The AtlasAmino acidsPositively charged
HistidineHis · H
The amino acid whose side chain changes charge at almost exactly the pH of a cell, which makes it the body’s buffer, its catalyst and its grip on metals.
Molecule · His · 11 heavy atoms
Histidine
C6H9N3O2155.16 g/mol
The amino acid whose side chain changes charge at almost exactly the pH of a cell, which makes it the body’s buffer, its catalyst and its grip on metals.
Built fromthe charted ones open their own entry
- Codes
- His · H
- Formula
- C6H9N3O2
- Molar mass
- 155.16 g/mol
- Systematic name
- (2S)-2-amino-3-(1H-imidazol-5-yl)propanoic acid
- Side chain
- Imidazol-4-ylmethyl: an aromatic five-membered ring with two nitrogens; partly protonated at the pH of a cell.
- Class
- Positively charged
- In the diet
- Essential
- Carbon skeleton
- Glucogenic
- pKa
- α-COOH 1.82 · α-NH3+ 9.17 · side chain 6.00
- Isoelectric point
- pH 7.59
- Hydropathy
- -3.2 (Kyte–Doolittle)
- Codons
CAUCAC- Main transporters
- SLC7A5 (LAT1, with CD98)
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
An essential amino acid with an imidazole ring for a side chain. The imidazole’s pKa is about 6, close to the pH of a cell, so histidine can carry or drop a proton with very little push 1,2.
Why it matters
That makes it the working part of many enzymes, the main proton buffer of haemoglobin, and the grip by which proteins hold copper, zinc and haem iron 1,2,3. It is also the precursor of histamine and of carnosine, the buffer of muscle 1,4.
Where it runs short
Adults need it too. Men fed a histidine-free diet for five weeks slowly went into negative nitrogen balance, lost a quarter of their haematocrit and developed scaly skin, all of which reversed when histidine was restored 5.
Where it turns
Histidinaemia, the inherited inability to break histidine down, keeps blood levels high from birth, and most people with it turn out to be well 6,7.
Too little is a real deficiency. Too much, at least the inherited kind, mostly is not.
The molecule
Histidine’s side chain is imidazole, a flat five-membered ring with two nitrogens. One of them can take up a proton and the other can give one, and the pKa that governs this is about 6, close to the pH inside cells. No other amino acid side chain sits so near neutral, which is why histidine shows up wherever a protein needs to move a proton or to respond to small changes in acidity 1,2.
The same nitrogens bind metals. In haemoglobin and myoglobin a histidine below the haem holds the iron; without that electron-donating ligand, model haem compounds simply oxidise in water 8. In proteins linked to neurodegeneration, the prion protein, amyloid-β and tau, imidazole nitrogens are the primary binding sites for copper and zinc 3.
Move across the chart to read the charge at any pH.
Computed from its pKa values (α-carboxyl 1.82, α-amino 9.17, side chain 6.00) 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 |
Where it comes from
Humans cannot make histidine. The adult requirement is 10 mg per kilogram a day 1. Histidine was long treated as essential only for infants; a 1975 depletion study in four healthy and three uraemic men showed that adults on a histidine-free diet slowly lose nitrogen, albumin and red cells 5.
The decline is gradual. In that study plasma histidine fell by 82% and muscle histidine by 62% over about five weeks, while nitrogen balance drifted rather than fell off a cliff 5.
EssentialCannot be made in humans; the adult requirement is 10 mg per kilogram a day 1. Its essentiality in adults was shown in 1975 by depletion in a metabolic unit 5.
How much
10 mg per kilogram a day for adults 1.
Where it is in food
- Any protein; meat also carries histidine in carnosine 4.
In the bottle · fermentedIndustrial histidine is made by fermentation in Corynebacterium glutamicum 9. It is the same molecule as in food.
What the body does with it
Histidine is the precursor of histamine, made by histidine decarboxylase in mast cells, the acid-controlling enterochromaffin-like cells of the stomach, and neurons of the brain 1.
