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[[File:Histidine-spin.gif|thumb|Histidine ball and stick model spinning]] | [[File:Histidine-spin.gif|thumb|Histidine ball and stick model spinning]] | ||
'''Histidine''' (symbol '''His''' or '''H''')<ref name=":7">{{cite web | url = http://www.chem.qmul.ac.uk/iupac/AminoAcid/AA1n2.html | title = Nomenclature and Symbolism for Amino Acids and Peptides | publisher = IUPAC-IUB Joint Commission on Biochemical Nomenclature | year = 1983 | access-date = 5 March 2018 | archive-url = https://web.archive.org/web/20081009023202/http://www.chem.qmul.ac.uk/iupac/AminoAcid/AA1n2.html | archive-date = 9 October 2008 | '''Histidine''' (symbol '''His''' or '''H''')<ref name=":7">{{cite web | url = http://www.chem.qmul.ac.uk/iupac/AminoAcid/AA1n2.html | title = Nomenclature and Symbolism for Amino Acids and Peptides | publisher = IUPAC-IUB Joint Commission on Biochemical Nomenclature | year = 1983 | access-date = 5 March 2018 | archive-url = https://web.archive.org/web/20081009023202/http://www.chem.qmul.ac.uk/iupac/AminoAcid/AA1n2.html | archive-date = 9 October 2008 }}</ref> is an [[essential amino acid]] that is used in the biosynthesis of [[protein]]s. It contains an [[Amine|α-amino group]] (which is in the [[protonated]] –NH<sub>3</sub><sup>+</sup> form under [[Physiological condition|biological conditions]]), a [[carboxylic acid]] group (which is in the deprotonated –COO<sup>−</sup> 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 amino acid|essential]] only for infants, it has now been shown in longer-term studies to be essential for adults also.<ref>{{cite journal |doi=10.1172/JCI108016 |title=Evidence that histidine is an essential amino acid in normal and chronically uremic man |year=1975 |last1=Kopple |first1=Joel D |last2=Swendseid |first2=Marian E |journal=Journal of Clinical Investigation |volume=55 |issue=5 |pages=881–91 |pmid=1123426 |pmc=301830}}</ref> It is [[Genetic code|encoded]] by the [[Genetic code|codons]] CAU and CAC. | ||
Histidine was first isolated by [[Albrecht Kossel]] and [[Sven Gustaf Hedin]] in 1896.<ref>{{Cite journal|last1=Vickery|first1=Hubert Bradford|last2=Leavenworth|first2=Charles S.|title=On the Separation of Histidine and Arginine|date=1928-08-01|url=http://www.jbc.org/content/78/3/627.full.pdf|journal=Journal of Biological Chemistry|language=en|volume=78|issue=3|pages=627–635|doi=10.1016/S0021-9258(18)83967-9|issn=0021-9258|doi-access=free}}</ref> The name stems from its discovery in tissue, from {{wikt-lang|grc|ἱστός}} ''histós'' "tissue".<ref name=":7" /> It is also a [[Precursor (chemistry)|precursor]] to [[histamine]], a vital inflammatory agent in immune responses. The acyl [[radical (chemistry)|radical]] is '''histidyl'''. | Histidine was first isolated by [[Albrecht Kossel]] and [[Sven Gustaf Hedin]] in 1896.<ref>{{Cite journal|last1=Vickery|first1=Hubert Bradford|last2=Leavenworth|first2=Charles S.|title=On the Separation of Histidine and Arginine|date=1928-08-01|url=http://www.jbc.org/content/78/3/627.full.pdf|journal=Journal of Biological Chemistry|language=en|volume=78|issue=3|pages=627–635|doi=10.1016/S0021-9258(18)83967-9|issn=0021-9258|doi-access=free}}</ref> The name stems from its discovery in tissue, from {{wikt-lang|grc|ἱστός}} ''histós'' "tissue".<ref name=":7" /> It is also a [[Precursor (chemistry)|precursor]] to [[histamine]], a vital inflammatory agent in immune responses. The acyl [[radical (chemistry)|radical]] is '''histidyl'''. | ||
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==Properties of the imidazole side chain== | ==Properties of the imidazole side chain== | ||
