Histidine
Encyclopedia
Histidine Histidine, an essential amino acid, has a positively charged imidazole
functional group. It is one of the 22 proteinogenic amino acid
s. 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.
sidechain of histidine has a pKa
of approximately 6.0, and, overall, the amino acid has a pKa of 6.5. 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 nitrogen
s and can be represented with two equally important resonance structures.
s 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.
in metalloprotein
s and is a part of catalytic sites in certain enzyme
s. In catalytic triad
s, 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 anhydrase
s, 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.
on the sigma scale, on which increased shielding corresponds to increased chemical shift
). 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 tautomer
s. 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.
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
.
s with an excretion rate 3 to 6 times normal.
Imidazole
Imidazole is an organic compound with the formula C3H4N2. This aromatic heterocyclic is a diazole and is classified as an alkaloid. Imidazole refers to the parent compound, whereas imidazoles are a class of heterocycles with similar ring structure, but varying substituents...
functional group. It is one of the 22 proteinogenic amino acid
Proteinogenic amino acid
Proteinogenic amino acids are those amino acids that can be found in proteins and require cellular machinery coded for in the genetic code of any organism for their isolated production. There are 22 standard amino acids, but only 21 are found in eukaryotes. Of the 22, 20 are directly encoded by...
s. Its codons are CAU and CAC. Histidine was first isolated by German physician Albrecht Kossel
Albrecht Kossel
Ludwig Karl Martin Leonhard Albrecht Kossel was a German biochemist and pioneer in the study of genetics. He was awarded the Nobel Prize for Physiology or Medicine in 1910 for his work in determining the chemical composition of nucleic acids, the genetic substance of biological cells.Kossel...
in 1896. Histidine is an essential amino acid
Essential amino acid
An essential amino acid or indispensable amino acid is an amino acid that cannot be synthesized de novo by the organism , and therefore must be supplied in the diet.-Essentiality vs. conditional essentiality in humans:...
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 imidazoleImidazole
Imidazole is an organic compound with the formula C3H4N2. This aromatic heterocyclic is a diazole and is classified as an alkaloid. Imidazole refers to the parent compound, whereas imidazoles are a class of heterocycles with similar ring structure, but varying substituents...
sidechain of histidine has a pKa
Acid dissociation constant
An acid dissociation constant, Ka, is a quantitative measure of the strength of an acid in solution. It is the equilibrium constant for a chemical reaction known as dissociation in the context of acid-base reactions...
of approximately 6.0, and, overall, the amino acid has a pKa of 6.5. This means that, at physiologically relevant pH values, relatively small shifts in pH
PH
In chemistry, pH is a measure of the acidity or basicity of an aqueous solution. Pure water is said to be neutral, with a pH close to 7.0 at . Solutions with a pH less than 7 are said to be acidic and solutions with a pH greater than 7 are basic or alkaline...
will change its average charge. Below a pH of 6, the imidazole ring is mostly protonated
Protonation
In chemistry, protonation is the addition of a proton to an atom, molecule, or ion. Some classic examples include*the protonation of water by sulfuric acid:*the protonation of isobutene in the formation of a carbocation:2C=CH2 + HBF4 → 3C+ + BF4−*the protonation of ammonia in the...
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 nitrogen
Nitrogen
Nitrogen is a chemical element that has the symbol N, atomic number of 7 and atomic mass 14.00674 u. Elemental nitrogen is a colorless, odorless, tasteless, and mostly inert diatomic gas at standard conditions, constituting 78.08% by volume of Earth's atmosphere...
s 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 bondDouble bond
A double bond in chemistry is a chemical bond between two chemical elements involving four bonding electrons instead of the usual two. The most common double bond, that between two carbon atoms, can be found in alkenes. Many types of double bonds between two different elements exist, for example in...
s and two from a nitrogen lone pair
Lone pair
In chemistry, a lone pair is a valence electron pair without bonding or sharing with other atoms. They are found in the outermost electron shell of an atom, so lone pairs are a subset of a molecule's valence electrons...
