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Not to be confused with histamine.
Histidin - Histidine.svg
IUPAC name
Other names
2-Amino-3-(1H-imidazol-4-yl)propanoic acid
71-00-1 YesY
ChEBI CHEBI:57595 YesY
ChemSpider 6038 YesY
DrugBank DB00117 YesY
Jmol interactive 3D Image
KEGG D00032 YesY
PubChem 773
UNII 4QD397987E YesY
Molar mass 155.16 g·mol−1
4.19g/100g @ 25 °C [1]
Safety data sheet See: data page
NFPA 704
Flammability code 1: Must be pre-heated before ignition can occur. Flash point over 93 °C (200 °F). E.g., canola oil Health code 1: Exposure would cause irritation but only minor residual injury. E.g., turpentine Reactivity code 0: Normally stable, even under fire exposure conditions, and is not reactive with water. E.g., liquid nitrogen Special hazards (white): no codeNFPA 704 four-colored diamond
Supplementary data page
Refractive index (n),
Dielectric constantr), etc.
Phase behaviour
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Infobox references

Histidine (abbreviated as His or H; encoded by the codons CAU and CAC) is an ɑ-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated –+NH3 form under biological conditions), a carboxylic acid group (which is in the deprotonated –COO- form under biological conditions), and a side chain imidazole, classifying it as a positively charged (at physiological pH), aromatic amino acid. Initially thought essential only for infants, longer-term studies shown it is essential for adults also.[2]

Histidine was first isolated by German physician Albrecht Kossel and Sven Hedin in 1896.[3] It is also a precursor to histamine, a vital inflammatory agent in immune responses.

Chemical properties[edit]

The conjugate acid (protonated form) of the imidazole side chain in histidine has a pKa of approximately 6.0. This means that, at physiologically relevant pH values, relatively small shifts in pH will change its average charge. Below a pH of 6, the imidazole ring is mostly protonated as described by the Henderson–Hasselbalch equation. When protonated, the imidazole ring bears two NH bonds and has a positive charge. The positive charge is equally distributed between both nitrogens and can be represented with two equally important resonance structures.


The imidazole ring of histidine is aromatic at all pH values.[4] It contains six pi electrons: four from two double bonds and two from a nitrogen lone pair. It can form pi stacking interactions,[5] but is complicated by the positive charge.[6] It does not absorb at 280 nm in either state, but does in the lower UV range more than some amino acids.[7][8]


The histidine-bound heme group of succinate dehydrogenase, an electron carrier in the mitochondrial electron transfer chain. The large semi-transparent sphere indicates the location of the iron ion. From PDB: 1YQ3​.

The imidazole sidechain of histidine is a common coordinating ligand in metalloproteins and is a part of catalytic sites in certain enzymes. In catalytic triads, the basic nitrogen of histidine is used to abstract a proton from serine, threonine, or cysteine to activate it as a nucleophile. In a histidine proton shuttle, histidine is used to quickly shuttle protons. It can do this by abstracting a proton with its basic nitrogen to make a positively charged intermediate and then use another molecule, a buffer, to extract the proton from its acidic nitrogen. In carbonic anhydrases, a histidine proton shuttle is utilized to rapidly shuttle protons away from a zinc-bound water molecule to quickly regenerate the active form of the enzyme. Histidine is also important in haemoglobin in helices E and F. Histidine assists in stabilising oxyhaemoglobin and destabilising CO-bound haemoglobin. As a result, carbon monoxide binding is only 200 times stronger in haemoglobin, compared to 20,000 times stronger in free haem.

Certain amino acids can be converted to intermediates of the TCA cycle. Carbons from four groups of amino acids form the TCA cycle intermediates α-ketoglutarate, succinyl CoA, fumarate, and oxaloacetate. Amino acids that form α-ketoglutarate are glutamate, glutamine, proline, arginine, and histidine. Histidine is converted to formiminoglutamate (FIGLU). The formimino group is transferred to tetrahydrofolate, and the remaining five carbons form glutamate. Glutamate can be deaminated by glutamate dehydrogenase or transaminated to form α-ketoglutarate.[9]


When protonated, the 15N chemical shifts of the side-chain nitrogens are similar (about 200 ppm, relative to nitric acid on the sigma scale, on which increased shielding corresponds to increased chemical shift). As the pH increases past approximately 6, the protonation of the imidazole ring is lost. The remaining proton of the now-neutral imidazole can exist on either nitrogen, giving rise to what is known as the N-1 or N-3 tautomers. NMR shows that the chemical shift of N-1 drops slightly, whereas the chemical shift of N-3 drops considerably (about 190 vs. 145 ppm). This indicates that the N-1-H tautomer is preferred, it is presumed due to hydrogen bonding to the neighboring ammonium. The shielding at N-3 is substantially reduced due to the second-order paramagnetic effect, which involves a symmetry-allowed interaction between the nitrogen lone pair and the excited pi* states of the aromatic ring. As the pH rises above 9, the chemical shifts of N-1 and N-3 become approximately 185 and 170 ppm. It is worth noting that the deprotonated form of imidazole, imidazolate ion, would be formed only above a pH of 14, and is therefore not physiologically relevant. This change in chemical shifts can be explained by the presumably decreased hydrogen bonding of an amine over an ammonium ion, and the favorable hydrogen bonding between a carboxylate and an NH. This should act to decrease the N-1-H tautomer preference.[10]