At neutral or [[physiological pH]], the [[imidazole]] [[side chain]] is neutral. The [[imidazole]] [[side chain]] in histidine has a [[Acid dissociation constant|p''K''<sub>a</sub>]] of approximately 6.0. Thus, below a pH of 6, the imidazole ring is mostly [[Protonation|protonated]] and carries a positive +1 charge (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 [[nitrogen]]s and can be represented with two equally important [[resonance structure]]s. Sometimes, the symbol '''Hip''' is used for this protonated form instead of the usual His.<ref name="Kim2013" /><ref name=":5">{{Cite web |title=AMBER Histidine residues |url=http://ambermd.org/Questions/HIS.html |access-date=2022-05-12 |website=ambermd.org}}</ref><ref name="Dokainish2016">{{Cite journal |last1=Dokainish |first1=Hisham M. |last2=Kitao |first2=Akio |date=2016-08-05 |title=Computational Assignment of the Histidine Protonation State in (6-4) Photolyase Enzyme and Its Effect on the Protonation Step |journal=ACS Catalysis |language=en |volume=6 |issue=8 |pages=5500–5507 |doi=10.1021/acscatal.6b01094 |s2cid=88813605 |issn=2155-5435|doi-access=free }}</ref> 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 N3-H or N1-H [[tautomer]]s | At neutral or [[physiological pH]], the [[imidazole]] [[side chain]] is neutral. The [[imidazole]] [[side chain]] in histidine has a [[Acid dissociation constant|p''K''<sub>a</sub>]] of approximately 6.0. Thus, below a pH of 6, the imidazole ring is mostly [[Protonation|protonated]] and carries a positive +1 charge (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 [[nitrogen]]s and can be represented with two equally important [[resonance structure]]s. Sometimes, the symbol '''Hip''' is used for this protonated form instead of the usual His.<ref name="Kim2013" /><ref name=":5">{{Cite web |title=AMBER Histidine residues |url=http://ambermd.org/Questions/HIS.html |access-date=2022-05-12 |website=ambermd.org}}</ref><ref name="Dokainish2016">{{Cite journal |last1=Dokainish |first1=Hisham M. |last2=Kitao |first2=Akio |date=2016-08-05 |title=Computational Assignment of the Histidine Protonation State in (6-4) Photolyase Enzyme and Its Effect on the Protonation Step |journal=ACS Catalysis |language=en |volume=6 |issue=8 |pages=5500–5507 |doi=10.1021/acscatal.6b01094 |s2cid=88813605 |issn=2155-5435|doi-access=free }}</ref> 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 N3-H or N1-H [[tautomer]]s. In the N1-H tautomer, the NH is nearer the backbone. These neutral tautomers, also referred to as N<sub>ε</sub> (or N<sub>τ</sub>, tau meaning ''tele'' — far) and N<sub>δ</sub> (or N<sub>π</sub>, pi meaning ''pros'' — near), are sometimes referred to with symbols '''Hie''' and '''Hid''', respectively.<ref>{{cite book |title=IUPAC Compendium of Chemical Terminology |date=2025 |publisher=International Union of Pure and Applied Chemistry |edition=5th |chapter-url=https://doi.org/10.1351/goldbook.P04890 |language=en |chapter=''pros''|doi=10.1351/goldbook.P04890 }}</ref><ref name="Kim2013">{{Cite journal |last1=Kim |first1=Meekyum Olivia |last2=Nichols |first2=Sara E. |last3=Wang |first3=Yi |last4=McCammon |first4=J. Andrew |date=March 2013 |title=Effects of histidine protonation and rotameric states on virtual screening of M. tuberculosis RmlC |journal=Journal of Computer-Aided Molecular Design |language=en |volume=27 |issue=3 |pages=235–246 |doi=10.1007/s10822-013-9643-9 |issn=0920-654X |pmc=3639364 |pmid=23579613|bibcode=2013JCAMD..27..235K }}</ref><ref name=":5" /><ref name="Dokainish2016" /> The imidazole/imidazolium ring of histidine is [[aromatic]] at all pH values.<ref>{{cite journal |doi=10.1016/S0022-2860(03)00282-5 |title=Five-membered heterocycles. Part III. Aromaticity of 1,3-imidazole in 5+n hetero-bicyclic molecules |year=2003 |last1=Mrozek |first1=Agnieszka |last2=Karolak-Wojciechowska |first2=Janina |last3=Kieć-Kononowicz |first3=Katarzyna |journal=Journal of Molecular Structure |volume=655 |issue=3 |pages=397–403 |bibcode=2003JMoSt.655..397M |url=https://ruj.uj.edu.pl/xmlui/handle/item/261742 }}</ref> Under certain conditions, all three ion-forming groups of histidine can be charged forming the histidinium cation.<ref>{{Cite journal |last1=Novikov |first1=Anton P. |last2=Safonov |first2=Alexey V. |last3=German |first3=Konstantin E. |last4=Grigoriev |first4=Mikhail S. |date=2023-12-01 |title=What kind of interactions we may get moving from zwitter to "dritter" ions: C–O⋯Re(O4) and Re–O⋯Re(O4) anion⋯anion interactions make structural difference between L-histidinium perrhenate and pertechnetate |url=https://pubs.rsc.org/en/content/articlelanding/2024/ce/d3ce01164j |journal=CrystEngComm |volume=26 |issue=1 |pages=61–69 |language=en |doi=10.1039/D3CE01164J |bibcode=2023CEG....26...61N |s2cid=265572280 |issn=1466-8033|url-access=subscription }}</ref> | ||
