-restricted diet emptied the mouse marrow niche enough for donor cells to engraft without irradiation or chemotherapy 19.
T-cell leukemia leans on it too. NOTCH1 drives up the enzyme that loads valine onto its tRNA, and restricting dietary valine in mice lowered the leukemic burden: it cut the translation of mitochondrial complex I subunits, so the complex assembled poorly 20. That finding has now been reproduced in a second, common solid tumor through a different enzyme. METTL1, which installs N7-methylguanosine on transfer RNAs, is overexpressed in pancreatic ductal adenocarcinoma and higher expression tracks worse survival; deleting it selectively reduced m7G-modified VALINE tRNAs — Val-AAC, Val-CAC and Val-TAC — which impaired translation of valine-enriched oxidative phosphorylation transcripts and disrupted mitochondrial respiration. Valine tRNA levels were raised in the tumor tissue, and depleting them reproduced the effect of losing METTL1 21. Two cancers, two different modifying enzymes, and the same bottleneck: how much valine-charged tRNA there is decides how well the mitochondria get built.
Penicillins and cephalosporins start as a tripeptide of aminoadipate, cysteine and valine, assembled by an enzyme rather than a ribosome 11.
How a human cell senses how much valine it has was answered in 2024 and un-answered in 2026, and the sequence is worth recording. The 2024 paper reported that human histone deacetylase 6 is the valine sensor, binding valine directly through a primate-specific SE14 repeat domain; that the nuclear-cytoplasmic shuttling of human but not mouse HDAC6 is controlled by intracellular valine; that valine deprivation keeps HDAC6 in the nucleus and causes DNA damage by deacetylating TET2 and driving active DNA demethylation; and that dietary valine restriction inhibited tumor growth in xenograft and patient-derived xenograft models and improved the efficacy of PARP inhibitors 22. Nature retracted it in 2026, with no reason stated in the record, and PubMed now flags the original as a retracted publication 23. That was the strongest published argument for dietary valine restriction as cancer therapy, and the mechanism by which human cells were said to read their own valine supply. Neither is available any more.
In three sentences each
One residue, one disease
Sickle hemoglobin differs from normal at a single residue: valine for glutamic acid at position 6 of the β chain 3,12. Hemoglobin carrying it can polymerize, and red cells full of polymer sickle and break 4.
A pathway that sheds its CoA
Valine is the branched chain whose breakdown releases a free acid midway: HIBCH hydrolyzes 3-hydroxyisobutyryl-CoA to 3-hydroxyisobutyrate, which muscle and fat cells release 7,8. In mice, that muscle-made 3-HIB pulled fatty acids across blood vessel walls into muscle and caused insulin resistance 8.
How it is made, moved and broken down
The first two steps are shared with leucine and isoleucine: transamination by BCAT, then the BCKDH complex 1.
Then valine goes its own way, through isobutyryl-CoA and methacrylyl-CoA to 3-hydroxyisobutyryl-CoA. HIBCH removes the CoA to give free 3-hydroxyisobutyrate, which can leave the cell, before the path continues to propionyl-CoA 5,7,8.
Methacrylyl-CoA is reactive. If ECHS1 or HIBCH is deficient it builds up and binds cysteine, which is both how the disorders are diagnosed and, it is thought, part of how they cause damage 5,6. A 2026 study proposes a different route to the damage entirely. Losing Echs1 in mouse neural stem and progenitor cells caused fatty acids to accumulate, which held back proliferation and differentiation and promoted apoptosis — and the mechanism ran through CROTONYL-CoA rather than methacrylyl-CoA: crotonyl-CoA rose, histones were globally crotonylated with H3K9cr enriched at neurodevelopmental gene promoters including the endoplasmic-reticulum stress regulator Atf4, and Atf4 then raised fatty acid synthase in a feed-forward loop that made the lipid accumulation worse. Inhibiting fatty acid synthase rescued the defects, and relieving the ER stress with tauroursodeoxycholic acid, or inhibiting Atf4, restored neurogenesis in culture and improved survival in the animals 24. The cysteine-binding account of ECHS1 damage is how the disorder is DIAGNOSED; it may not be how it does its harm, and this names a candidate drug.