As an essential amino acid, histidine is not synthesized de novo in humans and other animals, who must ingest histidine or histidine-containing proteins.


The amino acid is a precursor for histamine and carnosine biosynthesis.

Conversion of histidine to histamine by histidine decarboxylase

The enzyme histidine ammonia-lyase converts histidine into ammonia and urocanic acid. A deficiency in this enzyme is present in the rare metabolic disorder histidinemia, producing urocanic aciduria as a key diagnostic symptom. In Actinobacteria and filamentous fungi, such as Neurospora crassa, histidine can be converted into the antioxidant ergothioneine.[11]


Supplementation of histidine has been shown to cause rapid zinc excretion in rats with an excretion rate 3 to 6 times normal.[12][13]

Additional images[edit]

See also[edit]


  1. ^ http://prowl.rockefeller.edu/aainfo/solub.htm[full citation needed]
  2. ^ Kopple, J D; Swendseid, M E (1975). "Evidence that histidine is an essential amino acid in normal and chronically uremic man". Journal of Clinical Investigation 55 (5): 881–91. doi:10.1172/JCI108016. PMC 301830. PMID 1123426. 
  3. ^ Vickery, Hubert Bradford; Leavenworth, Charles S. (1928-08-01). "ON THE SEPARATION OF HISTIDINE AND ARGININE IV. THE PREPARATION OF HISTIDINE". Journal of Biological Chemistry 78 (3): 627–635. ISSN 0021-9258. 
  4. ^ Mrozek, Agnieszka; Karolak-Wojciechowska, Janina; Kieć-Kononowicz, Katarzyna (2003). "Five-membered heterocycles. Part III. Aromaticity of 1,3-imidazole in 5+n hetero-bicyclic molecules". Journal of Molecular Structure 655 (3): 397–403. Bibcode:2003JMoSt.655..397M. doi:10.1016/S0022-2860(03)00282-5. 
  5. ^ Wang, Lijun; Sun, Na; Terzyan, Simon; Zhang, Xuejun; Benson, David R. (2006). "A Histidine/Tryptophan π-Stacking Interaction Stabilizes the Heme-Independent Folding Core of Microsomal Apocytochrome b5Relative to that of Mitochondrial Apocytochrome b5". Biochemistry 45 (46): 13750–9. doi:10.1021/bi0615689. PMID 17105194. 
  6. ^ Blessing, Robert H.; McGandy, Edward L. (1972). "Base stacking and hydrogen bonding in crystals of imidazolium dihydrogen orthophosphate". Journal of the American Chemical Society 94 (11): 4034–4035. doi:10.1021/ja00766a075. 
  7. ^ Katoh, Ryuzi (2007). "Absorption Spectra of Imidazolium Ionic Liquids". Chemistry Letters 36 (10): 1256–1257. doi:10.1246/cl.2007.1256. 
  8. ^ A. Robert Goldfarb; Saidel, LJ; Mosovich, E (1951-11-01). "The Ultraviolet Absorption Spectra of Proteins". Journal of Biological Chemistry 193 (1): 397–404. PMID 14907727. 
  9. ^ Board review series (BRS)-- Biochemistry, Molecular Biology, and Genetics (fifth edition): Swanson, Kim, Glucksman
  10. ^ Roberts, John D. (2000). ABCs of FT-NMR. Sausalito, CA: University Science Books. pp. 258–9. ISBN 978-1-891389-18-4. 
  11. ^ Fahey, Robert C. (2001). "Novelthiols Ofprokaryotes". Annual Review of Microbiology 55: 333–56. doi:10.1146/annurev.micro.55.1.333. PMID 11544359. 
  12. ^ R M Freeman; Taylor, PR (1977-04-01). "Influence of histidine administration on zinc metabolism in the rat". The American Journal of Clinical Nutrition 30 (4): 523–7. PMID 851080. 
  13. ^ Wensink, Jan; Hamer, Cornelis J. A. (1988). "Effect of excess dietary histidine on rate of turnover of65Zn in brain of rat". Biological Trace Element Research 16 (2): 137–50. doi:10.1007/BF02797098. PMID 2484542. 

External links[edit]