The acid-base properties of the imidazole side chain are relevant to the [[catalyst|catalytic mechanism]] of many [[enzyme]]s.<ref name="Ingle2011">{{Cite journal|last=Ingle|first=Robert A.|title=Histidine Biosynthesis|journal=The Arabidopsis Book|volume=9| | The acid-base properties of the imidazole side chain are relevant to the [[catalyst|catalytic mechanism]] of many [[enzyme]]s.<ref name="Ingle2011">{{Cite journal|last=Ingle|first=Robert A.|title=Histidine Biosynthesis|journal=The Arabidopsis Book|volume=9|article-number=e0141|doi=10.1199/tab.0141|pmc=3266711|pmid=22303266|year=2011}}</ref> In [[catalytic triad]]s, 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 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. 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 O<sub>2</sub> 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 <sup>15</sup>N NMR spectroscopy. The two <sup>15</sup>N 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|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.<ref>{{cite book|title=ABCs of FT-NMR|last=Roberts|first=John D.|publisher=University Science Books|year=2000|isbn=978-1-891389-18-4|location=Sausalito, CA|pages=258–9}}</ref> | The tautomerism and acid-base properties of the imidazole side chain has been characterized by <sup>15</sup>N NMR spectroscopy. The two <sup>15</sup>N 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|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.<ref>{{cite book|title=ABCs of FT-NMR|last=Roberts|first=John D.|publisher=University Science Books|year=2000|isbn=978-1-891389-18-4|location=Sausalito, CA|pages=258–9}}</ref> | ||
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[[Image:Succinate Dehygrogenase 1YQ3 Haem group.png|thumb|left|The histidine-bound [[heme]] group of [[succinate dehydrogenase]], an [[electron carrier]] in the [[mitochondria]]l [[electron transfer chain]]. The large semi-transparent sphere indicates the location of the [[iron]] [[ion]]. From {{PDB|1YQ3}}.|205x205px]] | [[Image:Succinate Dehygrogenase 1YQ3 Haem group.png|thumb|left|The histidine-bound [[heme]] group of [[succinate dehydrogenase]], an [[electron carrier]] in the [[mitochondria]]l [[electron transfer chain]]. The large semi-transparent sphere indicates the location of the [[iron]] [[ion]]. From {{PDB|1YQ3}}.|205x205px]] | ||
[[Image:Cu3Im8laccase.png|thumb|left|The tricopper site found in many [[laccase]]s, notice that each [[copper]] center is bound to the [[imidazole]] sidechains of histidine (color code: copper is brown, [[nitrogen]] is blue).]] | [[Image:Cu3Im8laccase.png|thumb|left|The tricopper site found in many [[laccase]]s, notice that each [[copper]] center is bound to the [[imidazole]] sidechains of histidine (color code: copper is brown, [[nitrogen]] is blue).]] | ||
Histidine forms [[amino acid complex|complexes]] with many metal ions. The imidazole sidechain of the histidine residue commonly serves as a [[ligand]] in [[metalloprotein]]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.<ref>{{Cite book|last1=Bornhorst|first1=J. A.|last2=Falke|first2=J. J.|chapter=Purification of proteins using polyhistidine affinity tags |date=2000|title=Applications of Chimeric Genes and Hybrid Proteins Part A: Gene Expression and Protein Purification|series=Methods in Enzymology|volume=326|pages=245–254|doi=10.1016/s0076-6879(00)26058-8|issn=0076-6879|pmc=2909483|pmid=11036646|isbn=978-0-12-182227-9 }}</ref> Natural poly-histidine peptides, found in the venom of the viper ''[[Atheris squamigera]]'' have been shown to bind Zn(II), Ni(II) and Cu(II) and affect the function of venom metalloproteases.