Propionyl-CoA, the end of the pathway, is not only bookkeeping. In prostate cancer cells, catabolism of isoleucine and valine is the primary source of intracellular propionyl-CoA, which then acts as a signal: it propionylates specific lysines on nuclear SREBP2, raising its transcriptional activity, driving cholesterol synthesis and de novo androgen production, and sustaining androgen receptor signaling through metabolic and therapeutic stress including androgen deprivation 25. The enzyme at the very end of the pathway has a second job too. Methylmalonate semialdehyde dehydrogenase — ALDH6A1, which this page lists as the last step — was identified as a driver of gemcitabine resistance in pancreatic cancer: hypoxia drives GCN5-mediated lactylation of the enzyme at K113, the lactylated enzyme binds ACSL4 and generates propionyl-CoA to let KAT8 propionylate ACSL4 at K606, which strengthens ACSL4's binding to HSC70 and sends it for degradation by chaperone-mediated autophagy. That correlates with low ACSL4 and poor neoadjuvant chemotherapy response in patients, and combining dietary valine restriction with gemcitabine synergistically induced ferroptosis and suppressed tumor growth 26. This is the current, non-retracted case for restricting valine against a tumor.
And the same enzyme going the other way causes a different problem. A CRISPR-Cas9 metabolic knockout screen combined with patient transcriptomes identified ALDH6A1 as an ANTI-invasive factor in gastric cancer: losing it blocks the terminal step of valine catabolism, methylmalonic acid accumulates inside the cell and competitively occupies the α-ketoglutarate cofactor pocket of the histone demethylase KDM5C, which suppresses its activity and raises H3K4 dimethylation at the promoters of invasion genes including angiopoietin-2 and matrix metalloproteinase 7 — and that drove liver metastasis in mice. Activating ALDH6A1 pharmacologically with Alda-1, or clearing methylmalonic acid systemically with L-carnitine, lowered the mark, dampened the invasive program and reduced metastatic burden 27. A metabolite this page already names, inhibiting a demethylase by sitting in the wrong pocket, with carnitine as one of the levers.
Carbon skeleton · glucogenicIts carbons leave as propionyl-CoA, which becomes succinyl-CoA in the Krebs cycle; valine is one of the amino acids restricted in propionic and methylmalonic acidemia for that reason 2.
- Valine
- Branched-chain aminotransferaseBCAT1, BCAT2 · vitamin B6
- 2-Oxoisovalerate
- BCKDH complexBCKDHA, BCKDHB, DBT · thiamine, lipoate, NAD⁺
- Isobutyryl-CoA
- Isobutyryl-CoA dehydrogenaseACAD8 · FAD
- Methacrylyl-CoA
- Enoyl-CoA hydrataseECHS1
- 3-Hydroxyisobutyryl-CoA
- 3-Hydroxyisobutyryl-CoA hydrolaseHIBCH
- 3-Hydroxyisobutyrate
- 3-Hydroxyisobutyrate dehydrogenaseHIBADH · NAD⁺
- Methylmalonate semialdehyde
- Methylmalonate semialdehyde dehydrogenaseALDH6A1 · NAD⁺, CoA
- Propionyl-CoA
- Propionyl-CoA
- Propionyl-CoA carboxylasePCCA, PCCB · biotin
- Methylmalonyl-CoA
- Methylmalonyl-CoA mutaseMMUT · vitamin B12
- Succinyl-CoA
- L-Aminoadipate + L-cysteine + L-valine
- ACV synthetasepcbAB · ATP
- ACV tripeptide (with D-valine)
- Isopenicillin N synthasepcbC · Fe²⁺, O₂
- Isopenicillin N
Where it matters most
- Red cells
- Where the sickle valine does its harm 4.
- Bone marrow
- Stem cells need valine to proliferate, in mice and in culture 19.
- Skeletal muscle
- Secretes 3-hydroxyisobutyrate 8.
- Fat
- Adipocytes use more branched chains, and release more 3-HIB, as they mature 7.
- Brain
- ECHS1 deficiency damages the globus pallidus 29.
