Histidine

Not to be confused with histamine.

L-Histidine

Names
IUPAC name Histidine
Other names 2-Amino-3-(1H-imidazol-4-yl)propanoic acid
Identifiers
CAS Number	71-00-1 Y
ChEBI	CHEBI:57595 Y
ChEMBL	ChEMBL17962 Y
ChemSpider	6038 Y
DrugBank	DB00117 Y
IUPHAR/BPS	3310
Jmol 3D model	Interactive image Interactive image
KEGG	D00032 Y
PubChem	773
UNII	4QD397987E Y
InChI InChI=1S/C6H9N3O2/c7-5(6(10)11)1-4-2-8-3-9-4/h2-3,5H,1,7H2,(H,8,9)(H,10,11)/t5-/m0/s1 Y Key: HNDVDQJCIGZPNO-YFKPBYRVSA-N Y InChI=1S/C6H9N3O2/c7-5(6(10)11)1-4-2-8-3-9-4/h2-3,5H,1,7H2,(H,8,9)(H,10,11)/t5-/m0/s1 Key: HNDVDQJCIGZPNO-YFKPBYRVSA-N
SMILES O=C([C@H](CC1=CNC=N1)N)O O=C(O)[C@@H](N)Cc1c[nH]cn1
Properties
Chemical formula	C6H9N3O2
Molar mass	155.16 g·mol−1
Solubility in water	4.19g/100g @ 25 °C
Vapor pressure	{{{value}}}
Supplementary data page
Structure and properties	Refractive index (n), Dielectric constant (εr), etc.
Thermodynamic data	Phase behaviour solid–liquid–gas
Spectral data	UV, IR, NMR, MS
Y verify (what is YN ?)
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.

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

Chemical properties

The conjugate acid (protonated form) of the imidazole side chain in histidine has a pK_a 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.

Aromaticity

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

Biochemistry

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.

NMR

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.

Metabolism

Biosynthesis

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

Catabolism

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.

Supplementation

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

Additional images

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  Histidine

See also

• Carnosinemia
• Beta-alanine
• Diphthamide
• Pauly reaction

External links

• Histidine MS Spectrum
• Histidine biosynthesis (early stages)
• Histidine biosynthesis (later stages)
• Histidine catabolism
• Food Sources of Histidine