<ref>{{Cite journal|last1=Watly|first1=Joanna|last2=Simonovsky|first2=Eyal|last3=Barbosa|first3=Nuno|last4=Spodzieja|first4=Marta|last5=Wieczorek|first5=Robert|last6=Rodziewicz-Motowidlo|first6=Sylwia|last7=Miller|first7=Yifat|last8=Kozlowski|first8=Henryk|date=2015-08-17|title=African Viper Poly-His Tag Peptide Fragment Efficiently Binds Metal Ions and Is Folded into an α-Helical Structure | Histidine forms [[amino acid complex|complexes]] with many metal ions. The imidazole sidechain of the histidine residue commonly serves as a [[ligand]] in [[metalloprotein]]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.<ref>{{Cite book|last1=Bornhorst|first1=J. A.|last2=Falke|first2=J. J.|chapter=Purification of proteins using polyhistidine affinity tags |date=2000|title=Applications of Chimeric Genes and Hybrid Proteins Part A: Gene Expression and Protein Purification|series=Methods in Enzymology|volume=326|pages=245–254|doi=10.1016/s0076-6879(00)26058-8|issn=0076-6879|pmc=2909483|pmid=11036646|isbn=978-0-12-182227-9 }}</ref> Natural poly-histidine peptides, found in the venom of the viper ''[[Atheris squamigera]]'' have been shown to bind Zn(II), Ni(II) and Cu(II) and affect the function of venom metalloproteases.<ref>{{Cite journal|last1=Watly|first1=Joanna|last2=Simonovsky|first2=Eyal|last3=Barbosa|first3=Nuno|last4=Spodzieja|first4=Marta|last5=Wieczorek|first5=Robert|last6=Rodziewicz-Motowidlo|first6=Sylwia|last7=Miller|first7=Yifat|last8=Kozlowski|first8=Henryk|date=2015-08-17|title=African Viper Poly-His Tag Peptide Fragment Efficiently Binds Metal Ions and Is Folded into an α-Helical Structure|journal=Inorganic Chemistry|volume=54|issue=16|pages=7692–7702|doi=10.1021/acs.inorgchem.5b01029|issn=1520-510X|pmid=26214303}}</ref> | ||
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 N<sub> | 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 N<sub>δ</sub> of the histidine; the N<sub>ε</sub> is often methylated.<ref name="Walton2023">{{Cite journal |last1=Walton |first1=Paul H. |last2=Davies |first2=Gideon J. |last3=Diaz |first3=Daniel E. |last4=Franco-Cairo |first4=João P. |date=2023 |title=The histidine brace: nature's copper alternative to haem? |journal=FEBS Letters |language=en |volume=597 |issue=4 |pages=485–494 |doi=10.1002/1873-3468.14579 |issn=1873-3468 |pmc=10952591 |pmid=36660911}}</ref> Although recently discovered,<ref>{{Cite journal |last1=Quinlan |first1=R. Jason |last2=Sweeney |first2=Matt D. |last3=Lo Leggio |first3=Leila |last4=Otten |first4=Harm |last5=Poulsen |first5=Jens-Christian N. |last6=Johansen |first6=Katja Salomon |last7=Krogh |first7=Kristian B. R. M. |last8=Jørgensen |first8=Christian Isak |last9=Tovborg |first9=Morten |last10=Anthonsen |first10=Annika |last11=Tryfona |first11=Theodora |last12=Walter |first12=Clive P. |last13=Dupree |first13=Paul |last14=Xu |first14=Feng |last15=Davies |first15=Gideon J. |date=2011-09-13 |title=Insights into the oxidative degradation of cellulose by a copper metalloenzyme that exploits biomass components |journal=Proceedings of the National Academy of Sciences |volume=108 |issue=37 |pages=15079–15084 |doi=10.1073/pnas.1105776108 |doi-access=free |pmc=3174640 |pmid=21876164 |bibcode=2011PNAS..10815079Q }}</ref> 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.<ref>{{Cite journal |last1=Munzone |first1=Alessia |last2=Eijsink |first2=Vincent G. H. |last3=Berrin |first3=Jean-Guy |last4=Bissaro |first4=Bastien |date=February 2024 |title=Expanding the catalytic landscape of metalloenzymes with lytic polysaccharide monooxygenases |url=https://www.nature.com/articles/s41570-023-00565-z |journal=Nature Reviews Chemistry |language=en |volume=8 |issue=2 |pages=106–119 |doi=10.1038/s41570-023-00565-z |pmid=38200220 |issn=2397-3358|url-access=subscription }}</ref> 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|Carboniferous era]] and its mass [[Carboniferous#Coal formation|accumulation of coal deposits]].<ref name="Walton2023" /> | ||
