Histidine

Last updated
l-Histidine
L-Histidine physiological.svg
Skeletal formula of histidine (zwitterionic form)
Histidine-from-xtal-3D-bs-17.png
Histidine-from-xtal-3D-sf.png
Names
IUPAC name
Histidine
Other names
2-Amino-3-(1H-imidazol-4-yl)propanoic acid
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.000.678 OOjs UI icon edit-ltr-progressive.svg
KEGG
PubChem CID
UNII
  • 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 Yes check.svgY
    Key: HNDVDQJCIGZPNO-YFKPBYRVSA-N Yes check.svgY
  • O=C([C@H](CC1=CNC=N1)N)O
  • Zwitterion:O=C([C@H](CC1=CNC=N1)[NH3+])[O-]
  • Protonated zwitterion:O=C([C@H](CC1=CNC=[NH1+]1)[NH3+])[O-]
Properties
C6H9N3O2
Molar mass 155.157 g·mol−1
4.19g/100g @ 25 °C [1]
Hazards
NFPA 704 (fire diamond)
1
1
0
Supplementary data page
Histidine (data page)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Histidine (symbol His or H) [2] is an essential 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 an imidazole 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. [3] It is encoded by the codons CAU and CAC.

Contents

Histidine was first isolated by Albrecht Kossel and Sven Gustaf Hedin in 1896. [4] It is also a precursor to histamine, a vital inflammatory agent in immune responses. The acyl radical is histidyl.

Properties of the imidazole side chain

The conjugate acid (protonated form) of the imidazole side chain in histidine has a pKa of approximately 6.0. Thus, below a pH of 6, the imidazole ring is mostly protonated (as described by the Henderson–Hasselbalch equation). The resulting imidazolium 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. Sometimes, the symbol Hip is used for this protonated form instead of the usual His. [5] [6] [7] 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 tautomers. 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. [5] [6] [7] The imidazole/imidazolium ring of histidine is aromatic at all pH values. [8]

The acid-base properties of the imidazole side chain are relevant to the catalytic mechanism of many enzymes. [9] In catalytic triads, the basic nitrogen of histidine abstracts 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. In helices E and F of haemoglobin, histidine influences binding of dioxygen as well as carbon monoxide. 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 on the sigma scale, on which increased shielding corresponds to increased chemical shift). 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 shielding at N3 is substantially reduced due to the second-order paramagnetic effect, which involves a symmetry-allowed interaction between the nitrogen lone pair and the excited π* states of the aromatic ring. At pH > 9, the chemical shifts of N1 and N3 are approximately 185 and 170 ppm. [10]

Ligand

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 . Succinate Dehygrogenase 1YQ3 Haem group.png
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 tricopper site found in many laccases, notice that each copper center is bound to the imidazole sidechains of histidine (color code: copper is brown, nitrogen is blue). Cu3Im8laccase.png
The tricopper site found in many laccases, notice that each copper center is bound to the imidazole sidechains of histidine (color code: copper is brown, nitrogen is blue).

Histidine forms complexes with many metal ions. The imidazole sidechain of the histidine residue commonly serves as a ligand in metalloproteins. 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. [11] 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. [12]

Metabolism

Biosynthesis

Histidine Biosynthesis Pathway Eight different enzymes can catalyze ten reactions. In this image, His4 catalyzes four different reactions in the pathway. WP514 85639.svg
Histidine Biosynthesis Pathway Eight different enzymes can catalyze ten reactions. In this image, His4 catalyzes four different reactions in the pathway.

l-Histidine is an essential amino acid that is not synthesized de novo in humans. [13] 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. [14]

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 (ATP) by the enzyme ATP-phosphoribosyl transferase. ATP-phosphoribosyl transferase is indicated by His1 in the image. [14] 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. [15] His7 splits phosphoribulosylformimino-AICAR-P to form d-erythro-imidazole-glycerol-phosphate. After, His3 forms imidazole acetol-phosphate releasing water. His5 then makes l-histidinol-phosphate, which is then hydrolyzed by His2 making histidinol. His4 catalyzes the oxidation of l-histidinol to form l-histidinal, an amino aldehyde. In the last step, l-histidinal is converted to l-histidine. [15] [16]

Just like animals and microorganisms, plants need histidine for their growth and development. [9] Microorganisms and plants are similar in that they can synthesize histidine. [17] Both synthesize histidine from the biochemical intermediate phosphoribosyl pyrophosphate. In general, the histidine biosynthesis is very similar in plants and microorganisms. [18]

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. [19]

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). [20] 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 prokaryotes, 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. [21] The formimino group is transferred to tetrahydrofolate, and the remaining five carbons form glutamate. [20] Overall, these reactions result in the formation of glutamate and ammonia. [22] Glutamate can then be deaminated by glutamate dehydrogenase or transaminated to form α-ketoglutarate. [20]

Conversion to other biologically active amines

Conversion of histidine to histamine by histidine decarboxylase Histidine decarboxylase.svg
Conversion of histidine to histamine by histidine decarboxylase

