Histidine is an α-amino acid with an imidazole functional group. It is one of the 23 proteinogenic
amino acids. Its codons are CAU and CAC. Histidine was first isolated by German physician Albrecht
Kossel in 1896. Histidine is an essential amino acid in humans and other mammals. It
was initially thought that it was only essential for infants, but longer-term studies established
that it is also essential for adult humans.
Chemical properties The conjugate acid 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. 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 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. 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
As expected, the 15N chemical shifts of these nitrogens are indistinguishable. As the pH
increases to approximately 8, 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. 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 The amino acid is a precursor for histamine
and carnosine biosynthesis.
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.
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
See also Imidazole
Aromatic amino acids Urocanic aciduria
Carnosinemia Beta-alanine
Diphthamide Pauly reaction
References
External links Histidine MS Spectrum
Histidine biosynthesis Histidine biosynthesis
Histidine catabolism Food Sources of Histidine