. 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 ligandLigand
In coordination chemistry, a ligand is an ion or molecule that binds to a central metal atom to form a coordination complex. The bonding between metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The nature of metal-ligand bonding can range from...
in metalloprotein
Metalloprotein
Metalloprotein is a generic term for a protein that contains a metal ion cofactor. Metalloproteins have many different functions in cells, such as enzymes, transport and storage proteins, and signal transduction proteins. Indeed, about one quarter to one third of all proteins require metals to...
s and is a part of catalytic sites in certain enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
s. In catalytic triad
Catalytic triad
A catalytic triad refers to the three amino acid residues found inside the active site of certain protease enzymes: serine , aspartate , and histidine . They work together to break peptide bonds on polypeptides. In general terms, catalytic triad can refer to any set of three residues that function...
s, the basic nitrogen of histidine is used to abstract a proton from serine
Serine
Serine is an amino acid with the formula HO2CCHCH2OH. It is one of the proteinogenic amino acids. By virtue of the hydroxyl group, serine is classified as a polar amino acid.-Occurrence and biosynthesis:...
, threonine
Threonine
Threonine is an α-amino acid with the chemical formula HO2CCHCHCH3. Its codons are ACU, ACA, ACC, and ACG. This essential amino acid is classified as polar...
, or cysteine
Cysteine
Cysteine is an α-amino acid with the chemical formula HO2CCHCH2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is polar and thus cysteine is usually classified as a hydrophilic amino acid...
to activate it as a nucleophile
Nucleophile
A nucleophile is a species that donates an electron-pair to an electrophile to form a chemical bond in a reaction. All molecules or ions with a free pair of electrons can act as nucleophiles. Because nucleophiles donate electrons, they are by definition Lewis bases.Nucleophilic describes the...
. 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 anhydrase
Carbonic anhydrase
The carbonic anhydrases form a family of enzymes that catalyze the rapid interconversion of carbon dioxide and water to bicarbonate and protons , a reversible reaction that occurs rather slowly in the absence of a catalyst...
s, a histidine proton shuttle is utilized to rapidly shuttle protons away from a zinc
Zinc
Zinc , or spelter , is a metallic chemical element; it has the symbol Zn and atomic number 30. It is the first element in group 12 of the periodic table. Zinc is, in some respects, chemically similar to magnesium, because its ion is of similar size and its only common oxidation state is +2...
-bound water molecule to quickly regenerate the active form of the enzyme.
NMR
As expected, the 15N chemical shifts of these nitrogens are indistinguishable (about 200 ppm, relative to nitric acidNitric acid
Nitric acid , also known as aqua fortis and spirit of nitre, is a highly corrosive and toxic strong acid.Colorless when pure, older samples tend to acquire a yellow cast due to the accumulation of oxides of nitrogen. If the solution contains more than 86% nitric acid, it is referred to as fuming...
on the sigma scale, on which increased shielding corresponds to increased chemical shift
Chemical shift
In nuclear magnetic resonance spectroscopy, the chemical shift is the resonant frequency of a nucleus relative to a standard. Often the position and number of chemical shifts are diagnostic of the structure of a molecule...
). 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 tautomer
Tautomer
Tautomers are isomers of organic compounds that readily interconvert by a chemical reaction called tautomerization. This reaction commonly results in the formal migration of a hydrogen atom or proton, accompanied by a switch of a single bond and adjacent double bond...
s. 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
Ammonium
The ammonium cation is a positively charged polyatomic cation with the chemical formula NH. It is formed by the protonation of ammonia...
. The shielding at N-3 is substantially reduced due to the second-order paramagnetic
Paramagnetism
Paramagnetism is a form of magnetism whereby the paramagnetic material is only attracted when in the presence of an externally applied magnetic field. In contrast with this, diamagnetic materials are repulsive when placed in a magnetic field...
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
Amine
Amines are organic compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are derivatives of ammonia, wherein one or more hydrogen atoms have been replaced by a substituent such as an alkyl or aryl group. Important amines include amino acids, biogenic amines,...
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 histamineHistamine
Histamine is an organic nitrogen compound involved in local immune responses as well as regulating physiological function in the gut and acting as a neurotransmitter. Histamine triggers the inflammatory response. As part of an immune response to foreign pathogens, histamine is produced by...
and carnosine
Carnosine
Carnosine is a dipeptide of the amino acids beta-alanine and histidine. It is highly concentrated in muscle and brain tissues....
biosynthesis
Biosynthesis
Biosynthesis is an enzyme-catalyzed process in cells of living organisms by which substrates are converted to more complex products. The biosynthesis process often consists of several enzymatic steps in which the product of one step is used as substrate in the following step...
