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Histidine (symbol His or H) is an essential amino acid that is used in the biosynthesis of . It contains an Amine (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. It is Genetic code by the Genetic code CAU and CAC.
Histidine was first isolated by Albrecht Kossel and Sven Gustaf Hedin in 1896. The name stems from its discovery in tissue, from histós "tissue". It is also a precursor to histamine, a vital inflammatory agent in immune responses. The acyl radical is histidyl.
The acid-base properties of the imidazole side chain are relevant to the catalyst of many . In , 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 hemoglobin, 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 hemoglobin, compared to 20,000 times stronger in free heme.
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 Paramagnetism 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.
N-terminal histidines are known to function as bidentate ligands, with a metal (generally copper) bound to both the amine of the N-terminus and the Nε of the histidine; the Nδ is often methylated. Although recently discovered, this "histidine brace" motif is critical in biogeochemical cycles: it functions as the active site of lytic polysaccharide monooxygenases (LPMOs), which break down unreactive polysaccharides such as cellulose. It is proposed that the evolution of these enzymes in fungi corresponds to the first widespread ability to decompose woody plant mass, leading to the end of the Carboniferous and its mass accumulation of coal deposits.
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. 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.
The histidine biosynthesis pathway has been studied in the fungus Neurospora crassa, and a gene ( His-3) encoding a multienzyme complex was found that was similar to the His4 gene of the bacterium Escherichia coli.Ahmed A. Organization of the histidine-3 region of Neurospora. Mol Gen Genet. 1968;103(2):185-93. doi: 10.1007/BF00427145. PMID 4306011 A genetic study of N. crassa histidine indicated that the individual activities of the multienzyme complex occur in discrete, contiguous sections of the His-3 gene mapping, suggesting that the different activities of the multienzyme complex are encoded separately from each other. However, mutants were also found that lacked all three activities simultaneously, suggesting that some mutations cause loss of function of the complex as a whole.
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). (2025). 9780781798754, Wolters Kluwer Health/Lippincott Williams & Wilkins. ISBN 9780781798754 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 , 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
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. (2025). 9780309085250, The National Academies Press. ISBN 9780309085250 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
External links
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