==Metabolism== | ==Metabolism== | ||
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Eight different enzymes can catalyze ten reactions. In this image, His4 catalyzes four different reactions in the pathway. | Eight different enzymes can catalyze ten reactions. In this image, His4 catalyzes four different reactions in the pathway. | ||
]] | ]] | ||
{{sm|l}}-Histidine is an essential amino acid that is not synthesized ''[[De novo synthesis|de novo]]'' in humans.<ref>{{cite journal |last1=Moro |first1=Joanna |last2=Tomé |first2=Daniel |last3=Schmidely |first3=Philippe |last4=Demersay |first4=Tristan-Chalvon |last5=Azzout-Marniche |first5=Dalila |title=Histidine: A Systematic Review on Metabolism and Physiological Effects in Human and Different Animal Species |journal=Nutrients |date=14 May 2020 |volume=12 |issue=5 | | {{sm|l}}-Histidine is an essential amino acid that is not synthesized ''[[De novo synthesis|de novo]]'' in humans.<ref>{{cite journal |last1=Moro |first1=Joanna |last2=Tomé |first2=Daniel |last3=Schmidely |first3=Philippe |last4=Demersay |first4=Tristan-Chalvon |last5=Azzout-Marniche |first5=Dalila |title=Histidine: A Systematic Review on Metabolism and Physiological Effects in Human and Different Animal Species |journal=Nutrients |date=14 May 2020 |volume=12 |issue=5 |page=1414 |doi=10.3390/nu12051414 |doi-access=free|pmid=32423010 |pmc=7284872 }}</ref> 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, [[Histidinol dehydrogenase|His4]] catalyzes 4 different steps in the pathway.<ref name="Alifano1996">{{Cite journal|last1=Alifano|first1=P|last2=Fani|first2=R|last3=Liò|first3=P|last4=Lazcano|first4=A|last5=Bazzicalupo|first5=M|last6=Carlomagno|first6=M S|last7=Bruni|first7=C B|date=1996-03-01|title=Histidine biosynthetic pathway and genes: structure, regulation, and evolution.|journal=Microbiological Reviews|volume=60|issue=1|pages=44–69|issn=0146-0749|pmc=239417|pmid=8852895|doi=10.1128/MMBR.60.1.44-69.1996}}</ref> | ||
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 phosphoribosyltransferase|ATP-phosphoribosyl transferase]]. ATP-phosphoribosyl transferase is indicated by His1 in the image.<ref name="Alifano1996" /> 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.<ref name="Kulis-Horn2014">{{Cite journal|last1=Kulis-Horn|first1=Robert K|last2=Persicke|first2=Marcus|last3=Kalinowski|first3=Jörn|date=2014-01-01|title=Histidine biosynthesis, its regulation and biotechnological application in Corynebacterium glutamicum|journal=Microbial Biotechnology|volume=7|issue=1|pages=5–25|doi=10.1111/1751-7915.12055|issn=1751-7915|pmc=3896937|pmid=23617600}}</ref> His7 splits phosphoribulosylformimino-AICAR-P to form {{sm|d}}-erythro-imidazole-glycerol-phosphate. After, His3 forms imidazole acetol-phosphate releasing water. His5 then makes {{sm|l}}-histidinol-phosphate, which is then hydrolyzed by His2 making [[histidinol]]. [[Histidinol dehydrogenase|His4]] catalyzes the oxidation of {{sm|l}}-histidinol to form {{sm|l}}-histidinal, an amino aldehyde. In the last step, {{sm|l}}-histidinal is converted to {{sm|l}}-histidine.<ref name="Kulis-Horn2014" /><ref>{{Cite journal|last=Adams|first=E.|date=1955-11-01|title=L-Histidinal, a biosynthetic precursor of histidine|journal=The Journal of Biological Chemistry|volume=217|issue=1|pages=325–344|doi=10.1016/S0021-9258(19)57184-8|issn=0021-9258|pmid=13271397|doi-access=free}}</ref> | 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 phosphoribosyltransferase|ATP-phosphoribosyl transferase]]. ATP-phosphoribosyl transferase is indicated by His1 in the image.<ref name="Alifano1996" /> 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.