.
Histidine ammonia-lyase
Histidine ammonia-lyase is an enzyme that in humans is encoded by the HAL gene. Histidase converts histidine into ammonia and urocanic acid.- Function :...
converts histidine into ammonia
Ammonia
Ammonia is a compound of nitrogen and hydrogen with the formula . It is a colourless gas with a characteristic pungent odour. Ammonia contributes significantly to the nutritional needs of terrestrial organisms by serving as a precursor to food and fertilizers. Ammonia, either directly or...
and urocanic acid
Urocanic acid
Urocanic acid is an intermediate in the catabolism of L-histidine.-Metabolism:It is formed from L-histidine through the action of histidine ammonialyase by elimination of ammonium....
. A deficiency in this enzyme is present in the rare metabolic disorder histidinemia
Histidinemia
Histidinemia, also referred to as histidinuria, is a rare autosomal recessive metabolic disorder caused by a deficiency of the enzyme histidase. Histidase is needed for the metabolism of the amino acid histidine.-Diagnosis and symptoms:...
. In Actinobacteria
Actinobacteria
Actinobacteria are a group of Gram-positive bacteria with high guanine and cytosine content. They can be terrestrial or aquatic. Actinobacteria is one of the dominant phyla of the bacteria....
and filamentous fungi, such as Neurospora crassa
Neurospora crassa
Neurospora crassa is a type of red bread mold of the phylum Ascomycota. The genus name, meaning "nerve spore" refers to the characteristic striations on the spores. The first published account of this fungus was from an infestation of French bakeries in 1843. N...
, histidine can be converted into the antioxidant
Antioxidant
An antioxidant is a molecule capable of inhibiting the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons or hydrogen from a substance to an oxidizing agent. Oxidation reactions can produce free radicals. In turn, these radicals can start chain reactions. When...
ergothioneine
Ergothioneine
Ergothioneine is a naturally occurring amino acid and is a thiourea derivative of histidine, containing a sulfur atom in the imidazole ring. This compound is made in rather few organisms, notably Actinobacteria and filamentous fungi. Ergothioneine was discovered in 1909 and named after the ergot...
.
Supplementation
Supplementation of Histidine has been shown to cause rapid zinc excretion in ratRat
Rats are various medium-sized, long-tailed rodents of the superfamily Muroidea. "True rats" are members of the genus Rattus, the most important of which to humans are the black rat, Rattus rattus, and the brown rat, Rattus norvegicus...
s with an excretion rate 3 to 6 times normal.
See also
- ImidazoleImidazoleImidazole is an organic compound with the formula C3H4N2. This aromatic heterocyclic is a diazole and is classified as an alkaloid. Imidazole refers to the parent compound, whereas imidazoles are a class of heterocycles with similar ring structure, but varying substituents...
- Aromatic amino acidsAromatic amino acidsAromatic amino acids are amino acids that include an aromatic ring.Examples include:* Among 20 standard amino acids: phenylalanine, tryptophan, and tyrosine* Others: thyroxine-See also:* Aromatic L-amino acid decarboxylase...
- Urocanic aciduriaUrocanic aciduriaUrocanic aciduria, also called urocanate hydratase deficiency or urocanase deficiency, is an autosomal recessive metabolic disorder caused by a deficiency of the enzyme urocanase. It is a secondary disorder of histidine metabolism.-Pathophysiology:...
- CarnosinemiaCarnosinemiaCarnosinemia, also called carnosinase deficiency or aminoacyl-histidine dipeptidase deficiency, is a rare autosomal recessive metabolic disorder caused by a deficiency of carnosinase, a dipeptidase .Carnosine is a dipeptide composed of beta-alanine and histidine, and is found in skeletal...
- Beta-alanineBeta-alanineβ-Alanine is a naturally occurring beta amino acid, which are amino acids in which the amino group is at the β-position from the carboxylate group . The IUPAC name for β-alanine would be 3-aminopropanoic acid...