When it goes wrong
Inherited
Sickle cell disease
HBB · autosomal recessive
Valine for glutamate at position 6 of β-globin 3,12. Between 300,000 and 400,000 babies are born with it each year, most in sub-Saharan Africa. Pain crises, acute chest syndrome and stroke are the common acute complications, and chronic ones, kidney disease among them, can damage every organ; hydroxycarbamide, transfusion and stem cell transplantation reduce severity 4. One drug aimed squarely at the valine itself has since come off the market, and the way it went is instructive. Voxelotor blocks polymerization of sickle hemoglobin and reliably raised hemoglobin; its clinical development was suspended over safety and efficacy concerns. In 11 patients who had been stable on it for a mean of 191 weeks, withdrawal precipitated rapid vaso-occlusive crisis in 8 (73%) within a median of 4.7 days, with hemolysis, a significant fall in hemoglobin and raised reticulocytes, bilirubin and lactate dehydrogenase; one developed acute chest syndrome and five needed transfusion 30. A 2026 systematic review framed around the withdrawal makes the reason plain: L-glutamine reduced crisis burden in its pivotal trial (rate ratio 0.75, 95% CI 0.62 to 0.90), crizanlizumab prolonged time to first crisis in SUSTAIN (hazard ratio 0.50, 95% CI 0.33 to 0.75) on the strength of a single core randomized trial, and voxelotor primarily improved HEMOGLOBIN RESPONSE (risk ratio 7.84, 95% CI 3.52 to 17.4) — and the authors insist that benefit-risk interpretation must distinguish vaso-occlusive morbidity from hemoglobin-centered outcomes 31. A number that moved and an illness that did not.
How it is foundHemoglobin analysis; newborn screening where it exists 4.
Inherited
ECHS1 deficiency
ECHS1 · autosomal recessive
Leigh syndrome or exercise-induced dystonia; more than 60 patients have been reported, and protein restriction, including of valine, is reported to improve neurological symptoms 6. In 13 patients of Pacific ancestry, every symptomatic one had lesions of both globus pallidi, and illness or fasting set off the onset in 9 29.
How it is foundUrine conjugates by LC-MS/MS 6; a check for c.489G>A when only one variant is found 29.
Inherited
HIBCH deficiency
HIBCH · autosomal recessive
Leigh-like disease with low tone, developmental delay, seizures and regression 5,32. Only 22 cases had been reported when five more were described in one family in 2021 32.
How it is found3-Hydroxyisobutyryl-carnitine; HIBCH sequencing 32.
Inherited
BCKDK deficiency
BCKDK · autosomal recessive
The mirror image of maple syrup urine disease. The kinase that switches BCKDH off is lost, the enzyme keeps running, and plasma branched-chain amino acids fall; in consanguineous families it caused autism with epilepsy and intellectual disability, and the deficits of knockout mice responded to dietary supplementation 33.
How it is foundPlasma branched-chain amino acids; BCKDK sequencing 33.
Inherited
Maple syrup urine disease
BCKDHA, BCKDHB, DBT · autosomal recessive
The shared second step fails, and valine builds up with leucine and isoleucine; alloisoleucine is the pathognomonic marker 10. What it does to adults is the part worth knowing. Over eight years at one center, seven adults with the disease were admitted with ten episodes of encephalopathy; cerebral edema was present in nine of those episodes, and one asymptomatic patient had cerebral edema found on an elective admission. Five recovered fully to baseline and two died. The authors note that recognizing and treating the encephalopathy early is particularly hard in adults, because the multidisciplinary teams who receive them may not know the disease 34.
How it is foundNewborn screening, then plasma amino acids and alloisoleucine 10.
Biomarker
3-Hydroxyisobutyrate and insulin resistance
In 4,942 men and women, circulating 3-HIB rose with hyperglycemia and in established type 2 diabetes, and correlated with insulin resistance 7. In mice it carried fatty acids into muscle and caused insulin resistance 8. The direction of that arrow has since been tested genetically, and it does not point the way the biomarker story implies. An integrative analysis in UK Biobank — phenome-wide association, polygenic scores and then Mendelian randomization — found all three branched-chain amino acids strongly associated with type 2 diabetes observationally and robustly associated with obesity, hypertension, sleep apnoea and chronic kidney disease. But the Mendelian randomization supported positive effects only of leucine and isoleucine on hypertension; for the rest it showed either reverse causality or no clear direction, notably effects of OBESITY AND TYPE 2 DIABETES ON all three branched chains, with limited or borderline evidence for other outcomes 35. On this reading, raised branched-chain metabolites are substantially a consequence of metabolic disease rather than a cause of it.
How it is measured
Plasma valine is part of the amino acid panel 36.
For ECHS1 and HIBCH deficiency the useful sample is urine: LC-MS/MS of the cysteine and cysteamine conjugates 6, with 3-hydroxyisobutyryl-carnitine raised in HIBCH deficiency 5,32.
