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Histidine (symbol His or H) is an
essential amino acid An essential amino acid, or indispensable amino acid, is an amino acid that cannot be synthesized from scratch by the organism fast enough to supply its demand, and must therefore come from the diet. Of the 21 amino acids common to all life form ...
that is used in the biosynthesis of
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metabo ...
s. It contains an α-amino group (which is in the protonated –NH3+ form under biological conditions), a
carboxylic acid In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an R-group. The general formula of a carboxylic acid is or , with substituent, R referring to the alkyl, alkenyl, aryl, or other group. ...
group (which is in the deprotonated –COO form under biological conditions), and an
imidazole Imidazole (ImH) is an organic compound with the formula C3N2H4. It is a white or colourless solid that is soluble in water, producing a mildly alkaline solution. In chemistry, it is an aromatic heterocycle, classified as a diazole, and has non-ad ...
side chain (which is partially protonated), classifying it as a positively charged amino acid at physiological pH. Initially thought essential only for infants, it has now been shown in longer-term studies to be essential for adults also. It is
encoded In communications and information processing, code is a system of rules to convert information—such as a letter (alphabet), letter, word, sound, image, or gesture—into another form, sometimes data compression, shortened or secrecy, secret ...
by the
codons The genetic code is the set of rules used by living cells to translate information encoded within genetic material ( DNA or RNA sequences of nucleotide triplets, or codons) into protein Proteins are large biomolecules and macromolecules ...
CAU and CAC. Histidine was first isolated by
Albrecht Kossel Ludwig Karl Martin Leonhard Albrecht Kossel (; 16 September 1853 – 5 July 1927) was a German biochemist and pioneer in the study of genetics. He was awarded the Nobel Prize for Nobel Prize in Physiology or Medicine, Physiology or Medicine in 1 ...
and Sven Gustaf Hedin in 1896. It is also a precursor to
histamine Histamine is an organic nitrogen Nitrogen is the chemical element with the Symbol (chemistry), symbol N and atomic number 7. Nitrogen is a nonmetal and the lightest member of pnictogen, group 15 of the periodic table, often called the pnicto ...
, a vital inflammatory agent in immune responses. The acyl
radical Radical may refer to: Politics and ideology Politics *Radical politics, the political intent of fundamental societal change *Radicalism (historical), the Radical Movement that began in late 18th century Britain and spread to continental Europe and ...
is histidyl.


