The AtlasAmino acidsNonpolar, aliphatic
ValineVal · V
The smallest of the branched chains: the residue that, put in place of one glutamate, makes sickle haemoglobin; 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 haemoglobin; 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 acidaemia 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: haemoglobin carrying it can polymerise 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 polymerise 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 anaemia 12 | Normal haemoglobin |
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.
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 16, and the international adult figure is now 26 17.
How much
26 mg per kilogram per day for adults 17: 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 haematopoietic 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 18.
T-cell leukaemia leans on it too. NOTCH1 drives up the enzyme that loads valine onto its tRNA, and restricting dietary valine in mice lowered the leukaemic burden: it cut the translation of mitochondrial complex I subunits, so the complex assembled poorly 19.
Penicillins and cephalosporins start as a tripeptide of aminoadipate, cysteine and valine, assembled by an enzyme rather than a ribosome 11.
In three sentences each
One residue, one disease
Sickle haemoglobin differs from normal at a single residue: valine for glutamic acid at position 6 of the β chain 3,12. Haemoglobin carrying it can polymerise, 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 hydrolyses 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.
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 acidaemia 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 18.
- 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 21.
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.
How it is foundHaemoglobin 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 21.
How it is foundUrine conjugates by LC-MS/MS 6; a check for c.489G>A when only one variant is found 21.
Inherited
HIBCH deficiency
HIBCH · autosomal recessive
Leigh-like disease with low tone, developmental delay, seizures and regression 5,22. Only 22 cases had been reported when five more were described in one family in 2021 22.
How it is found3-Hydroxyisobutyryl-carnitine; HIBCH sequencing 22.
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 23.
How it is foundPlasma branched-chain amino acids; BCKDK sequencing 23.
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.
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 hyperglycaemia 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.
How it is measured
Plasma valine is part of the amino acid panel 24.
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 5,22.
Sickle haemoglobin is found by haemoglobin 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 21.
- 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 16.
Uncertainsmall, short, mixed, surrogate or preclinical
- Valine restriction as treatment for ECHS1 deficiency, with a high-energy diet and an emergency plan 6,21.
- Cutting valine to prepare for stem cell transplants, or to slow T-cell leukaemia: so far in mice 18,19.
- Lifelong valine restriction raised median lifespan in male mice by 23% and reduced frailty and cancer in both sexes 25.
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 26.
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 21.
In mice, removing one amino acid from the diet did what radiation does before a marrow transplant, and emptied the stem-cell niche 18.
The sickle mutation is common because one copy protects: both haemoglobin S and haemoglobin 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
26 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.
- 16Kurpad 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.
- 17Joint WHO/FAO/UNU Expert Consultation. Protein and amino acid requirements in human nutrition.PMID 18330140
The international requirement figures.
- 18Taya 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.
- 19Thandapani 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.
- 20Fernstrom 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.
- 21Bernhardt 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.
- 22Çakar 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.
- 23Novarino 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.
- 24Sharer 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.
- 25Calubag 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%.
- 26Wolfe 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.
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.