Histidine decarboxylase explained

Histidine Decarboxylase
Ec Number:	4.1.1.22
Cas Number:	9024-61-7
Go Code:	0004398
Histidine Decarboxylase

The enzyme histidine decarboxylase (HDC) is transcribed on chromosome 15, region q21.1-21.2, and catalyzes the decarboxylation of histidine to form histamine. In mammals, histamine is an important biogenic amine with regulatory roles in neurotransmission, gastric acid secretion and immune response.^[1] Histidine decarboxylase is the sole member of the histamine synthesis pathway, producing histamine in a one-step reaction. Histamine cannot be generated by any other known enzyme. HDC is therefore the primary source of histamine in most mammals and eukaryotes. The enzyme employs a pyridoxal 5'-phosphate (PLP) cofactor, in similarity to many amino acid decarboxylases.^{[2] [3]} Eukaryotes, as well as gram-negative bacteria share a common HDC, while gram-positive bacteria employ an evolutionarily unrelated pyruvoyl-dependent HDC.^[4] In humans, histidine decarboxylase is encoded by the HDC gene.^{[5] [6]}

Structure

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.^[7] 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.^[8] This is particularly evident in the vicinity of the active site lysine 305.^[9]

Mechanism

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 ^[10] and fitting the experimental turnover of 1.73 s^.^[11] 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.^[12] HDC is highly specific for its histidine substrate.^[13]

Biological relevance

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,^[14] 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.^[15] H₂ activation results in gastric acid secretion and smooth muscle relaxation.^{[16] [17]} H₃ controls histamine turnover by feedback inhibition of histamine synthesis and release.^[18] 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.^[19]

Inhibition

HDC can be inhibited by α-fluoromethylhistidine and histidine methyl ester.^{[20] [21]}

Clinical significance

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.^[22] 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.^[23]

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.^[24]