<ref name="Kulis-Horn2014">{{Cite journal|last1=Kulis-Horn|first1=Robert K|last2=Persicke|first2=Marcus|last3=Kalinowski|first3=Jörn|date=2014-01-01|title=Histidine biosynthesis, its regulation and biotechnological application in Corynebacterium glutamicum|journal=Microbial Biotechnology|volume=7|issue=1|pages=5–25|doi=10.1111/1751-7915.12055|issn=1751-7915|pmc=3896937|pmid=23617600}}</ref> His7 splits phosphoribulosylformimino-AICAR-P to form {{sm|d}}-erythro-imidazole-glycerol-phosphate. After, His3 forms imidazole acetol-phosphate releasing water. His5 then makes {{sm|l}}-histidinol-phosphate, which is then hydrolyzed by His2 making [[histidinol]]. [[Histidinol dehydrogenase|His4]] catalyzes the oxidation of {{sm|l}}-histidinol to form {{sm|l}}-histidinal, an amino aldehyde. In the last step, {{sm|l}}-histidinal is converted to {{sm|l}}-histidine.<ref name="Kulis-Horn2014" /><ref>{{Cite journal|last=Adams|first=E.|date=1955-11-01|title=L-Histidinal, a biosynthetic precursor of histidine|journal=The Journal of Biological Chemistry|volume=217|issue=1|pages=325–344|doi=10.1016/S0021-9258(19)57184-8|issn=0021-9258|pmid=13271397|doi-access=free}}</ref> | ||
| Line 93: | Line 93: | ||
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|E. coli]]''.<ref name="Ahmed1968">Ahmed A. Organization of the histidine-3 region of Neurospora. Mol Gen Genet. 1968;103(2):185-93. doi: 10.1007/BF00427145. PMID 4306011</ref> A genetic study of ''N. crassa'' histidine [[mutant]]s indicated that the individual activities of the multienzyme complex occur in discrete, contiguous sections of the ''His-3'' [[gene mapping|genetic map]], suggesting that the different activities of the multienzyme complex are encoded separately from each other.<ref name = Ahmed1968/> 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. | 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|E. coli]]''.<ref name="Ahmed1968">Ahmed A. Organization of the histidine-3 region of Neurospora. Mol Gen Genet. 1968;103(2):185-93. doi: 10.1007/BF00427145. PMID 4306011</ref> A genetic study of ''N. crassa'' histidine [[mutant]]s indicated that the individual activities of the multienzyme complex occur in discrete, contiguous sections of the ''His-3'' [[gene mapping|genetic map]], suggesting that the different activities of the multienzyme complex are encoded separately from each other.<ref name = Ahmed1968/> 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. | ||
Like animals and microorganisms, plants need histidine for their growth and development.<ref name="Ingle2011" /> But unlike animals, microorganisms and plants can synthesize histidine.<ref>{{cite web |last=DeNofrio |first=Jan |url=https://www.thetech.org/ask-a-geneticist/articles/2011/ask396/ |title=How come plants can make essential amino acids but people can't? |website=[[The Tech Interactive]] |series=Ask a Geneticist |date=2011-02-08 |access-date=2024-08-04}}</ref> Both synthesize histidine from the biochemical intermediate phosphoribosyl pyrophosphate. In general, the histidine biosynthesis is very similar in plants and microorganisms.<ref>{{Cite journal|last1=Stepansky|first1=A.|last2=Leustek|first2=T.|date=2006-03-01|title=Histidine biosynthesis in plants|journal=Amino Acids|volume=30|issue=2|pages=127–142|doi=10.1007/s00726-005-0247-0|issn=0939-4451|pmid=16547652|s2cid=23733445}}</ref> | |||
==== Regulation of biosynthesis ==== | ==== Regulation of biosynthesis ==== | ||
| Line 99: | Line 99: | ||
=== Degradation === | === Degradation === | ||
Histidine is one of the amino acids | Histidine can be metabolized into [[glutamate]], which is readily metabolized into AKG ([[alpha-ketoglutarate]]), making histidine one of the amino acids whose metabolites can become [[citric acid cycle]] intermediates.<ref name="Swanson2010">{{cite book |last1=Swanson |first1=Todd A. |last2=Kim |first2=Sandra I. |last3=Glucksman |first3=Marc J. |last4=Lieberman |first4=Michael |last5=Swanson |first5=Todd A. |title=Biochemistry, molecular biology, and genetics |date=2010 |publisher=Wolters Kluwer Health/Lippincott Williams & Wilkins |location=Philadelphia |isbn=978-0-7817-9875-4 |edition=5th}}{{Page needed|date=March 2025}}</ref> The process requires several steps. In [[prokaryote]]s, histidine first undergoes [[deamination]], the removal of its amino group by the emzyme [[histidase]]. This step produces ammonia and urocanic acid (urocanate).