Properties of the imidazole side chain

The conjugate acid (protonated form) of the
imidazole Imidazole (ImH) is an organic compound with the formula C3N2H4. It is a white or colourless solid that is soluble in water, producing a mildly alkaline solution. In chemistry, it is an aromatic heterocycle, classified as a diazole, and has non-ad ...
side chain In organic chemistry Organic chemistry is a subdiscipline within chemistry involving the science, scientific study of the structure, properties, and reactions of organic compounds and organic materials, i.e., matter in its various forms that ...
in histidine has a p''K''a of approximately 6.0. Thus, below a pH of 6, the imidazole ring is mostly protonated (as described by the
Henderson–Hasselbalch equation In chemistry and biochemistry, the Henderson–Hasselbalch equation :\ce = \ceK_\ce + \log_ \left( \frac \right) relates the pH of a Solution (chemistry), chemical solution of a weak acid to the numerical value of the acid dissociation constant, ' ...
). The resulting imidazolium ring bears two NH bonds and has a positive charge. The positive charge is equally distributed between both
nitrogen Nitrogen is the chemical element with the Symbol (chemistry), symbol N and atomic number 7. Nitrogen is a nonmetal and the lightest member of pnictogen, group 15 of the periodic table, often called the pnictogens. It is a common element in the ...
s and can be represented with two equally important resonance structures. Sometimes, the symbol Hip is used for this protonated form instead of the usual His. Above pH 6, one of the two protons is lost. The remaining proton of the imidazole ring can reside on either nitrogen, giving rise to what are known as the N1-H or N3-H
tautomer Tautomers () are structural isomers (constitutional isomers) of chemical compounds that readily interconvert. The chemical reaction interconverting the two is called tautomerization. This conversion commonly results from the relocation of a hydr ...
s. The N3-H tautomer is shown in the figure above. In the N1-H tautomer, the NH is nearer the backbone. These neutral tautomers, also referred to as Nδ and Nε, are sometimes referred to with symbols Hid and Hie, respectively. The imidazole/imidazolium ring of histidine is
aromatic In chemistry, aromaticity is a chemical property of cyclic compound, cyclic (ring (chemistry), ring-shaped), ''typically'' plane (geometry), planar (flat) molecular structures with pi bonds in Resonance (chemistry), resonance (those containing ...
at all pH values. The acid-base properties of the imidazole side chain are relevant to the
catalytic mechanism Enzyme catalysis is the increase in the reaction rate, rate of a process by a Biomolecule, biological molecule, an "enzyme". Most enzymes are proteins, and most such processes are chemical reactions. Within the enzyme, generally catalysis occurs ...
of many
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...
s. In
catalytic triad A catalytic triad is a set of three coordinated amino acids that can be found in the active site of some enzymes. Catalytic triads are most commonly found in hydrolase and transferase enzymes (e.g. proteases, amidases, esterases, acylas ...
s, the basic nitrogen of histidine abstracts a proton from
serine Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − form un ...
,
threonine Threonine (symbol Thr or T) is an amino acid that is used in the biosynthesis of proteins. It contains an Amine, α-amino group (which is in the protonated −NH form under biological conditions), a carboxyl group (which is in the deprotonated ...
, or
cysteine Cysteine (symbol Cys or C; ) is a semiessential proteinogenic amino acid with the chemical formula, formula . The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile. When present as a deprotonated catalytic ...
to activate it as a
nucleophile In chemistry, a nucleophile is a chemical species that forms bonds by donating an electron pair. All molecules and ions with a free pair of electrons or at least one pi bond can act as nucleophiles. Because nucleophiles donate electrons, they are ...
. 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 The carbonic anhydrases (or carbonate dehydratases) () form a family of enzymes that catalyst, catalyze the interconversion between carbon dioxide and water and the Dissociation (chemistry), dissociated ions of carbonic acid (i.e. bicarbonate a ...
s, a histidine proton shuttle is utilized to rapidly shuttle protons away from a
zinc Zinc is a chemical element with the Symbol (chemistry), symbol Zn and atomic number 30. Zinc is a slightly brittle metal at room temperature and has a shiny-greyish appearance when oxidation is removed. It is the first element in group 12 eleme ...
-bound water molecule to quickly regenerate the active form of the enzyme. In helices E and F of
haemoglobin Hemoglobin (haemoglobin BrE) (from the Greek word αἷμα, ''haîma'' 'blood' + Latin ''globus'' 'ball, sphere' + ''-in'') (), abbreviated Hb or Hgb, is the iron-containing oxygen-transport metalloprotein present in red blood cells (erythrocyte ...
, histidine influences binding of dioxygen as well as
carbon monoxide Carbon monoxide (chemical formula CO) is a colorless, poisonous, odorless, tasteless, flammable gas that is slightly less dense than air. Carbon monoxide consists of one carbon atom and one oxygen atom connected by a triple bond. It is the simple ...
. This interaction enhances the affinity of Fe(II) for O2 but destabilizes the binding of CO, which binds only 200 times stronger in haemoglobin, compared to 20,000 times stronger in free haem. The tautomerism and acid-base properties of the imidazole side chain has been characterized by 15N NMR spectroscopy. The two 15N chemical shifts are similar (about 200 ppm, relative to
nitric acid Nitric acid is the inorganic compound with the formula . It is a highly corrosive mineral acid. The compound is colorless, but older samples tend to be yellow cast due to decomposition into oxides of nitrogen. Most commercially available ni ...
on the sigma scale, on which increased shielding corresponds to increased
chemical shift In nuclear magnetic resonance (NMR) spectroscopy, the chemical shift is the resonance, resonant frequency of an atomic nucleus relative to a standard in a magnetic field. Often the position and number of chemical shifts are diagnostic of the str ...
). NMR spectral measurements shows that the chemical shift of N1-H drops slightly, whereas the chemical shift of N3-H drops considerably (about 190 vs. 145 ppm). This change indicates that the N1-H tautomer is preferred, possibly due to hydrogen bonding to the neighboring
ammonium The ammonium cation is a positively-charged polyatomic ion with the chemical formula or . It is formed by the protonation of ammonia (). Ammonium is also a general name for positively charged or protonated substituted amines and quaternary amm ...
. The shielding at N3 is substantially reduced due to the second-order
paramagnetic Paramagnetism is a form of magnetism whereby some materials are weakly attracted by an externally applied magnetic field, and form internal, induced magnetic fields in the direction of the applied magnetic field. In contrast with this behavior ...
effect, which involves a symmetry-allowed interaction between the nitrogen lone pair and the excited π* states of the
aromatic ring In chemistry Chemistry is the scientific study of the properties and behavior of matter. It is a natural science that covers the elements that make up matter to the compounds made of atoms, molecules and ions: their composition, st ...
. At pH > 9, the chemical shifts of N1 and N3 are approximately 185 and 170 ppm.