Sickle hemoglobin is found by hemoglobin analysis. Universal newborn screening is in place in some countries but hard to deliver where the disease is commonest 4.
- Urine valine conjugatesCysteine and cysteamine conjugates of methacrylyl-CoA and acryloyl-CoA, such as S-(2-carboxypropyl)cysteine, measured by LC-MS/MS 6.They separated six ECHS1 patients from six controls 6; in HIBCH deficiency the cysteine conjugate of methacrylate was greatly increased 5.In patients of Pacific ancestry with a mild ECHS1 variant, they were normal or only mildly raised 29.
- Plasma 3-hydroxyisobutyrateA valine intermediate made and released by fat and muscle cells 7,8.In 4,942 people it rose with blood glucose and in type 2 diabetes and correlated with insulin resistance; after bariatric surgery it rose briefly and then fell sharply 7.An association in people; the causal evidence comes from mice 8.
Food, supplements and the evidence
Establishedreplicated in people, for a named outcome
- The old valine requirement was too low: 10 mg/kg/day from nitrogen balance, against a breakpoint of 17 by isotope methods 17. The evidence behind the current figure is thinner than the figure looks. A 2025 systematic review of human protein and indispensable amino acid requirement research from 2000 to 2024 — commissioned because the US reference intakes were published in 2005 and have not been revised — screened 11,408 studies, found 68 articles reporting 66 studies eligible and rated 45 at low or moderate risk of bias. For adults aged 19 to 50 the valine requirement studies were in MALES ONLY, as was the infant valine study, and the reviewers found the literature limited across the life cycle, particularly in pregnancy, lactation, infancy and childhood 37.
Uncertainsmall, short, mixed, surrogate or preclinical
- Valine restriction as treatment for ECHS1 deficiency, with a high-energy diet and an emergency plan 6,29.
- Cutting valine to prepare for stem cell transplants, or to slow T-cell leukemia: so far in mice 19,20. One pillar of that case has been withdrawn: the 2024 Nature paper identifying human HDAC6 as the valine sensor and reporting that dietary valine restriction inhibited tumor growth and improved PARP inhibitor efficacy was retracted in 2026, with no reason stated in the record 22,23. What remains is newer and narrower: in pancreatic cancer, dietary valine restriction combined with gemcitabine synergistically induced ferroptosis by disrupting a lactylation-propionylation axis that otherwise degrades ACSL4 26, and in gastric cancer the opposite problem — too LITTLE valine catabolism — promotes metastasis through methylmalonic acid inhibiting a histone demethylase 27. Restricting valine is not a single intervention with a single direction, and the tumor decides which.
- Lifelong valine restriction raised median lifespan in male mice by 23% and reduced frailty and cancer in both sexes 38.
- Whether higher valine is sometimes protective, which every other line on this page would not predict. Across two independent cohorts, valine was the only metabolite associated with a REDUCED risk of incident Alzheimer's disease specifically among APOE ε4 carriers, with a significant valine-by-ε4 interaction replicated in both. Higher valine went with greater total white matter and posterior cingulate volumes, lower cerebrospinal fluid tau and a slower decline in FDG-PET metabolism, with no association with amyloid-β, and plasma proteomic mediation analyses implicating GFAP, NEFL and APOE 39. The authors say plainly that this was observational and causality cannot be inferred. It is the counterweight on a page where almost everything else points toward restriction.
- And a quantified estimate pointing the other way, in a specific cancer. Two-sample two-step Mendelian randomization identified 55 circulating metabolites associated with pancreatic cancer risk with no evidence of pleiotropy, heterogeneity or reverse causality; five of them, valine included, were causally associated with body mass index. Replicating the first step in UK Biobank instead of FinnGen, and the second with whole-body fat mass instead of BMI, both confirmed valine, and mediation analysis put the effect of obesity on pancreatic cancer transmitted through valine at about 19% 40. That sits alongside the two 2026 pancreatic-cancer mechanism papers on this page rather than independently of them.