It is also half of carnosine, β-alanyl-L-histidine, a dipeptide discovered in meat in 1900 and abundant in muscle and other excitable tissues, where it buffers acid, binds metals and quenches reactive aldehydes 4. Carnosine synthase joins the two using ATP; the supply of β-alanine, not histidine, limits how much is made 4,10.
Proteins rich in histidine have their own jobs. Histidine-rich glycoprotein in plasma binds heparin, haem, zinc, plasminogen and immune molecules 11. Filaggrin, the skin-barrier protein, is rich in histidine; when it is broken down in the outer skin, the released histidine and its product urocanic acid become part of the skin’s natural moisturising factor 12,13.
In three sentences each
A proton on a hair trigger
The imidazole ring gains or loses a proton near pH 6, so small shifts in acidity flip its charge; histidine side chains carry much of haemoglobin’s buffering and its release of oxygen in acid tissue, the Bohr effect 2.
The catalyst in the middle
In serine proteases such as trypsin, a histidine sits between serine and aspartate in the catalytic triad and shuttles the proton that makes the serine reactive 1.
How it is made, moved and broken down
Histidine’s breakdown begins with histidase, in the liver and in the skin, which makes trans-urocanic acid. In the skin, ultraviolet light converts trans- to cis-urocanate 1, which suppresses immune responses; blocking it reduced UV-induced immune suppression and skin cancer in animals 14. In the liver the pathway runs on to formiminoglutamate and then glutamate, a last step that needs folate 1.
Carbon skeleton · glucogenicBroken down in the liver to glutamate, which can make glucose; the last step needs folate 1.
- Histidine
- Histidine decarboxylaseHDC · vitamin B6
- Histamine
- Carnosine synthaseCARNS1 · ATP
- Carnosine
- Histidine
- HistidaseHAL
- trans-Urocanate
- Urocanase, then imidazolonepropionaseUROC1, AMDHD1
- Formiminoglutamate (FIGLU)
- Glutamate formiminotransferaseFTCD · folate (THF)
- Glutamate
How it crosses membranes
- SLC7A5 · LAT1, with CD98blood–brain barrier and placenta — in reconstituted human LAT1, histidine was the preferred substrate 15
Where it matters most
When it goes wrong
Inherited
Histidinaemia
HAL · autosomal recessive
High histidine and low urocanic acid in blood and skin from loss of histidase; the commonest inborn error found by screening in Japan. Early reports linked it to intellectual disability, but most people identified by newborn screening have normal intelligence 6.
How it is foundPlasma histidine, low skin and blood urocanic acid, HAL sequencing 6.
Too little
Histidine deficiency
Seen experimentally on histidine-free diets: negative nitrogen balance, falling albumin and haematocrit, rising serum iron and a scaly skin rash, reversed by repletion 5.
How it is foundPlasma histidine with the clinical picture 5.
Biomarker
Folate deficiency, by FIGLU
FTCD
Without folate the last step of histidine breakdown stalls and formiminoglutamate appears in urine. In the original reports, giving histidine for the test produced a blood response in folate-deficient patients but not in B12-deficient ones 16.
How it is foundUrine FIGLU after a histidine load; now superseded 16.
Association
Atopic dermatitis and filaggrin
FLG
Filaggrin variants predispose to eczema, and the skin’s levels of histidine and its breakdown products track both the genotype and the severity of the disease 12,13.
How it is foundResearch measures from tape-stripped skin 13.
How it is measured
Plasma histidine is part of any amino acid panel, but the measurements that have mattered clinically are its products: urocanic acid, low in histidinaemia 6; formiminoglutamate, high in folate deficiency 16; and 3-methylhistidine, a research marker of muscle breakdown and meat intake 17,18,19.
- Urine FIGLU after a histidine loadHistidine’s breakdown needs folate at its last step, so in folate deficiency the intermediate formiminoglutamate spills into urine after a histidine dose; this was the old FIGLU test 1,16.Historical; replaced by direct folate and B12 measurement.Separated folate deficiency from B12 deficiency and controls in the original reports 16.
