Cyclooxygenase-2
| Cyclooxygenase-2 | ||
|---|---|---|
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| COX-2 according to PDB 4COX | ||
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Existing structure data : PDB 6COX , 1CX2 , 3PGH , 4COX , 5COX , 1PXX , 1CVU , 1DDX |
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| Properties of human protein | ||
| Mass / length primary structure | 587 amino acids | |
| Secondary to quaternary structure | Homodimer | |
| Cofactor | Heme b | |
| Identifier | ||
| Gene names | PTGS2 ; COX2; PGG / HS; COX-2; PGHS-2; PHS-2; hCox-2 | |
| External IDs | ||
| Enzyme classification | ||
| EC, category | 1.14.99.1 , dioxygenase | |
| Response type | Oxidation + peroxidation | |
| Substrate | Arachidonic acid + AH 2 + 2 O 2 | |
| Products | Prostaglandin H 2 + A + H 2 O | |
| Occurrence | ||
| Homology family | Prostaglandin synthase | |
| Parent taxon | Chordates | |
The cyclooxygenase-2 ( COX-2 ), also prostaglandin synthase-2 (PGHS-2), is an enzyme which as the cyclooxygenase-1 (COX-1) arachidonic acid to the eicosanoid prostaglandin H 2 in two steps oxidized . While COX-1 is constitutively expressed , the synthesis of COX-2 is only induced by cytokines and mitogens in the event of injury, inflammation or sprouting of cells . Blocking COX-2 by specific COX-2 inhibitors therefore does not cause any of the side effects known from non-steroidal anti-inflammatory drugs . COX-2 is also the dominant isoform in the placenta and the fetal male genitalia. It may regulate the formation of new blood vessels, which is why the inhibition of COX-2 in cancer is currently being investigated. COX-2 belongs to the cyclooxygenases , which in turn belong to the large family of pathogen-inducible oxygenases (PIOXs).
biosynthesis
regulation
The following promotes the biosynthesis of COX-2:
- Inflammation mediators such as TNFα or interleukin-1β and lipopolysaccharides .
- Growth factors , oncogenes , the MAP kinase pathway , NF-κB .
- Methandamide, an analogue of the endocannabinoids .
The following inhibits the biosynthesis of COX-2:
- Vitamin K 2 inhibits COX-2.
- Dexamethasone destabilizes the COX-2 mRNA .
- The tocotrienol- rich fraction of palm oils has an anti-inflammatory effect, presumably by blocking the COX-2.
- The hop bitter substance humulone suppresses the transcription of the gene belonging to COX-2.
- The cannabinoids cannabidiol and cannabigerol inhibit COX-2 synthesis at the transcriptional level.
biosynthesis
The human gene for cyclooxygenase-2 is on chromosome 1 (1q25.2-q25.3). In comparison with the gene for COX-1, it is a smaller gene (8 kb) with 10 exons . The transcription of the COX-2 gene can be induced in many cases (see regulation). The transcribed mRNA has 4,465 bases and the translated protein consists of 587 amino acids .
General structural aspects are described under cyclooxygenases .
Occurrence in the organism
Cyclooxygenases are located inside the endoplasmic reticulum , inside the nuclear envelope and in the Golgi apparatus and adhere to the inside of the membranes of these cell compartments .
The COX-2 occurs in the following tissues and organs:
- Macrophages , there it is z. B. activated via the activation of the CD14 receptor by lipopolysaccharides , from here comes the prostaglandin E 2 , which causes the first increase in fever .
- COX-2 is found in the endothelial cells of proliferating blood vessels, inflamed tissues, and in the endothelial cells and monocytic foam cells in atherosclerotic lesions (while COX-1 is found in endothelial cells of normal blood vessels). COX-2 is also induced by shear forces in endothelial cells. The role of COX-2 in atherosclerosis and angiogenesis is the subject of current research.
- COX-2 is very abundant in a number of tumor cells . Since the prostaglandin-E2 formed by them stimulates the formation of vascular endothelial growth factors and thus promotes angiogenesis , it is assumed that COX-2 could play a role in tumor growth.
- In the kidneys , COX-2 is primarily found in the macula densa and leads to increased prostacyclin formation , which activates the formation of renin .
- In the brain , COX-2 is increasingly induced in inflammation. This is in the endothelial cells of the vessels of the hypothalamus z. B. the case in the areas of the circumventricular organs , there then fever-inducing PGE 2 is formed. But COX-2 formation can also be induced in glial cells and neurons. It is higher in newborns and can be induced in the hippocampus after epileptic seizures.
- In the spinal cord COX-2 always comes before and is there in the pain stimulus processing involved.
function
In addition to the cyclooxygenases general function of the formation of prostaglandin H 2 from arachidonic acid cyclooxygenase-2 are also bulky substrates can as endocannabinoids , z. B. oxidize anandamide or 2-arachidonylglycerol to prostanoids , which are further metabolized by isomerases. The function of the resulting metabolites is still unknown.
Catalyzed reaction
+ 2 O 2 + AH 2 → 
→ 
+ A + H 2 O
Significance for diseases
- Inflammation: COX-2 is increasingly transcribed during inflammatory processes, the associated symptoms ( fever , pain ) can be effectively treated with COX-2 inhibitors , with significantly fewer side effects of an inhibition of cyclooxygenase-1 (e.g. on the kidneys and stomach ).
