Histidine: Difference between revisions

| Name = {{sm|l}}-Histidine

| ImageFile1 = L-HistidineAmino physiologicalAcid Histidine.svgpng

| ImageCaption1 = [[Skeletal formula]]Structure of histidine ([[zwitterion]]ic form)Histidine

The conjugate acid (protonated form) of the [[imidazole]] [[side chain]] in histidine has a [[Acid dissociation constant|p''K''_a]] of approximately 6.0. Thus, below a pH of 6, the imidazole ring is mostly [[Protonation|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 [[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=":4" /><ref name=":5">{{Cite web |title=HISTIDINE |url=http://ambermd.org/Questions/HIS.html |access-date=2022-05-12 |website=ambermd.org}}</ref><ref name=":6">{{Cite journal |lastlast1=Dokainish |firstfirst1=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 |url=https://pubs.acs.org/doi/10.1021/acscatal.6b01094 |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 N1N3-H or N3N1-H [[tautomer]]s. The N3-H tautomer, is shown in the figure above,. is protonated on the #3 nitrogen, farther from the amino acid backbone bearing the amino and carboxyl groups, whereasIn the N1-H tautomer, isthe protonatedNH on the nitrogenis nearer the backbone. These neutral tautomers, also referred to as Nε and Nδ, are sometimes referred to with symbols '''HidHie''' and '''HieHid''', depending on which nitrogen is protonated (Nδ and Nε, respectively).<ref name=":4">{{Cite journal |lastlast1=Kim |firstfirst1=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 |url=http://link.springer.com/10.1007/s10822-013-9643-9 |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=":6" /> 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}}</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 |pages=61–69 |language=en |doi=10.1039/D3CE01164J |s2cid=265572280 |issn=1466-8033}}</ref>

The acid-base properties of the imidazole side chain are relevant to the [[catalyst|catalytic mechanism]] of many [[enzyme]]s.<ref name=":0">{{Cite journal|last=Ingle|first=Robert A.|title=Histidine Biosynthesis|journal=The Arabidopsis Book|volume=9|pages=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 [[haemoglobinhemoglobin]], 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 haemoglobinhemoglobin, compared to 20,000 times stronger in free [[haemheme]].

[[Image:Cu3Im8laccase.png|thumb|left|The tricopper site found in many laccases[[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 journalbook|last1=Bornhorst|first1=J. A.|last2=Falke|first2=J. J.|date=2000|titlechapter=Purification of proteins using polyhistidine affinity tags |date=2000|title=Applications of Chimeric Genes and Hybrid Proteins Part A: Gene Expression and Protein Purification|journalseries=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(2+), Ni(2+) and Cu(2+) 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|url=https://pubmed.ncbi.nlm.nih.gov/26214303|journal=Inorganic Chemistry|volume=54|issue=16|pages=7692–7702|doi=10.1021/acs.inorgchem.5b01029|issn=1520-510X|pmid=26214303}}</ref>

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.<ref>{{Cite journal|last1=Cheng|first1=Yongsong|last2=Zhou|first2=Yunjiao|last3=Yang|first3=Lei|last4=Zhang|first4=Chenglin|last5=Xu|first5=Qingyang|last6=Xie|first6=Xixian|last7=Chen|first7=Ning|date=2013-05-01|title=Modification of histidine biosynthesis pathway genes and the impact on production of L-histidine in Corynebacterium glutamicum|journal=Biotechnology Letters|volume=35|issue=5|pages=735–741|doi=10.1007/s10529-013-1138-1|issn=1573-6776|pmid=23355034|s2cid=18380727}}</ref> {{Expand section|date=January 2016}}

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).<ref name=":3">Board review series (BRS)-- Biochemistry, Molecular Biology, and Genetics (fifth edition): Swanson, Kim, Glucksman</ref> 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]]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.<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 formimino group is transferred to [[tetrahydrofolate]], and the remaining five carbons form glutamate.<ref name=":3" /> Overall, these reactions result in the formation of glutamate and ammonia.<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> Glutamate can then be deaminated by [[glutamate dehydrogenase]] or transaminated to form α-ketoglutarate.<ref name=":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&nbsp;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 |pages=848 |doi=10.3390/nu12030848 |issn=2072-6643 |pmc=7146355 |pmid=32235743|doi-access=free }}</ref>