- 3-MethylhistidineHistidine methylated in the actin and myosin of muscle is released when muscle protein is broken down, so urinary 3-methylhistidine has been used as a marker of muscle breakdown 17,20.It also comes from meat in the diet, so it tracks meat intake as well, and as a muscle marker it has not found wide clinical use 17,18.
Food, supplements and the evidence
Establishedreplicated in people, for a named outcome
Uncertainsmall, short, mixed, surrogate or preclinical
- Histidine for insulin resistance: one 12-week trial of 4 g a day in 100 Chinese women with the metabolic syndrome improved insulin resistance and waist size; it has not been replicated 23.
- Histidine for eczema: a 24-person adult pilot and a small children’s pilot reported falls in severity scores; the author is associated with a company developing the supplement 12,24.
- β-Alanine for exercise: benefits are mainly in efforts lasting one to four minutes, with tingling skin as the common side effect; several position-stand authors have industry ties 22.
Sold asthe claim on the label, against the evidence
- Nothing in this column.
What is strange about it
Histidinaemia was screened for in newborns for years and treated with diet, until follow-up showed that most of those found had normal intelligence; a million-baby screening programme found no benefit for conditions like it that turned out to be benign 6,7,25.
Most animals carry methylated versions of carnosine, anserine or balenine, in their muscle. Humans are the exception 4.
In the men fed no histidine, serum iron rose as the haematocrit fell; when histidine was restored the iron fell abruptly and a burst of new red cells followed 5.
Where it connects
In the Atlas
Topics on the map
On the map
A star in The essential amino acids, one of 14. Essential in adults too, not only infants: adults on a histidine-free diet slowly lose nitrogen, albumin and red cells.
Sources
25 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 ME, Brosnan JT. Histidine metabolism and function.doi:10.1093/jn/nxaa079 · PMID 33000155
Requirement, catalytic triad, histidase, urocanate, FIGLU, carnosine, histamine.
- 2Berenbrink M. Evolution of vertebrate haemoglobins: histidine side chains, specific buffer value and Bohr effect.doi:10.1016/j.resp.2006.01.002 · PMID 16481225
Histidines and haemoglobin buffering across 77 species.
- 3Sóvágó I, Várnagy K, Kállay C, Grenács Á. Interactions of copper(II) and zinc(II) ions with the peptide fragments of proteins related to neurodegenerative disorders: similarities and differences.doi:10.2174/0929867329666220915140852 · PMID 36111758
Imidazole nitrogens as the primary copper and zinc binding sites.
- 4Boldyrev AA, Aldini G, Derave W. Physiology and pathophysiology of carnosine.doi:10.1152/physrev.00039.2012 · PMID 24137022
Carnosine’s discovery, roles and the human lack of anserine.
- 5Kopple JD, Swendseid ME. Evidence that histidine is an essential amino acid in normal and chronically uremic man.doi:10.1172/JCI108016 · PMID 1123426
Seven men in a metabolic unit; about 35 days without histidine.
- 6Kawai Y, Moriyama A, Asai K, et al. Molecular characterization of histidinemia: identification of four missense mutations in the histidase gene.doi:10.1007/s00439-004-1232-5 · PMID 15806399
50 screened cases; most with normal intelligence.
- 7Wilcken B, Smith A, Brown DA. Urine screening for aminoacidopathies: is it beneficial? Results of a long-term follow-up of cases detected by screening one million babies.doi:10.1016/s0022-3476(80)80216-2 · PMID 7411317
No benefit for conditions that proved benign.
- 8Kitagishi H, Kano K. Synthetic heme protein models that function in aqueous solution.doi:10.1039/d0cc07044k · PMID 33346275
The proximal histidine’s role, shown by its absence in model compounds.
- 9Reiter A, Wesseling L, Wiechert W, Oldiges M. Rapid exometabolome footprinting combined with multivariate statistics: a powerful tool for bioprocess optimization.doi:10.1002/elsc.202300222 · PMID 39990767
Corynebacterium glutamicum as the industrial platform for L-histidine.
- 10Drozak J, Veiga-da-Cunha M, Vertommen D, et al. Molecular identification of carnosine synthase as ATP-grasp domain-containing protein 1 (ATPGD1).doi:10.1074/jbc.M109.095505 · PMID 20097752
The enzyme that makes carnosine.