Sold asthe claim on the label, against the evidence
- Valine sold in a fixed ratio with leucine and isoleucine for muscle. Muscle protein needs all the essential amino acids, and no human study had measured muscle protein synthesis after oral branched chains alone 41. The count is now available. A 2025 systematic review of randomized trials of pure branched-chain supplements in healthy adults — 22 studies, 511 participants in total, 11 in trained athletes and 11 in untrained, daily doses from 1.5 g to 82 g, durations from one day to six months — found that exactly ONE study showed a significant difference in body composition. Thirteen studies had significant findings on some performance outcome; the authors conclude the evidence moderately supports a reduction in post-exercise muscle soreness and remains inconsistent for strength, endurance and body composition, and they did not pool anything because the risk of bias was too high 42. And in cirrhosis, the one condition where these supplements are genuinely prescribed, a network meta-analysis of 23 trials and 1,525 participants found exercise alone or with protein or branched chains increased muscle mass while protein or branched-chain supplementation ALONE did not, with the effect on strength inconclusive 43.
What is strange about it
A variant that changes no amino acid causes ECHS1 deficiency in Pacific peoples. c.489G>A is synonymous, reduces correct splicing, is missed by standard genomic testing, and has an allele frequency of 0.17 in Samoans 29.
In mice, removing one amino acid from the diet did what radiation does before a marrow transplant, and emptied the stem-cell niche 19.
The sickle mutation is common because one copy protects: both hemoglobin S and hemoglobin C are reported to reduce the severity and fatality of malaria 12.
Where it connects
In the Atlas
On the map
A star in The essential amino acids, one of 14. The third branched-chain, and the one with the least to say for itself — which is itself worth saying, because it is sold in a fixed ratio with the others.
Sources
43 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.
- 1Brosnan JT, Brosnan ME. Branched-chain amino acids: enzyme and substrate regulation.doi:10.1093/jn/136.1.207S · PMID 16365084
Structure and the shared first steps of breakdown.
- 2Margoses D, Imbard A, Pontoizeau C, et al. Nutritional management in severe methylmalonic and propionic acidemias: how much medical food is too much?doi:10.1002/jimd.70114 · PMID 41344680
Valine and isoleucine catabolism feed propionyl-CoA.
- 3Ingram VM. Gene mutations in human haemoglobin: the chemical difference between normal and sickle cell haemoglobin.doi:10.1038/180326a0 · PMID 13464827
The single amino acid change.
- 4Kato GJ, Piel FB, Reid CD, et al. Sickle cell disease.doi:10.1038/nrdp.2018.10 · PMID 29542687
Primer: burden, mechanism, treatment.
- 5Peters H, Ferdinandusse S, Ruiter JP, et al. Metabolite studies in HIBCH and ECHS1 defects: implications for screening.doi:10.1016/j.ymgme.2015.06.008 · PMID 26163321
Methacrylyl-CoA conjugates in urine.
- 6Kuwajima M, Kojima K, Osaka H, et al. Valine metabolites analysis in ECHS1 deficiency.doi:10.1016/j.ymgmr.2021.100809 · PMID 34667719
LC-MS/MS of urine and plasma conjugates.
- 7Nilsen MS, Jersin RÅ, Ulvik A, et al. 3-Hydroxyisobutyrate, a strong marker of insulin resistance in type 2 diabetes and obesity that modulates white and brown adipocyte metabolism.doi:10.2337/db19-1174 · PMID 32586980
4,942 people; adipocyte studies.
- 8Jang C, Oh SF, Wada S, et al. A branched-chain amino acid metabolite drives vascular fatty acid transport and causes insulin resistance.doi:10.1038/nm.4057 · PMID 26950361
3-HIB from muscle, in mice.
- 9Manoli 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.doi:10.1038/gim.2015.102 · PMID 26270765
Leucine-to-valine ratio and growth.
- 10Blackburn PR, Gass JM, Vairo FPE, et al. Maple syrup urine disease: mechanisms and management.doi:10.2147/TACG.S125962 · PMID 28919799
Clinical review.
- 11Martín JF. New aspects of genes and enzymes for beta-lactam antibiotic biosynthesis.doi:10.1007/s002530051249 · PMID 9720195
The ACV tripeptide and isopenicillin N synthase.
- 12Harp KO, Botchway F, Dei-Adomakoh Y, et al. Hemoglobin genotypes modulate inflammatory response to Plasmodium infection.doi:10.3389/fimmu.2020.593546 · PMID 33424841
HbS (E6V), HbC and malaria.
- 13Kamel MD, Ibrahim RK, Obaead WR. Comparative in silico analysis of hemoglobin subunits HBB, HbS (p.Glu7Val), and HBA: sequence-structure insights into sickle cell anemia.doi:10.1016/j.compbiolchem.2026.109162 · PMID 42247988
Used for the variant name only.
