histidine decarboxylase

File:HDC Active Site Diagram.tif is normally covalently bound to HDC at lysine 305. It is also held in place with hydrogen bonds to other nearby amino acids. Here, the active site is shown with PLP bound to histidine methyl ester, which was necessary for crystallization.{{cite journal | vauthors = Komori H, Nitta Y, Ueno H, Higuchi Y | title = Structural study reveals that Ser-354 determines substrate specificity on human histidine decarboxylase | journal = The Journal of Biological Chemistry | volume = 287 | issue = 34 | pages = 29175–83 | date = August 2012 | pmid = 22767596 | pmc = 3436558 | doi = 10.1074/jbc.M112.381897 | doi-access = free }} Generated from 4E1O.|left]]

Histidine decarboxylase is a group II pyridoxal-dependent decarboxylase, along with aromatic-L-amino-acid decarboxylase, and tyrosine decarboxylase. HDC is expressed as a 74 kDa polypeptide which is not enzymatically functional.{{Cite journal|last=Nitta|first=Yoko|year=2010|title=Expression of recombinant human histidine decarboxylase with full length and C-terminal truncated forms in yeast and bacterial cells|url=http://www.jsb.gr.jp/jbm/2010/1003_1.pdf|journal=J. Biol. Macromol.|volume=10}} Only after post-translational processing does the enzyme become active. This processing consists of truncating much of the protein's C-terminal chain, reducing the peptide molecular weight to 54 kDa.

Histidine decarboxylase exists as a homodimer, with several amino acids from the respective opposing chain stabilizing the HDC active site. In HDC's resting state, PLP is covalently bound in a Schiff base to lysine 305, and stabilized by several hydrogen bonds to nearby amino acids aspartate 273, serine 151 and the opposing chain's serine 354. HDC contains several regions that are sequentially and structurally similar to those in a number of other pyridoxal-dependent decarboxylases.{{Cite journal|last=Jackson|first=F. Rob|date=1990-10-01|title=Prokaryotic and eukaryotic pyridoxal-dependent decarboxylases are homologous|journal=Journal of Molecular Evolution|language=en|volume=31|issue=4|pages=325–329|doi=10.1007/BF02101126|pmid=2124279|bibcode=1990JMolE..31..325J|s2cid=9206252|issn=0022-2844|doi-access=free}} This is particularly evident in the vicinity of the active site lysine 305.{{cite journal | vauthors = Sandmeier E, Hale TI, Christen P | title = Multiple evolutionary origin of pyridoxal-5'-phosphate-dependent amino acid decarboxylases | journal = European Journal of Biochemistry | volume = 221 | issue = 3 | pages = 997–1002 | date = May 1994 | pmid = 8181483 | doi = 10.1111/j.1432-1033.1994.tb18816.x | doi-access = free }}