Ligand

Histidine forms complexes with many metal ions. The imidazole sidechain of the histidine residue commonly serves as a
ligand In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's electro ...
in
metalloprotein Metalloprotein is a generic term for a protein that contains a metal ion Cofactor (biochemistry), cofactor. A large proportion of all proteins are part of this category. For instance, at least 1000 human proteins (out of ~20,000) contain zinc-bi ...
s. One example is the axial base attached to Fe in myoglobin and hemoglobin. Poly-histidine tags (of six or more consecutive H residues) are utilized for protein purification by binding to columns with nickel or cobalt, with micromolar affinity. Natural poly-histidine peptides, found in the venom of the viper ''Atheris squamigera'' have been shown to bind Zn(2+), Ni(2+) and Cu(2+) and affect the function of venom metalloproteases.


Metabolism


Biosynthesis

-Histidine is an essential amino acid that is not synthesized '' de novo'' in humans. Humans and other animals must ingest histidine or histidine-containing proteins. The biosynthesis of histidine has been widely studied in prokaryotes such as ''E. coli''. Histidine synthesis in ''E. coli'' involves eight gene products (His1, 2, 3, 4, 5, 6, 7, and 8) and it occurs in ten steps. This is possible because a single gene product has the ability to catalyze more than one reaction. For example, as shown in the pathway, His4 catalyzes 4 different steps in the pathway. Histidine is synthesized from phosphoribosyl pyrophosphate (PRPP), which is made from ribose-5-phosphate by ribose-phosphate diphosphokinase in the pentose phosphate pathway. The first reaction of histidine biosynthesis is the condensation of PRPP and
adenosine triphosphate Adenosine triphosphate (ATP) is an organic compound that provides energy to drive many processes in living cell (biology), cells, such as muscle contraction, nerve impulse propagation, condensate dissolution, and chemical synthesis. Found in all ...
(ATP) by the enzyme ATP-phosphoribosyl transferase. ATP-phosphoribosyl transferase is indicated by His1 in the image. His4 gene product then hydrolyzes the product of the condensation, phosphoribosyl-ATP, producing phosphoribosyl-AMP (PRAMP), which is an irreversible step. His4 then catalyzes the formation of phosphoribosylformiminoAICAR-phosphate, which is then converted to phosphoribulosylformimino-AICAR-P by the His6 gene product. His7 splits phosphoribulosylformimino-AICAR-P to form -erythro-imidazole-glycerol-phosphate. After, His3 forms imidazole acetol-phosphate releasing water. His5 then makes -histidinol-phosphate, which is then hydrolyzed by His2 making histidinol. His4 catalyzes the oxidation of -histidinol to form -histidinal, an amino aldehyde. In the last step, -histidinal is converted to -histidine. Just like animals and microorganisms, plants need histidine for their growth and development. Microorganisms and plants are similar in that they can synthesize histidine. Both synthesize histidine from the biochemical intermediate phosphoribosyl pyrophosphate. In general, the histidine biosynthesis is very similar in plants and microorganisms.


Regulation of biosynthesis

This pathway requires energy in order to occur therefore, the presence of ATP activates the first enzyme of the pathway, ATP-phosphoribosyl transferase (shown as His1 in the image on the right). ATP-phosphoribosyl transferase is the rate determining enzyme, which is regulated through feedback inhibition meaning that it is inhibited in the presence of the product, histidine.