- 11Poon IKH, Patel KK, Davis DS, et al. Histidine-rich glycoprotein: the Swiss Army knife of mammalian plasma.doi:10.1182/blood-2010-09-303842 · PMID 20971949
Its many ligands and roles.
- 12Gibbs NK. L-histidine supplementation in adults and young children with atopic dermatitis (eczema).doi:10.1093/jn/nxaa200 · PMID 33000160
Pilot data; filaggrin and natural moisturising factor. Author has commercial ties.
- 13Kezic S, O’Regan GM, Yau N, et al. Levels of filaggrin degradation products are influenced by both filaggrin genotype and atopic dermatitis severity.doi:10.1111/j.1398-9995.2010.02540.x · PMID 21261659
Skin histidine and urocanic acid track genotype and severity.
- 14Ullrich SE. Sunlight and skin cancer: lessons from the immune system.doi:10.1002/mc.20328 · PMID 17443748
cis-Urocanic acid in UV immune suppression. Largely animal work.
- 15Scalise M, Galluccio M, Console L, et al. The human SLC7A5 (LAT1): the intriguing histidine/large neutral amino acid transporter and its relevance to human health.doi:10.3389/fchem.2018.00243 · PMID 29988369
Histidine is LAT1’s preferred substrate in reconstituted protein.
- 16Cooperman JM, Lopez R. The role of histidine in the anemia of folate deficiency.doi:10.1177/153537020222701107 · PMID 12486209
The FIGLU test and its history.
- 17Keller U. Nutritional laboratory markers in malnutrition.doi:10.3390/jcm8060775 · PMID 31159248
3-Methylhistidine as a muscle breakdown marker has not found wide use.
- 18Said MY, Rodriguez-Niño A, Post A, et al. Meat intake and risk of mortality and graft failure in kidney transplant recipients.doi:10.1093/ajcn/nqab185 · PMID 34091671
Urinary 1- and 3-methylhistidine as markers of meat intake.
- 19Yin X, Gibbons H, Rundle M, et al. Estimation of chicken intake by adults using metabolomics-derived markers.doi:10.3945/jn.117.252197 · PMID 28794208
Plasma 3-methylhistidine as a marker of chicken intake.
- 20Aguilera JA, Tinline-Goodfellow CT, Lees MJ, et al. Dileucine-supplemented essential amino acids support whole-body anabolism after resistance exercise and serum-stimulated cell-based anabolism.doi:10.1080/15502783.2025.2590090 · PMID 41321015
Uses urinary 3-methylhistidine to creatinine to estimate muscle breakdown.
- 21Harris RC, Tallon MJ, Dunnett M, et al. The absorption of orally supplied beta-alanine and its effect on muscle carnosine synthesis in human vastus lateralis.doi:10.1007/s00726-006-0299-9 · PMID 16554972
Four weeks of β-alanine raised muscle carnosine 42–64%.
- 22Trexler ET, Smith-Ryan AE, Stout JR, et al. International Society of Sports Nutrition position stand: beta-alanine.doi:10.1186/s12970-015-0090-y · PMID 26175657
Doses, effects and paraesthesia; several authors with industry ties.
- 23Feng RN, Niu YC, Sun XW, et al. Histidine supplementation improves insulin resistance through suppressed inflammation in obese women with the metabolic syndrome: a randomised controlled trial.doi:10.1007/s00125-013-2839-7 · PMID 23361591
100 women, 4 g/day, 12 weeks; single centre.
- 24Tan SP, Brown SB, Griffiths CEM, et al. Feeding filaggrin: effects of L-histidine supplementation in atopic dermatitis.doi:10.2147/CCID.S146760 · PMID 29042806
24 adults; SCORAD −34% at four weeks.
- 25Brosco JP, Sanders LM, Dharia R, et al. The lure of treatment: expanded newborn screening and the curious case of histidinemia.doi:10.1542/peds.2009-2060 · PMID 20156889
History of screening for a benign condition.
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