Ah receptor

from Wikipedia, the free encyclopedia
Ah receptor
Properties of human protein
Mass / length primary structure 838 amino acids
Secondary to quaternary structure Heterodimer
Cofactor HLH protein
Identifier
Gene name AHR
External IDs
Occurrence
Parent taxon Vertebrates

AHR Signaling.jpg

The aryl hydrocarbon receptor ( AhR , Ah receptor , also dioxin receptor (out of date)) is a ligand-activated transcription factor from the PAS family (Per-ARNT-Sim family) of the basic helix-loop-helix family. The AhR is in a non-active form in the cytosol in a complex with other proteins ( hsp90 , AIP , p23 ). After binding to a ligand and the resulting change in conformation, the protein complex dissolves and translocation into the cell nucleus is possible. Within the cell nucleus, the Ah receptor forms a dimer with the protein ARNT and can therefore bind to certain short DNA sequences in gene promoters. This triggers the transcription of the relevant gene. The Ahr degrades again after leaving the cell nucleus. The affinity of the AhR for ligands is different in different species. In addition, gene variants are also known that lead to different affinities. The AhR is present in many cells; it is particularly pronounced in cells of interfacial organs such as skin, intestines and lungs, as well as in most cells of the immune system.

Target genes of the Ah receptor

Many genes contain one or more AhR binding sites in their promoter and are therefore potential target genes. The strength of the induced transcription fluctuates and appears to depend on the quality and positioning of the AhR-responsive promoter elements as well as cell-specific factors. The induction of genes of the foreign substance metabolizing enzyme system, in particular cytochrome P450 1A1, has been well studied. This enzyme belongs to the phase I enzymes and breaks down ring molecules, including ligands of the AhR itself. In fact, one of the first functions of the AhR was to break down polycyclic hydrocarbons (aryl hydrocarbons). Further detected target genes were identified in the immune system (TGFβ, IL-2, IL-22, c-kit).

Ligands of the Ah receptor

The AhR has only one binding site and can bind a large number of structurally different molecules, provided they are of a certain size and planar shape. These are a number of polycyclic hydrocarbons such as benzo [a] pyrene, dioxins or furans, as well as molecules and indole derivatives derived from plants. The 6-formylindole [3,2b] carbazole molecule can be formed in the skin from the amino acid tryptophan in sunlight. Similarly kynurenines (metabolites of tryptophan) known AhR ligands. The affinity of the different ligands is very different. Ligands with high affinity (Kd values ​​<10 −9 M) are TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin), indolocarbazole, ITE ( methyl indolylcarboxythiazolecarboxylate) and FICZ (6-formylindole [3,2b] carbazole), low affinity ligands are z. B. kynurenine (Kd 10 −6 M, i.e. about 1000 times worse binding force). Ligands are broken down again after the AhR is activated. The exception is TCDD, which is barely metabolized and has a very long half-life of approx. 7 years in humans .

Functions of the Ah receptor

The tasks of the receptor are to metabolize organic molecules, control cell growth and cellular differentiation . In the years since 2008, the database for biological-medical literature PubMed has listed 300–500 specialist articles annually on the keyword aryl hydrocarbon receptor .

The receptor has an important function for the immune system.

The AhR is relevant in carcinogenesis and tumor invasion, u. a. Tumors can use the AhR to generate an immunocompromised micromileu.

In the intestine, various intestinal bacteria form AhR ligands that are important for a functioning intestinal immune system. AHR ligands can also be ingested through food. Absence of the AHR and an AHR-ligand-poor diet were associated with a weakened intestinal barrier in mice.

Others

Scientific conferences on the Ah receptor lasting several days were held in Düsseldorf in 2005 and 2011 (organized by the Leibniz Institute for Environmental Medicine Research ), in 2016 at the University of Rochester , NY, USA, and in Paris in 2018.