See also

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

Further reading

• Need AC, Keefe RS, Ge D, Grossman I, Dickson S, McEvoy JP, Goldstein DB . Pharmacogenetics of antipsychotic response in the CATIE trial: a candidate gene analysis . European Journal of Human Genetics . 17 . 7 . 946–57 . July 2009 . 19156168 . 2986499 . 10.1038/ejhg.2008.264 .
• Masini E, Fabbroni V, Giannini L, Vannacci A, Messerini L, Perna F, Cortesini C, Cianchi F . Histamine and histidine decarboxylase up-regulation in colorectal cancer: correlation with tumor stage . Inflammation Research . 54 . S80–1 . April 2005 . Suppl 1 . 15928846 . 10.1007/s00011-004-0437-3 . 2158/762726 . 28682686 . free .
• Li Z, Liu J, Tang F, Liu Y, Waldum HL, Cui G . Expression of non-mast cell histidine decarboxylase in tumor-associated microvessels in human esophageal squamous cell carcinomas . . 116 . 12 . 1034–42 . December 2008 . 19133005 . 10.1111/j.1600-0463.2008.01048.x . 19980875 .
• Szafranski K, Schindler S, Taudien S, Hiller M, Huse K, Jahn N, Schreiber S, Backofen R, Platzer M . Violating the splicing rules: TG dinucleotides function as alternative 3' splice sites in U2-dependent introns . Genome Biology . 8 . 8 . R154 . 2007 . 17672918 . 2374985 . 10.1186/gb-2007-8-8-r154 . free .
• Ai W, Liu Y, Langlois M, Wang TC . Kruppel-like factor 4 (KLF4) represses histidine decarboxylase gene expression through an upstream Sp1 site and downstream gastrin responsive elements . The Journal of Biological Chemistry . 279 . 10 . 8684–93 . March 2004 . 14670968 . 10.1074/jbc.M308278200 . free .
• Raychowdhury R, Fleming JV, McLaughlin JT, Bulitta CJ, Wang TC . Identification and characterization of a third gastrin response element (GAS-RE3) in the human histidine decarboxylase gene promoter . Biochemical and Biophysical Research Communications . 297 . 5 . 1089–95 . October 2002 . 12372397 . 10.1016/S0006-291X(02)02345-8 .
• Kimura K, Wakamatsu A, Suzuki Y, Ota T, Nishikawa T, Yamashita R, Yamamoto J, Sekine M, Tsuritani K, Wakaguri H, Ishii S, Sugiyama T, Saito K, Isono Y, Irie R, Kushida N, Yoneyama T, Otsuka R, Kanda K, Yokoi T, Kondo H, Wagatsuma M, Murakawa K, Ishida S, Ishibashi T, Takahashi-Fujii A, Tanase T, Nagai K, Kikuchi H, Nakai K, Isogai T, Sugano S . Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes . Genome Research . 16 . 1 . 55–65 . January 2006 . 16344560 . 1356129 . 10.1101/gr.4039406 .
• Sköldberg F, Portela-Gomes GM, Grimelius L, Nilsson G, Perheentupa J, Betterle C, Husebye ES, Gustafsson J, Rönnblom A, Rorsman F, Kämpe O . Histidine decarboxylase, a pyridoxal phosphate-dependent enzyme, is an autoantigen of gastric enterochromaffin-like cells . The Journal of Clinical Endocrinology and Metabolism . 88 . 4 . 1445–52 . April 2003 . 12679420 . 10.1210/jc.2002-021761 . free .
• Brew O, Lakasing L, Sullivan M . Differential activity of histidine decarboxylase in normal and pre-eclamptic placentae . Placenta . 28 . 5–6 . 585–7 . 2007 . 16822545 . 10.1016/j.placenta.2006.05.003 .
• Zhang F, Xiong DH, Wang W, Shen H, Xiao P, Yang F, Recker RR, Deng HW . HDC gene polymorphisms are associated with age at natural menopause in Caucasian women . Biochemical and Biophysical Research Communications . 348 . 4 . 1378–82 . October 2006 . 16919600 . 1803761 . 10.1016/j.bbrc.2006.08.008 .
• Tippens AS, Gruetter CA . Detection of histidine decarboxylase mRNA in human vascular smooth muscle and endothelial cells . Inflammation Research . 53 . 6 . 215–6 . June 2004 . 15167966 . 10.1007/s00011-004-1252-6 .