- 14Oldiges M, Eikmanns BJ, Blombach B. Application of metabolic engineering for the biotechnological production of L-valine.doi:10.1007/s00253-014-5782-8 · PMID 24816722
Uses and microbial production.
- 15Sheremetieva ME, Anufriev KE, Khlebodarova TM, et al. Rational metabolic engineering of Corynebacterium glutamicum to create a producer of L-valine.doi:10.18699/VJGB-22-90 · PMID 36694718
Feed use and production strains.
- 16Goo D, Lee DJ, Gudidoddi SR, Ragyari SKR, Kim Y, Kim WK. Plasma metabolomic profiling reveals metabolic shifts linked to growth depression in broilers fed high level of valine.doi:10.1016/j.psj.2026.107572 · PMID 42623767
960 birds, 24 replicates per treatment, to day 42. Half again as much valine made them smaller.
- 17Kurpad AV, Regan MM, Raj TD, et al. The daily valine requirement of healthy adult Indians determined by the 24-h indicator amino acid balance approach.doi:10.1093/ajcn.82.2.373 · PMID 16087981
Breakpoint at 17 mg/kg/day.
- 18Joint WHO/FAO/UNU Expert Consultation. Protein and amino acid requirements in human nutrition.PMID 18330140
The international requirement figures.
- 19Taya Y, Ota Y, Wilkinson AC, et al. Depleting dietary valine permits nonmyeloablative mouse hematopoietic stem cell transplantation.doi:10.1126/science.aag3145 · PMID 27934766
Stem cells need valine.
- 20Thandapani P, Kloetgen A, Witkowski MT, et al. Valine tRNA levels and availability regulate complex I assembly in leukaemia.doi:10.1038/s41586-021-04244-1 · PMID 34937946
T-ALL and dietary valine, in mice.
- 21Zhu J, Zhang Q, Evans D, Su R, Pan Q, Goel A. METTL1-mediated m7G modification of valine tRNAs drives metabolic adaptation in pancreatic ductal adenocarcinoma cells.doi:10.1172/JCI204312 · PMID 42579742
A second tumor and a different modifying enzyme, arriving at the same place: valine tRNA supply governing which proteins get made.
- 22Jin J, Meng T, Yu Y, et al. Human HDAC6 senses valine abundancy to regulate DNA damage.doi:10.1038/s41586-024-08248-5 · PMID 39567688
PubMed types this as a Retracted Publication. It is cited here as the claim that was made, not as evidence.
- 23Jin J, Meng T, Yu Y, et al. Retraction Note: Human HDAC6 senses valine abundancy to regulate DNA damage.doi:10.1038/s41586-026-10942-5 · PMID 42527612
The notice carries no abstract, so PubMed records no stated reason.
- 24Duan CH, Liu PP, Sun X, et al. Loss of Echs1 in neural stem and progenitor cells impairs neurogenesis via ER stress activation and lipid metabolic reprogramming.doi:10.1038/s41467-026-75063-z · PMID 42386732
A different route to the damage than the one this page described, with a candidate treatment attached. Mice and cells.
- 25Li Z, Liu S, Jin W, et al. Isoleucine and valine promote prostate cancer progression via propionyl-CoA-mediated cholesterol metabolism.doi:10.1038/s42255-026-01583-z · PMID 42625032
Propionyl-CoA as a signal that acylates a transcription factor, rather than only as the place valine's carbons end up.
- 26Zheng P, Lin Y, Zhang M, et al. MMSDH facilitates ACSL4 propionylation to counteract ferroptosis upon hypoxia and impairs PDAC chemotherapy efficacy.doi:10.1038/s43018-026-01236-w · PMID 42728394
The last enzyme of valine catabolism given a job nobody had assigned it, and the current non-retracted basis for dietary valine restriction in cancer.
- 27Wang J, Han L, Li G, et al. Reprogramming of valine metabolism mediated by abnormally low ALDH6A1 expression promotes invasive metastasis of gastric cancer.doi:10.1126/sciadv.aeb2892 · PMID 42418576
A CRISPR screen, a metabolite blocking a demethylase's cofactor pocket, and two interventions — one of them L-carnitine.
- 28Fernstrom JD. Large neutral amino acids: dietary effects on brain neurochemistry and function.doi:10.1007/s00726-012-1330-y · PMID 22677921
Competition at the blood–brain barrier.