- Oncology : COX-2 is induced in a large number of malignant tumors, both in the actual tumor cells and in the surrounding stroma. The prostaglandins formed in the tumor tissue, in particular PGE 2 , can influence both the tumor stroma (angiogenesis, immunosuppression etc.) and tumor cells directly (proliferation, inhibition of programmed cell death - apoptosis) in multiple ways. Therefore, hopes are currently being placed on the preventive or therapeutic effect of COX-2 inhibitors in cancer treatment, especially of tumors of the gastrointestinal tract, which are currently used in several clinical trials, mostly in combination with other therapeutic agents. One of the, at least theoretical, advantages of COX-2 directed therapy is that both the highly variable tumor cells, which can escape therapy very quickly, and the relatively invariable stroma can be attacked, which should reduce the likelihood of resistance developing.
- Neurology : The normal function of COX-2 in brain neurons is unclear, so it is not known whether long-term use of COX-2 inhibitors has a physiological effect on the brain. However, COX-2 is induced by many stimuli (e.g. hypoxia , excitatory toxins, inflammation, epileptic seizures ) in astrocytes , neurons and microglia . It is not clear whether this induction protects against cell death or has an apoptotic effect. The cyclooxygenases may influence the development of Alzheimer's disease .
Pharmacological influence
COX-2 inhibitors mainly inhibit the activity of cyclooxygenase-2. This group of active substances includes celecoxib (Celebrex ® ), etodolac (Lodine), rofecoxib (Vioxx ® ), valdecoxib (Bextra ® ) and etoricoxib (Arcoxia ® ), and more recently lumiracoxib (Prexige ® ).
- It is theoretically conceivable that selective COX-2 inhibition promotes thrombotic events (since only COX-1 occurs in the thrombocytes and primarily the thrombosis-promoting thromboxane -A 2 is formed there, which would then dominate over the thrombosis-inhibiting prostacyclin ). In fact, for this reason , rofecoxib had to be withdrawn from the market in 2004. Lumiracoxib was approved in Germany in November 2006 in the form of 100 mg tablets (Prexige® 100 mg) according to a non-centralized EU procedure; in November 2007 the Federal Institute for Drugs and Medical Devices ordered the approval to be suspended.
- Although theoretical considerations and test results suggest that COX-2 plays a major role in angiogenesis, it can not be inhibited to a clinically relevant extent by COX-2 inhibitors in chronic diseases ( rheumatism , cancer ) .
history
From 1972 it was speculated that there was more than one cyclooxygenase . There were three groups who discovered Cox-2 as another Cox enzyme and its role in inflammation around 1990 and were later involved in patent litigation: David Young and Kerry O'Banion at the University of Rochester (1989), the group of Harvey Hirschmann at the University of California, Los Angeles , and Daniel Simmons' group at Brigham Young University . The discovery was made public at a conference in Montreal in 1992. In the patent disputes, Young's group won after years. In addition, Philip Needleman , then at Washington University in St. Louis and later associated with Pfizer and the development of the Cox-2 inhibitor Celebrex , claimed to have started a program to search for Cox-2 as early as the mid-1980s and suspected its existence (with a prediction at an international conference in Florence 1990).
In 1992 the gene and the primary protein structure for human cyclooxygenase-2 were sequenced. 1996–1999 the crystallographic structure was elucidated, which at first glance showed a great similarity to cyclooxygenase-1 . The first cyclooxygenase-2-selective pharmacological agents were available in 1999. The first was rofecoxib (Vioxx) from Merck, followed by celecoxib (Celebrex) from Monsanto / Searle (later acquired by Pfizer). Since then, the essential differences in structure, origin, occurrence, function and regulation of these two cyclooxygenases have been examined and clarified more and more closely.
Individual evidence
- ↑ Cyclooxygenase-2. In: Online Mendelian Inheritance in Man . (English).
- ↑ a b c d e Simmons, DL et al. (2004): Cyclooxygenase isozymes: the biology of prostaglandin synthesis and inhibition. In: Pharmacol. Rev. Vol. 56, pp. 387-437. PMID 15317910 .
- ↑ SM Plaza, DW Lamson: Vitamin K2 in bone metabolism and osteoporosis. In: Alternative medicine review: a journal of clinical therapeutic. Volume 10, Number 1, March 2005, pp. 24-35, PMID 15771560 (review).
- ↑ Wu SJ, et al .: Tocotrienol-rich fraction of palm oil exhibits anti-inflammatory property by suppressing the expression of inflammatory mediators in human monocytic cells. Mol Nutr Food Res. 2008 Aug; 52 (8): 921-9 PMID 18481320 .
- ↑ K. Yamamoto, J. Wang, S. Yamamoto, H. Tobe: Suppression of Cyclooxygenase-2 Gene Transcription by Humulone. In: Kenneth V. Honn, Lawrence J. Marnett, Santosh Nigam, Edward Dennis, Charles Serhan (Eds.): Eicosanoids and other bioactive lipids in cancer, inflammation, and radiation injury, Volume 5. Springer, 2002, ISBN 978-0 -30647283-1 , pp. 73-76.
- ↑ Investigations into the anti-inflammatory effect of Cannabis sativa L. extracts in the model of tissue cultures
- ↑ ENSEMBL entry
- ↑ Steiner, AA et al. (2006): Cellular and Molecular Bases of the Initiation of Fever . PLoS Biology 4 (9): e284.
- ↑ Tom Nesi, Poison Pills: The Untold Story of the Vioxx Drug Scandal, 2008, pp. 75ff
- ↑ Needleman's account was included in the article Superaspirin by Jerome Groopman, The New Yorker , June 15, 1998. pdf