<ref>{{Cite journal|last1=Mehler|first1=A. H.|last2=Tabor|first2=H.|date=1953-04-01|title=Deamination of histidine to form urocanic acid in liver|journal=The Journal of Biological Chemistry|volume=201|issue=2|pages=775–784|doi=10.1016/S0021-9258(18)66234-9|issn=0021-9258|pmid=13061415|doi-access=free}}</ref> The enzyme [[urocanase]] then converts urocanic acid into imidazolonepropionate (4-imidazolone-5-propionate). The enzyme imidazolonepropionase then converts imidazolonepropionate into [[formiminoglutamate]] (FIGLU).<ref>{{Cite journal|last1=Coote|first1=J. G.|last2=Hassall|first2=H.|date=1973-03-01|title=The degradation of l-histidine, imidazolyl-l-lactate and imidazolylpropionate by Pseudomonas testosteroni|journal=Biochemical Journal|volume=132|issue=3|pages=409–422|issn=0264-6021|pmc=1177604|pmid=4146796|doi=10.1042/bj1320409}}</ref> The enzyme [[formimidoyltransferase cyclodeaminase]] removes the formimino group (which is transferred to [[tetrahydrofolate]]), leaving behind a glutamate molecule.<ref name="Swanson2010" /> Glutamate can then be deaminated by [[glutamate dehydrogenase]] or transaminated to form α-ketoglutarate.<ref name="Swanson2010" /> | ||
=== Conversion to other biologically active amines === | === Conversion to other biologically active amines === | ||
| Line 110: | Line 110: | ||
==Requirements== | ==Requirements== | ||
The [[Food and Nutrition Board]] (FNB) of the [[U.S. Institute of Medicine]] set [[Recommended Dietary Allowances]] (RDAs) for [[essential amino acid]]s in 2002. For histidine, for adults 19 years and older, 14 mg/kg body weight/day.<ref name="DRItext">{{cite book | last1 = Institute of Medicine | title = Dietary Reference Intakes for Energy, Carbohydrates, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids | chapter = Protein and Amino Acids | publisher = The National Academies Press | year = 2002 | location = Washington, DC | pages = 589–768 | doi = 10.17226/10490 | isbn = 978-0-309-08525-0 | chapter-url = https://www.nap.edu/read/10490/chapter/12| author1-link = Institute of Medicine }}</ref> 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.<ref>{{Cite journal |last=Holeček |first=Milan |date=2020-03-22 |title=Histidine in Health and Disease: Metabolism, Physiological Importance, and Use as a Supplement |journal=Nutrients |volume=12 |issue=3 | | The [[Food and Nutrition Board]] (FNB) of the [[U.S. Institute of Medicine]] set [[Recommended Dietary Allowances]] (RDAs) for [[essential amino acid]]s in 2002. For histidine, for adults 19 years and older, 14 mg/kg body weight/day.<ref name="DRItext">{{cite book | last1 = Institute of Medicine | title = Dietary Reference Intakes for Energy, Carbohydrates, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids | chapter = Protein and Amino Acids | publisher = The National Academies Press | year = 2002 | location = Washington, DC | pages = 589–768 | doi = 10.17226/10490 | bibcode = 2002nap..book10490I | isbn = 978-0-309-08525-0 | chapter-url = https://www.nap.edu/read/10490/chapter/12| author1-link = Institute of Medicine }}</ref> 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.<ref>{{Cite journal |last=Holeček |first=Milan |date=2020-03-22 |title=Histidine in Health and Disease: Metabolism, Physiological Importance, and Use as a Supplement |journal=Nutrients |volume=12 |issue=3 |page=848 |doi=10.3390/nu12030848 |issn=2072-6643 |pmc=7146355 |pmid=32235743|doi-access=free }}</ref> | ||
== See also == | == See also == | ||
Latest revision as of 00:18, 15 October 2025
Template:Short description Template:Chembox
Histidine (symbol His or H)[1] 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.[2] It is encoded by the codons CAU and CAC.