File:HDC mechanism.tif co-factor.{{cite journal | vauthors = Wu F, Yu J, Gehring H | title = Inhibitory and structural studies of novel coenzyme-substrate analogs of human histidine decarboxylase | journal = FASEB Journal | volume = 22 | issue = 3 | pages = 890–7 | date = March 2008 | pmid = 17965265 | doi = 10.1096/fj.07-9566com | doi-access = free | s2cid = 39078427 | url = http://www.fasebj.org/content/22/3/890 }} This mechanism is similar to many other PLP-dependent carboxylases.|thumb]]HDC decarboxylates histidine through the use of a PLP cofactor initially bound in a Schiff base to lysine 305. Histidine initiates the reaction by displacing lysine 305 and forming an aldimine with PLP. Then, histidine's carboxyl group leaves the substrate, forming carbon dioxide. This is the rate-limiting step of the all process, requiring an activation energy of 17.6 kcal/mol {{cite journal | vauthors = Fernandes HS, Ramos MJ, Cerqueira NM | title = The Catalytic Mechanism of the Pyridoxal-5'-phosphate-Dependent Enzyme, Histidine Decarboxylase: A Computational Study | journal = Chemistry: A European Journal | volume = 23 | issue = 38 | pages = 9162–9173 | date = July 2017 | pmid = 28613002 | doi = 10.1002/chem.201701375 }} and fitting the experimental turnover of 1.73 s^{-1}.{{cite journal | vauthors = Komori H, Nitta Y, Ueno H, Higuchi Y | title = Structural study reveals that Ser-354 determines substrate specificity on human histidine decarboxylase | journal = The Journal of Biological Chemistry | volume = 287 | issue = 34 | pages = 29175–83 | date = August 2012 | pmid = 22767596 | pmc = 3436558 | doi = 10.1074/jbc.m112.381897 | doi-access = free }} After the decarboxylation takes place, the PLP intermediate is protonated by tyrosine 334 from the second subunit. The protonation is mediated by a water molecule and it is very fast and also very exergonic. Finally, PLP re-forms its original Schiff base at lysine 305, and histamine is released. This mechanism is very similar to those employed by other pyridoxal-dependent decarboxylases. In particular, the aldimine intermediate is a common feature of all known PLP-dependent decarboxylases.{{Cite web|url=http://www.ebi.ac.uk/interpro/entry/IPR002129|title=Pyridoxal phosphate-dependent decarboxylase|website=InterPro}} HDC is highly specific for its histidine substrate.{{cite journal | vauthors = Toney MD | title = Reaction specificity in pyridoxal phosphate enzymes | journal = Archives of Biochemistry and Biophysics | volume = 433 | issue = 1 | pages = 279–87 | date = January 2005 | pmid = 15581583 | doi = 10.1016/j.abb.2004.09.037 | series = Highlight issue on Enzyme Mechanisms }}

Histidine decarboxylase is the primary biological source of histamine. Histamine is an important biogenic amine that moderates numerous physiologic processes. There are four different histamine receptors, H₁, H₂, H₃, and H₄,{{Cite journal |last1=Jutel |first1=M. |last2=Akdis |first2=M. |last3=Akdis |first3=C. A. |date=2009-11-13 |title=Histamine, histamine receptors and their role in immune pathology |url=http://dx.doi.org/10.1111/j.1365-2222.2009.03374.x |journal=Clinical & Experimental Allergy |volume=39 |issue=12 |pages=1786–1800 |doi=10.1111/j.1365-2222.2009.03374.x |pmid=20085595 |issn=0954-7894}} each of which carries a different biological significance. H₁ modulates several functions of the central and peripheral nervous system, including circadian rhythm, body temperature and appetite.{{cite journal | vauthors = Panula P, Chazot PL, Cowart M, Gutzmer R, Leurs R, Liu WL, Stark H, Thurmond RL, Haas HL | title = International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors | journal = Pharmacological Reviews | volume = 67 | issue = 3 | pages = 601–55 | date = July 2015 | pmid = 26084539 | pmc = 4485016 | doi = 10.1124/pr.114.010249 }} H₂ activation results in gastric acid secretion and smooth muscle relaxation.{{cite journal | vauthors = Canonica GW, Blaiss M | title = Antihistaminic, anti-inflammatory, and antiallergic properties of the nonsedating second-generation antihistamine desloratadine: a review of the evidence | journal = The World Allergy Organization Journal | volume = 4 | issue = 2 | pages = 47–53 | date = February 2011 | pmid = 23268457 | pmc = 3500039 | doi = 10.1097/WOX.0b013e3182093e19 | url = http://www.waojournal.org/content/4/2/47/abstract }}{{Cite journal|last=Hill|first=S.J.|year=1997|title=Classification of Histamine Receptors|url=http://pharmrev.aspetjournals.org/content/49/3/253|journal=Pharmacological Reviews|volume=49|pages=253–278|via=ASPET}} H₃ controls histamine turnover by feedback inhibition of histamine synthesis and release.{{cite journal | vauthors = West RE, Zweig A, Shih NY, Siegel MI, Egan RW, Clark MA | title = Identification of two H3-histamine receptor subtypes | journal = Molecular Pharmacology | volume = 38 | issue = 5 | pages = 610–3 | date = November 1990 | pmid = 2172771 }} Finally, H₄ plays roles in mast cell chemotaxis and cytokine production.