Degradation

Histidine is one of the amino acids that can be converted to intermediates of the tricarboxylic acid (TCA) cycle (also known as the citric acid cycle).Board review series (BRS)-- Biochemistry, Molecular Biology, and Genetics (fifth edition): Swanson, Kim, Glucksman Histidine, along with other amino acids such as proline and arginine, takes part in deamination, a process in which its amino group is removed. In
prokaryote A prokaryote () is a Unicellular organism, single-celled organism that lacks a cell nucleus, nucleus and other membrane-bound organelles. The word ''prokaryote'' comes from the Greek language, Greek wikt:πρό#Ancient Greek, πρό (, 'before') a ...
s, histidine is first converted to urocanate by histidase. Then, urocanase converts urocanate to 4-imidazolone-5-propionate. Imidazolonepropionase catalyzes the reaction to form formiminoglutamate (FIGLU) from 4-imidazolone-5-propionate. The formimino group is transferred to tetrahydrofolate, and the remaining five carbons form glutamate. Overall, these reactions result in the formation of glutamate and ammonia. Glutamate can then be deaminated by glutamate dehydrogenase or transaminated to form α-ketoglutarate.


Conversion to other biologically active amines

* The histidine amino acid is a precursor for
histamine Histamine is an organic nitrogen Nitrogen is the chemical element with the Symbol (chemistry), symbol N and atomic number 7. Nitrogen is a nonmetal and the lightest member of pnictogen, group 15 of the periodic table, often called the pnicto ...
, an amine produced in the body necessary for inflammation. * The enzyme histidine ammonia-lyase converts histidine into
ammonia Ammonia is an inorganic chemical compound, compound of nitrogen and hydrogen with the chemical formula, formula . A Binary compounds of hydrogen, stable binary hydride, and the simplest pnictogen hydride, ammonia is a colourless gas with a dis ...
and urocanic acid. A deficiency in this enzyme is present in the rare metabolic disorder histidinemia, producing urocanic aciduria as a key diagnostic finding. * Histidine can be converted to 3-methylhistidine, which serves as a
biomarker In biomedical contexts, a biomarker, or biological marker, is a measurable wikt:indicator, indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biologic ...
for skeletal muscle damage, by certain
methyltransferase Methyltransferases are a large group of enzymes that all Methylation, methylate their substrates but can be split into several subclasses based on their structural features. The most common class of methyltransferases is class I, all of which co ...
enzymes. * Histidine is also a precursor for carnosine
biosynthesis Biosynthesis is a multi-step, enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts ...
, which is a dipeptide found in skeletal muscle. * In
Actinomycetota The ''Actinomycetota'' (synonym ''Actinobacteria'') are a phylum of mostly Gram-positive bacteria. They can be terrestrial animal, terrestrial or aquatic animal, aquatic. They are of great economic importance to humans because agriculture and fo ...
and filamentous fungi, such as ''
Neurospora crassa ''Neurospora crassa'' is a type of red bread mold of the phylum Ascomycota. The genus name, meaning "nerve spore" in Greek, refers to the characteristic striations on the spores. The first published account of this fungus was from an infestation ...
'', histidine can be converted into the
antioxidant Antioxidants are compounds that inhibit oxidation, a chemical reaction A chemical reaction is a process that leads to the IUPAC nomenclature for organic transformations, chemical transformation of one set of chemical substances to anothe ...
ergothioneine.


Requirements

The Food and Nutrition Board (FNB) of the U.S. Institute of Medicine set Recommended Dietary Allowances (RDAs) for
essential amino acid An essential amino acid, or indispensable amino acid, is an amino acid that cannot be synthesized from scratch by the organism fast enough to supply its demand, and must therefore come from the diet. Of the 21 amino acids common to all life form ...
s in 2002. For histidine, for adults 19 years and older, 14 mg/kg body weight/day. Supplemental histidine is being investigated for use in a variety of different conditions, including neurological disorders, atopic dermatitis, metabolic syndrome, diabetes, uraemic anaemia, ulcers, inflammatory bowel diseases, malignancies, and muscle performance during strenuous exercise.


See also

* Carnosinemia * Beta-Alanine * Diphthamide * Pauly reaction


References


External links


Histidine MS Spectrum
* * {{Authority control Proteinogenic amino acids Basic amino acids Essential amino acids Imidazoles Carbonic anhydrase activators