• Siezen CL, Bont L, Hodemaekers HM, Ermers MJ, Doornbos G, Van't Slot R, Wijmenga C, Houwelingen HC, Kimpen JL, Kimman TG, Hoebee B, Janssen R . Genetic susceptibility to respiratory syncytial virus bronchiolitis in preterm children is associated with airway remodeling genes and innate immune genes . The Pediatric Infectious Disease Journal . 28 . 4 . 333–5 . April 2009 . 19258923 . 10.1097/INF.0b013e31818e2aa9 . 25601837 . free .
• Morgan TK, Montgomery K, Mason V, West RB, Wang L, van de Rijn M, Higgins JP . Upregulation of histidine decarboxylase expression in superficial cortical nephrons during pregnancy in mice and women . Kidney International . 70 . 2 . 306–14 . July 2006 . 16760908 . 10.1038/sj.ki.5001553 . free .
• Papadopoulou N, Kalogeromitros D, Staurianeas NG, Tiblalexi D, Theoharides TC . Corticotropin-releasing hormone receptor-1 and histidine decarboxylase expression in chronic urticaria . The Journal of Investigative Dermatology . 125 . 5 . 952–5 . November 2005 . 16297195 . 10.1111/j.0022-202X.2005.23913.x . free .
• Janssen R, Bont L, Siezen CL, Hodemaekers HM, Ermers MJ, Doornbos G, van 't Slot R, Wijmenga C, Goeman JJ, Kimpen JL, van Houwelingen HC, Kimman TG, Hoebee B . Genetic susceptibility to respiratory syncytial virus bronchiolitis is predominantly associated with innate immune genes . The Journal of Infectious Diseases . 196 . 6 . 826–34 . September 2007 . 17703412 . 10.1086/520886 . free .
• Strausberg RL, Feingold EA, Grouse LH, Derge JG, Klausner RD, Collins FS, Wagner L, Shenmen CM, Schuler GD, Altschul SF, Zeeberg B, Buetow KH, Schaefer CF, Bhat NK, Hopkins RF, Jordan H, Moore T, Max SI, Wang J, Hsieh F, Diatchenko L, Marusina K, Farmer AA, Rubin GM, Hong L, Stapleton M, Soares MB, Bonaldo MF, Casavant TL, Scheetz TE, Brownstein MJ, Usdin TB, Toshiyuki S, Carninci P, Prange C, Raha SS, Loquellano NA, Peters GJ, Abramson RD, Mullahy SJ, Bosak SA, McEwan PJ, McKernan KJ, Malek JA, Gunaratne PH, Richards S, Worley KC, Hale S, Garcia AM, Gay LJ, Hulyk SW, Villalon DK, Muzny DM, Sodergren EJ, Lu X, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madan A, Young AC, Shevchenko Y, Bouffard GG, Blakesley RW, Touchman JW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Krzywinski MI, Skalska U, Smailus DE, Schnerch A, Schein JE, Jones SJ, Marra MA . 6 . Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences . Proceedings of the National Academy of Sciences of the United States of America . 99 . 26 . 16899–903 . December 2002 . 12477932 . 139241 . 10.1073/pnas.242603899 . 2002PNAS...9916899M . free .
• Aichberger KJ, Mayerhofer M, Vales A, Krauth MT, Gleixner KV, Bilban M, Esterbauer H, Sonneck K, Florian S, Derdak S, Pickl WF, Agis H, Falus A, Sillaber C, Valent P . The CML-related oncoprotein BCR/ABL induces expression of histidine decarboxylase (HDC) and the synthesis of histamine in leukemic cells . Blood . 108 . 10 . 3538–47 . November 2006 . 16849647 . 10.1182/blood-2005-12-028456 . free .
• Lee JK, Kim HT, Cho SM, Kim KH, Jin HJ, Ryu GM, Oh B, Park C, Kimm K, Jo SA, Jung SC, Kim S, In SM, Lee JE, Jo I . Characterization of 458 single nucleotide polymorphisms of disease candidate genes in the Korean population . Journal of Human Genetics . 48 . 5 . 213–6 . 2003 . 12768436 . 10.1007/s10038-003-0011-9 . free .
• Jeong HJ, Moon PD, Kim SJ, Seo JU, Kang TH, Kim JJ, Kang IC, Um JY, Kim HM, Hong SH . Activation of hypoxia-inducible factor-1 regulates human histidine decarboxylase expression . Cellular and Molecular Life Sciences . 66 . 7 . 1309–19 . April 2009 . 19266161 . 10.1007/s00018-009-9001-1 . 23800803 . 11131467 .