Histidine was first isolated by Albrecht Kossel and Sven Gustaf Hedin in 1896.[3] The name stems from its discovery in tissue, from Template:Wikt-lang histós "tissue".[1] 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
At neutral or physiological pH, the imidazole side chain is neutral. 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 and carries a positive +1 charge (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.[4][5][6] 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 N3-H or N1-H tautomers. In the N1-H tautomer, the NH is nearer the backbone. These neutral tautomers, also referred to as Nε (or Nτ, tau meaning tele — far) and Nδ (or Nπ, pi meaning pros — near), are sometimes referred to with symbols Hie and Hid, respectively.[7][4][5][6] The imidazole/imidazolium ring of histidine is aromatic at all pH values.[8] Under certain conditions, all three ion-forming groups of histidine can be charged forming the histidinium cation.[9]
The acid-base properties of the imidazole side chain are relevant to the catalytic mechanism of many enzymes.[10] 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 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 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.[11]
Ligand
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.[12] Natural poly-histidine peptides, found in the venom of the viper Atheris squamigera have been shown to bind Zn(II), Ni(II) and Cu(II) and affect the function of venom metalloproteases.[13]
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 Nδ of the histidine; the Nε is often methylated.[14] Although recently discovered,[15] 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.[16] 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 era and its mass accumulation of coal deposits.[14]
Metabolism
Biosynthesis
Template:Sm-Histidine is an essential amino acid that is not synthesized de novo in humans.[17] 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.[18]
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.[18] 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.[19] His7 splits phosphoribulosylformimino-AICAR-P to form Template:Sm-erythro-imidazole-glycerol-phosphate. After, His3 forms imidazole acetol-phosphate releasing water. His5 then makes Template:Sm-histidinol-phosphate, which is then hydrolyzed by His2 making histidinol. His4 catalyzes the oxidation of Template:Sm-histidinol to form Template:Sm-histidinal, an amino aldehyde. In the last step, Template:Sm-histidinal is converted to Template:Sm-histidine.[19][20]
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 E. coli.[21] A genetic study of N. crassa histidine mutants indicated that the individual activities of the multienzyme complex occur in discrete, contiguous sections of the His-3 genetic map, suggesting that the different activities of the multienzyme complex are encoded separately from each other.[21] 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.
Like animals and microorganisms, plants need histidine for their growth and development.[10] But unlike animals, microorganisms and plants can synthesize histidine.[22] Both synthesize histidine from the biochemical intermediate phosphoribosyl pyrophosphate. In general, the histidine biosynthesis is very similar in plants and microorganisms.[23]
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.[24]
Degradation
Histidine can be metabolized into glutamate, which is readily metabolized into AKG (alpha-ketoglutarate), making histidine one of the amino acids whose metabolites can become citric acid cycle intermediates.[25] The process requires several steps. In prokaryotes, histidine first undergoes deamination, the removal of its amino group by the emzyme histidase. This step produces ammonia and urocanic acid (urocanate).[26] The enzyme urocanase then converts urocanic acid into imidazolonepropionate (4-imidazolone-5-propionate). The enzyme imidazolonepropionase then converts imidazolonepropionate into formiminoglutamate (FIGLU).[27] The enzyme formimidoyltransferase cyclodeaminase removes the formimino group (which is transferred to tetrahydrofolate), leaving behind a glutamate molecule.[25] Glutamate can then be deaminated by glutamate dehydrogenase or transaminated to form α-ketoglutarate.[25]
Conversion to other biologically active amines
- The histidine amino acid is a precursor for histamine, an amine produced in the body necessary for inflammation.[28]
- 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 finding.
- Histidine can be converted to 3-methylhistidine, which serves as a biomarker for skeletal muscle damage, by certain methyltransferase enzymes.[29]
- Histidine is also a precursor for carnosine biosynthesis, which is a dipeptide found in skeletal muscle.[30]
- In Actinomycetota and filamentous fungi, such as Neurospora crassa, histidine can be converted into the antioxidant ergothioneine.[31]
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.[32] 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.[33]
See also
References
External links
Template:Amino acids Template:Amino acid metabolism intermediates Template:Histaminergics
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