- 29Bernhardt I, Frajman LE, Ryder B, et al. Further delineation of short-chain enoyl-CoA hydratase deficiency in the Pacific population.doi:10.1016/j.ymgme.2024.108508 · PMID 38820906
The synonymous c.489G>A variant.
- 30Alkindi S, Al Subhi A, Pathare A. Rapid withdrawal of voxelotor can precipitate sickle cell disease related crisis.doi:10.1007/s00277-025-06503-x · PMID 40627162
Eleven patients, a mean of 191 weeks on the drug, and what happened when it was taken away. A letter, not a trial.
- 31Wang J, Lu H. Benefit-risk of voxelotor, crizanlizumab, and l-glutamine in sickle cell disease: a systematic review.doi:10.1016/j.amjms.2026.08.010 · PMID 42628795
Searched to April 2026, framed around the withdrawal. The distinction it insists on — crisis burden against a hemoglobin number — is the whole argument.
- 32Çakar NE, Görükmez O. 3-Hydroxyisobutyryl-CoA hydrolase (HIBCH) deficiency cases diagnosed by only HIBCH gene analysis and novel pathogenic mutation.doi:10.4103/aian.AIAN_192_20 · PMID 34447000
Five patients in one family.
- 33Novarino G, El-Fishawy P, Kayserili H, et al. Mutations in BCKD-kinase lead to a potentially treatable form of autism with epilepsy.doi:10.1126/science.1224631 · PMID 22956686
Low branched chains, autism and epilepsy.
- 34Sulaiman RA, Altassan R, Alshammari R, et al. Cerebral edema in maple syrup urine disease: spectrum of clinical presentation and treatment outcomes.doi:10.1186/s13023-025-04043-1 · PMID 41257986
Seven adults, ten episodes, eight years. What actually kills people with this diagnosis, and why it gets missed in adults.
- 35Konarkowski J, Astore C, Gibson G. Assessment of genetic and metabolite associations of branched chain amino acids with metabolic disease in the UK Biobank using Mendelian randomization.doi:10.1186/s12920-025-02232-2 · PMID 41102794
Observational associations, polygenic scores and Mendelian randomization side by side. The three disagree, and the disagreement is the finding.
- 36Sharer 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).doi:10.1038/s41436-018-0328-6 · PMID 30459394
Methods for amino acid analysis.
- 37Burstad KM, Lamina T, Erickson A, et al. Evaluation of dietary protein and amino acid requirements: a systematic review.doi:10.1016/j.ajcnut.2025.04.017 · PMID 40610129
An audit of the evidence behind the reference values, commissioned because the US figures have not been revised since 2005.
- 38Calubag MF, Ademi I, Green CL, et al. Lifelong restriction of dietary valine has sex-specific benefits for health and lifespan in mice.doi:10.1038/s43587-026-01169-0 · PMID 42498891
Median male lifespan up 23%.
- 39Yang ZL, Zhang C, Tang S, et al. Valine modulates Alzheimer's disease risk in APOE ε4 carriers: evidence from two cohorts.doi:10.1016/j.jare.2026.08.014 · PMID 42567350
Two independent cohorts with a replicated interaction, and authors who state plainly that causality cannot be inferred.
- 40Li K, Zhang C, Yan C. Metabolome-wide Mendelian randomization identifies valine as a potential mediator of the effect of obesity on pancreatic cancer risk.doi:10.1096/fj.202501757R · PMID 40892529
Two-sample two-step Mendelian randomization, replicated in a second cancer dataset and with fat mass substituted for BMI.
- 41Wolfe RR. Branched-chain amino acids and muscle protein synthesis in humans: myth or reality?doi:10.1186/s12970-017-0184-9 · PMID 28852372
No human study of oral BCAAs alone.
- 42Julea M, Saleh SN. The effect of oral pure branched-chain amino acid supplementation on exercise performance and body composition: a systematic review.doi:10.7759/cureus.96017 · PMID 41346907
22 trials, 511 participants, doses from 1.5 g to 82 g a day. No meta-analysis, because the risk of bias was too high to pool.
- 43Kittiprachakul S, Maung ST, Poorirerngpoom N, et al. Exercise and nutrition interventions for sarcopenia in cirrhosis: a systematic review and network meta-analysis of randomized controlled trials.doi:10.1038/s41430-025-01642-w · PMID 40925921
23 trials, 1,525 people, in the one indication where these supplements are actually prescribed.
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