Notes and References

1. Epps HM . Studies on bacterial amino-acid decarboxylases: 4. l(-)-histidine decarboxylase from Cl. welchii Type A . The Biochemical Journal . 39 . 1 . 42–6 . 1945 . 16747851 . 1258146 . 10.1042/bj0390042.
2. Riley WD, Snell EE . Histidine decarboxylase of Lactobacillus 30a. IV. The presence of covalently bound pyruvate as the prosthetic group . Biochemistry . 7 . 10 . 3520–8 . October 1968 . 5681461 . 10.1021/bi00850a029 .
3. Rosenthaler J, Guirard BM, Chang GW, Snell EE . Purification and properties of histidine decarboxylase from Lactobacillus 30a . Proceedings of the National Academy of Sciences of the United States of America . 54 . 1 . 152–8 . July 1965 . 5216347 . 285813 . 10.1073/pnas.54.1.152 . 1965PNAS...54..152R . free .
4. Kimura B, Takahashi H, Hokimoto S, Tanaka Y, Fujii T . Induction of the histidine decarboxylase genes of Photobacterium damselae subsp. damselae (formally P. histaminum) at low pH . Journal of Applied Microbiology . 107 . 2 . 485–97 . August 2009 . 19302297 . 10.1111/j.1365-2672.2009.04223.x . free .
5. Web site: Entrez Gene: histidine decarboxylase.
6. Bruneau G, Nguyen VC, Gros F, Bernheim A, Thibault J . Preparation of a rat brain histidine decarboxylase (HDC) cDNA probe by PCR and assignment of the human HDC gene to chromosome 15 . Human Genetics . 90 . 3 . 235–8 . November 1992 . 1487235 . 10.1007/bf00220068 . 23444983 .
7. Nitta. Yoko. 2010. Expression of recombinant human histidine decarboxylase with full length and C-terminal truncated forms in yeast and bacterial cells. J. Biol. Macromol.. 10.
8. Jackson. F. Rob. 1990-10-01. Prokaryotic and eukaryotic pyridoxal-dependent decarboxylases are homologous. Journal of Molecular Evolution. en. 31. 4. 325–329. 10.1007/BF02101126. 2124279. 1990JMolE..31..325J. 9206252. 0022-2844. free.
9. Sandmeier E, Hale TI, Christen P . Multiple evolutionary origin of pyridoxal-5'-phosphate-dependent amino acid decarboxylases . European Journal of Biochemistry . 221 . 3 . 997–1002 . May 1994 . 8181483 . 10.1111/j.1432-1033.1994.tb18816.x . free .
10. Fernandes HS, Ramos MJ, Cerqueira NM . The Catalytic Mechanism of the Pyridoxal-5'-phosphate-Dependent Enzyme, Histidine Decarboxylase: A Computational Study . Chemistry: A European Journal . 23 . 38 . 9162–9173 . July 2017 . 28613002 . 10.1002/chem.201701375 .
11. Komori H, Nitta Y, Ueno H, Higuchi Y . Structural study reveals that Ser-354 determines substrate specificity on human histidine decarboxylase . The Journal of Biological Chemistry . 287 . 34 . 29175–83 . August 2012 . 22767596 . 3436558 . 10.1074/jbc.m112.381897 . free .
12. Web site: Pyridoxal phosphate-dependent decarboxylase. InterPro.
13. Toney MD . Reaction specificity in pyridoxal phosphate enzymes . Archives of Biochemistry and Biophysics . 433 . 1 . 279–87 . January 2005 . 15581583 . 10.1016/j.abb.2004.09.037 . Highlight issue on Enzyme Mechanisms .
14. Jutel . M. . Akdis . M. . Akdis . C. A. . 2009-11-13 . Histamine, histamine receptors and their role in immune pathology . Clinical & Experimental Allergy . 39 . 12 . 1786–1800 . 10.1111/j.1365-2222.2009.03374.x . 20085595 . 0954-7894.
15. Panula P, Chazot PL, Cowart M, Gutzmer R, Leurs R, Liu WL, Stark H, Thurmond RL, Haas HL . International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors . Pharmacological Reviews . 67 . 3 . 601–55 . July 2015 . 26084539 . 4485016 . 10.1124/pr.114.010249 .
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17. Hill. S.J.. 1997. Classification of Histamine Receptors. Pharmacological Reviews. 49. 253–278. ASPET.
18. West RE, Zweig A, Shih NY, Siegel MI, Egan RW, Clark MA . Identification of two H3-histamine receptor subtypes . Molecular Pharmacology . 38 . 5 . 610–3 . November 1990 . 2172771 .
19. Blandina P, Munari L, Provensi G, Passani MB . Histamine neurons in the tuberomamillary nucleus: a whole center or distinct subpopulations? . en . Frontiers in Systems Neuroscience . 6 . 33 . 2012-01-01 . 22586376 . 3343474 . 10.3389/fnsys.2012.00033 . free .
20. August TF, Musson DG, Hwang SS, Duggan DE, Hooke KF, Roman IJ, Ferguson RJ, Bayne WF . Bioanalysis and disposition of alpha-fluoromethylhistidine, a new histidine decarboxylase inhibitor . Journal of Pharmaceutical Sciences . 74 . 8 . 871–5 . August 1985 . 4032273 . 10.1002/jps.2600740814 .
21. Lane RS, Manning JM, Snell EE . Histidine decarboxylase of Lactobacillus 30a: inactivation and active-site labeling by L-histidine methyl ester . Biochemistry . 15 . 19 . 4180–5 . September 1976 . 963031 . 10.1021/bi00664a008 .
22. Web site: Diphenhydramine Hydrochloride. Drugs.com.
23. Melgarejo E, Medina MA, Sánchez-Jiménez F, Urdiales JL . Targeting of histamine producing cells by EGCG: a green dart against inflammation? . Journal of Physiology and Biochemistry . 66 . 3 . 265–70 . September 2010 . 20652470 . 10.1007/s13105-010-0033-7 . 24835261 .
24. Web site: Online Mendelian Inheritance in Man: histidine decarboxylase .