Individual evidence

  1. ↑ Homologues at OMA
  2. ↑ Bruno Lamas, Jane M. Natividad, Harry Sokol: Aryl hydrocarbon receptor and intestinal immunity . In: Mucosal Immunology . April 7, 2018, ISSN  1933-0219 , doi : 10.1038 / s41385-018-0019-2 ( nature.com [accessed May 4, 2018]).
  3. ↑ YV Sun: Comparative analysis of dioxin response elements in human, mouse and rat genomic sequences . In: Nucleic Acids Research . tape 32 , no. 15 , August 18, 2004, ISSN  1362-4962 , p. 4512–4523 , doi : 10.1093 / nar / gkh782 ( oup.com [accessed May 4, 2018]).
  4. ↑ Michael S. Denison, Scott R. Nagy: Activation of the Aryl Hydrocarbon Receptor by Structurally Diverse Exogenous and Endogenous Chemicals . In: Annual Review of Pharmacology and Toxicology . tape 43 , no. 1 , April 1, 2003, ISSN  0362-1642 , p. 309–334 , doi : 10.1146 / annurev.pharmtox.43.100901.135828 ( annualreviews.org [accessed May 4, 2018]).
  5. ↑ Emma Wincent, Nahid Amini, Sandra Luecke, Hansruedi Glatt, Jan Bergman: The Suggested Physiologic Aryl Hydrocarbon Receptor Activator and Cytochrome P4501 Substrate 6-Formylindolo [3,2-b] carbazole Is Present in Humans . In: Journal of Biological Chemistry . tape 284 , no. 5 , January 30, 2009, ISSN  0021-9258 , p. 2690–2696 , doi : 10.1074 / jbc.M808321200 , PMID 19054769 ( jbc.org [accessed May 4, 2018]).
  6. ↑ pubmeddev: aryl hydrocarbon receptor - PubMed - NCBI. Retrieved May 4, 2018 .
  7. ↑ Charlotte Esser , Agneta Rannug: The Aryl Hydrocarbon Receptor in Barrier Organ Physiology, Immunology, and Toxicology . In: Pharmacological Reviews . tape 67 , no. 2 , April 1, 2015, ISSN  0031-6997 , p. 259-279 , doi : 10.1124 / pr.114.009001 , PMID 25657351 ( aspetjournals.org [accessed May 4, 2018]).
  8. ↑ Ping Xue, Jinrong Fu, Yufeng Zhou: The Aryl Hydrocarbon Receptor and Tumor Immunity . In: Frontiers in Immunology . tape 9 , 2018, ISSN  1664-3224 , doi : 10.3389 / fimmu.2018.00286 ( frontiersin.org [accessed May 4, 2018]).
  9. ↑ J. Gao, K. Xu et al. a .: Impact of the Gut Microbiota on Intestinal Immunity Mediated by Tryptophan Metabolism. In: Frontiers in cellular and infection microbiology. Volume 8, 2018, p. 13, doi : 10.3389 / fcimb.2018.00013 , PMID 29468141 , PMC 5808205 (free full text) (review)
  10. ↑ TD Hubbard, IA Murray et al. a .: Dietary Broccoli Impacts Microbial Community Structure and Attenuates Chemically Induced Colitis in Mice in an Ah receptor dependent manner. In: Journal of functional foods. Volume 37, October 2017, pp. 685–698, doi : 10.1016 / j.jff.2017.08.038 , PMID 29242716 , PMC 5726276 (free full text).
  11. ↑ JM Natividad, A. Agus et al. a .: Impaired Aryl Hydrocarbon Receptor Ligand Production by the Gut Microbiota Is a Key Factor in Metabolic Syndrome. In: Cell metabolism. [Electronic publication before printing] July 2018, doi : 10.1016 / j.cmet.2018.07.001 , PMID 30057068 .
  12. ↑ Charlotte Esser: Biology and function of the aryl hydrocarbon receptor: report of an international and interdisciplinary conference . In: Archives of Toxicology . tape 86 , no. 8 , August 1, 2012, ISSN  0340-5761 , p. 1323-1329 , doi : 10.1007 / s00204-012-0818-2 ( springer.com [accessed May 4, 2018]).