Histidine
Histidine is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group, a carboxylic acid group, and an imidazole side chain, 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 by the codons CAU and CAC.
Histidine was first isolated by German physician Albrecht Kossel and Sven Gustaf Hedin in 1896. 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 of the imidazole side chain in histidine has a pKa of approximately 6.0. Thus, at below a pH of 6, the imidazole ring is mostly protonated. 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. 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, shown in the figure above, is protonated on the #3 nitrogen, farther from the amino acid backbone bearing the amino and carboxyl groups, whereas the N1-H tautomer is protonated on the nitrogen nearer the backbone. The imidazole/imidazolium ring of histidine is aromatic at all pH values.The acid-base properties of the imidazole side chain are relevant to the catalytic mechanism of many enzymes. In catalytic triads, the basic nitrogen of histidine 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. In helices E and F of haemoglobin, histidine influences binding of dioxygen as well as carbon monoxide. This interaction enhances the affinity of Fe 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 14N chemical shifts are similar. NMR spectral measurements shows that the chemical shift of N1-H drops slightly, whereas the chemical shift of N3-H drops considerably. 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.
Ligand
The imidazole sidechain of histidine commonly serves as a ligand in metalloproteins. One example is the axial base attached to Fe in myoglobin and hemoglobin.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 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, 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 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, 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. 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 cycle. 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 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, an amine produced in the body necessary for inflammation.
- 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.
- Histidine can be converted to 3-methylhistidine, which serves as a biomarker for skeletal muscle damage, by certain methyltransferase enzymes.
- Histidine is also a precursor for carnosine biosynthesis, which is a dipeptide found in skeletal muscle.
- In Actinobacteria and filamentous fungi, such as Neurospora crassa, histidine can be converted into the antioxidant ergothioneine.