Requirements

The Food and Nutrition Board (FNB) of the U.S. Institute of Medicine set Recommended Dietary Allowances (RDAs) for essential amino acids in 2002. For histidine, for adults 19 years and older, 14 mg/kg body weight/day. [27] 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. [28]

See also

Related Research Articles

<span class="mw-page-title-main">Ribonucleotide</span> Nucleotide containing ribose as its pentose component

In biochemistry, a ribonucleotide is a nucleotide containing ribose as its pentose component. It is considered a molecular precursor of nucleic acids. Nucleotides are the basic building blocks of DNA and RNA. Ribonucleotides themselves are basic monomeric building blocks for RNA. Deoxyribonucleotides, formed by reducing ribonucleotides with the enzyme ribonucleotide reductase (RNR), are essential building blocks for DNA. There are several differences between DNA deoxyribonucleotides and RNA ribonucleotides. Successive nucleotides are linked together via phosphodiester bonds.

A nucleoside triphosphate is a nucleoside containing a nitrogenous base bound to a 5-carbon sugar, with three phosphate groups bound to the sugar. They are the molecular precursors of both DNA and RNA, which are chains of nucleotides made through the processes of DNA replication and transcription. Nucleoside triphosphates also serve as a source of energy for cellular reactions and are involved in signalling pathways.

<span class="mw-page-title-main">Pyridoxal phosphate</span> Active form of vitamin B6

Pyridoxal phosphate (PLP, pyridoxal 5'-phosphate, P5P), the active form of vitamin B6, is a coenzyme in a variety of enzymatic reactions. The International Union of Biochemistry and Molecular Biology has catalogued more than 140 PLP-dependent activities, corresponding to ~4% of all classified activities. The versatility of PLP arises from its ability to covalently bind the substrate, and then to act as an electrophilic catalyst, thereby stabilizing different types of carbanionic reaction intermediates.

Biosynthesis is a multi-step, enzyme-catalyzed process where substrates are converted into more complex products in living organisms. In biosynthesis, simple compounds are modified, converted into other compounds, or joined to form macromolecules. This process often consists of metabolic pathways. Some of these biosynthetic pathways are located within a single cellular organelle, while others involve enzymes that are located within multiple cellular organelles. Examples of these biosynthetic pathways include the production of lipid membrane components and nucleotides. Biosynthesis is usually synonymous with anabolism.

<span class="mw-page-title-main">Phosphoenolpyruvate carboxylase</span> Class of enzymes

Phosphoenolpyruvate carboxylase (also known as PEP carboxylase, PEPCase, or PEPC; EC 4.1.1.31, PDB ID: 3ZGE) is an enzyme in the family of carboxy-lyases found in plants and some bacteria that catalyzes the addition of bicarbonate (HCO3) to phosphoenolpyruvate (PEP) to form the four-carbon compound oxaloacetate and inorganic phosphate:

<span class="mw-page-title-main">Phosphoribosyl pyrophosphate</span> Chemical compound

Phosphoribosyl pyrophosphate (PRPP) is a pentose phosphate. It is a biochemical intermediate in the formation of purine nucleotides via inosine-5-monophosphate, as well as in pyrimidine nucleotide formation. Hence it is a building block for DNA and RNA. The vitamins thiamine and cobalamin, and the amino acid tryptophan also contain fragments derived from PRPP. It is formed from ribose 5-phosphate (R5P) by the enzyme ribose-phosphate diphosphokinase:

<span class="mw-page-title-main">Amino acid synthesis</span> The set of biochemical processes by which amino acids are produced

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<span class="mw-page-title-main">Long-chain-fatty-acid—CoA ligase</span> Class of enzymes

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<span class="mw-page-title-main">Ribose 5-phosphate</span> Chemical compound

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<span class="mw-page-title-main">GMP synthase</span>

Guanosine monophosphate synthetase, also known as GMPS is an enzyme that converts xanthosine monophosphate to guanosine monophosphate.

<span class="mw-page-title-main">Ribose-phosphate diphosphokinase</span> Class of enzymes

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<span class="mw-page-title-main">Dihydrofolate synthase</span> Class of enzymes

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<span class="mw-page-title-main">Phosphoribosylaminoimidazolesuccinocarboxamide synthase</span> Class of enzymes

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<span class="mw-page-title-main">ATP phosphoribosyltransferase</span> Class of enzymes

In enzymology, an ATP phosphoribosyltransferase is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">5-Aminoimidazole ribotide</span> Chemical compound

5′-Phosphoribosyl-5-aminoimidazole is a biochemical intermediate in the formation of purine nucleotides via inosine-5-monophosphate, and hence is a building block for DNA and RNA. The vitamins thiamine and cobalamin also contain fragments derived from AIR. It is an intermediate in the adenine pathway and is synthesized from 5′-phosphoribosylformylglycinamidine by AIR synthetase.

References

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