In humans, HDC is primarily expressed in mast cells and basophil granulocytes. Accordingly, these cells contain the body's highest concentrations of histamine granules. Non-mast cell histamine is also found in the brain, where it is used as a neurotransmitter.{{cite journal | vauthors = Blandina P, Munari L, Provensi G, Passani MB | title = Histamine neurons in the tuberomamillary nucleus: a whole center or distinct subpopulations? | language = en | journal = Frontiers in Systems Neuroscience | volume = 6 | pages = 33 | date = 2012-01-01 | pmid = 22586376 | pmc = 3343474 | doi = 10.3389/fnsys.2012.00033 | doi-access = free }}

HDC can be inhibited by α-fluoromethylhistidine and histidine methyl ester.{{cite journal | vauthors = August TF, Musson DG, Hwang SS, Duggan DE, Hooke KF, Roman IJ, Ferguson RJ, Bayne WF | title = Bioanalysis and disposition of alpha-fluoromethylhistidine, a new histidine decarboxylase inhibitor | journal = Journal of Pharmaceutical Sciences | volume = 74 | issue = 8 | pages = 871–5 | date = August 1985 | pmid = 4032273 | doi = 10.1002/jps.2600740814 }}{{cite journal | vauthors = Lane RS, Manning JM, Snell EE | title = Histidine decarboxylase of Lactobacillus 30a: inactivation and active-site labeling by L-histidine methyl ester | journal = Biochemistry | volume = 15 | issue = 19 | pages = 4180–5 | date = September 1976 | pmid = 963031 | doi = 10.1021/bi00664a008 }}

Antihistamines are a class of medications designed to reduce unwanted effects of histamine in the body. Typical antihistamines block specific histamine receptors, depending on what physiological purpose they serve. For example, diphenhydramine (Benadryl™), targets and inhibits the H1 histamine receptor to relieve symptoms of allergic reactions.{{Cite web|url=https://www.drugs.com/monograph/diphenhydramine-hydrochloride.html|title=Diphenhydramine Hydrochloride|website=Drugs.com}} Inhibitors of histidine decarboxylase can conceivably be used as atypical antihistamines. Tritoqualine, as well as various catechins, such as epigallocatechin-3-gallate, a major component of green tea, have been shown to target HDC and histamine-producing cells, reducing histamine levels and providing anti-inflammatory, anti-tumoral, and anti-angiogenic effects.{{cite journal | vauthors = Melgarejo E, Medina MA, Sánchez-Jiménez F, Urdiales JL | title = Targeting of histamine producing cells by EGCG: a green dart against inflammation? | journal = Journal of Physiology and Biochemistry | volume = 66 | issue = 3 | pages = 265–70 | date = September 2010 | pmid = 20652470 | doi = 10.1007/s13105-010-0033-7 | s2cid = 24835261 }}

Mutations in the gene for Histidine decarboxylase have been observed in one family with Tourette syndrome (TS) and are not thought to account for most cases of TS.{{cite web | title = Online Mendelian Inheritance in Man: histidine decarboxylase | url = https://www.ncbi.nlm.nih.gov/omim/142704}}

• Aromatic L-amino acid decarboxylase
• Tyrosine decarboxylase
• Decarboxylation
• Histamine
• Antihistamine
• Pyridoxal 5'-phosphate
• Mast cell

{{Reflist}}

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{{refend}}

• {{MeshName|Histidine+Decarboxylase}}

{{NLM content}}

{{Neurotransmitter metabolism enzymes}}

{{Histaminergics}}

{{Monoamine metabolism modulators}}

{{Carbon-carbon lyases}}

{{Enzymes}}

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Category:EC 4.1.1

Category:Histamine