Prostaglandin-endoperoxide synthase 2

  • OMIM: 600262
  • UniProt: P35354
  • MGI: 97798

Cyclooxygenase -2 ( COX-2), also prostaglandin synthase -2 ( PGHS -2), is an enzyme that oxidizes such as cyclooxygenase -1 ( COX-1) arachidonic acid to prostaglandin H2 in two steps. While COX-1 is constitutively expressed, the synthesis of COX-2 only when injury, inflammation or budding of cells is induced by cytokines, and mitogens. Blockage of COX-2 by means of specific COX -2 inhibitors therefore does not cause any of the known side effects of the NSAIDs. COX-2 is the predominant isoform in the placenta and fetal male genitalia. It may regulate the formation of new blood vessels, which is why the inhibition of COX -2 is currently being studied in cancer. COX -2 is one of the cyclooxygenases, which, in turn, to the great family of pathogen - inducible oxygenase ( PIOXs ) count.

  • 3.1 catalyzed reaction
  • 3.2 Importance for diseases

Biosynthesis

Control

Following promotes the biosynthesis of COX -2:

  • Inflammatory mediators such as TNF and interleukin- 1β and lipopolysaccharide.
  • Growth factors, oncogenes, the MAP kinase pathway, NFkB.
  • Methandamid, an analogue of the endocannabinoids.

Following inhibits the biosynthesis of COX -2:

  • Vitamin K2 inhibits COX-2.
  • Dexamethasone leads to destabilization of the mRNA of the COX-2.
  • Tocotrienols - rich fraction of palm oil has anti-inflammatory, presumably by blocking the COX -2.
  • The hop bitter substance humulone suppressed the transcription of the COX -2 gene associated.

Biosynthesis

The human gene for cyclooxygenase -2, is located on chromosome 1 ( 1q25.2 - q25.3 ). Is compared with the gene for COX-1 to a smaller gene (8 kb ) with 10 exons. Transcription of the COX -2 gene is frequently induced (see control). The transcribed mRNA has 4465 bases and the translated protein consists of 587 amino acids.

General structure aspects are described below cyclooxygenases.

Deposits in the organism

Cyclooxygenases are inside the endoplasmic reticulum, localized within the nuclear envelope and in the Golgi apparatus and adhere the inner faces of the membranes of the cell compartments at.

The COX- 2 comes in the following tissues and organs before:

  • Macrophages, there it is, for example, activated via the activation of the CD14 receptor by lipopolysaccharide, from here comes the prostaglandin E2, which causes the first increase in fever.
  • COX-2 is found in the endothelial cells of blood vessels proliferating, inflamed tissue, and the endothelial cells, monocytic and foam cells in atherosclerotic lesions ( for COX-1 is present 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 comes in a variety of tumor cells from proliferated. Since the formed therethrough prostaglandin E2 stimulates the production of vascular endothelial growth factor, thus promoting angiogenesis is believed that COX-2 may play a role in tumor growth.
  • In the kidneys, COX -2 is mainly in the macula densa before constitutively and leads to increased prostacyclin what the renin formation activated.
  • In the brain, COX -2 is induced increases in inflammation. This is in the endothelial cells of the vessels of the hypothalamus, for example, in the areas of the circumventricular organs of the case, there is then formed fieberinduzierendes PGE2. But also in glial cells and neurons, the COX- 2 production can be induced. It is higher in newborns and can be induced in the hippocampus after seizures.
  • In the spinal cord COX -2 occurs again and is involved there in the pain stimulus processing.

Function

In addition to the general for the cyclooxygenase function of the formation of prostaglandin H2 from arachidonic acid, the cyclooxygenase -2 also bulkier substrates such as endocannabinoids, such as Oxidize anandamide and 2- arachidonyl glycerol to prostanoids, which are metabolized by isomerases on. The function of this resulting metabolites is still unknown.

Catalyzed reaction

2 O2 AH2 → → A H2O

Importance for diseases

  • Inflammation: COX -2 is transcribed increases in inflammatory processes, the associated symptoms (fever, pain ) can be effectively treated with COX -2 inhibitors, without the side effects of inhibition of cyclooxygenase- 1 (eg, kidneys and stomach).
  • Oncology: COX -2 both in the actual tumor cells as well as in the surrounding stroma, induced in a variety of malignant tumors. The prostaglandins formed in the tumor tissue, particularly PGE2, can there both the tumor stroma (angiogenesis, immunosuppression, etc.) as well as tumor cells directly (proliferation, inhibition of programmed cell death - apoptosis) influence on multiple ways. Thus, hopes for the preventive or therapeutic effect of COX -2 inhibitors in cancer treatment are currently being particular set of tumors of the gastrointestinal tract, which are currently mostly used in several clinical trials in combination with other therapeutic agents. One of the, at least theoretical, benefits of COX -2 targeted therapy is that both the highly variable tumor cells to escape therapy very quickly, as well as the relatively invariable stroma can be attacked, thus reducing the likelihood of development of resistance should be lowered.
  • 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. COX-2 but is induced by many stimuli (such as hypoxia, excitatory acting toxins, inflammation, epileptic seizures ), this being in astrocytes, neurons and microglia. Whether this induction protects against cell death or apoptotic effect is not clear. Perhaps the cyclooxygenases influence the development of Alzheimer's disease.

Pharmacological influence

COX -2 inhibitors inhibit in particular the activity of cyclooxygenase -2. Belong to this group of active ingredients celecoxib ( Celebrex ®), etodolac ( Lodine ), rofecoxib ( Vioxx ®), valdecoxib ( Bextra ®), etoricoxib ( Arcoxia ®), and more recently lumiracoxib ( Prexige ®).

  • Whether a selective COX-2 inhibiting thrombotic events supports ( as in the platelet only COX-1 exists, where especially the thrombosis -promoting thromboxane A2 is formed, which would then dominate the antithrombotic prostacyclin ) is theoretically possible. Indeed, rofecoxib had to be taken off the market again for this reason in 2004. Lumiracoxib was in November 2006 in the form of 100 mg tablets ( 100 mg Prexige ® ) approved in Germany for a non- EU centralized procedure, in November 2007 ordered the Federal Institute for Drugs and Medical Devices, the suspension of admission to.
  • Although theoretical considerations and experimental results suggest a significant involvement of COX -2 in angiogenesis, these chronic diseases ( rheumatism, cancer) can probably not be inhibited in a clinically relevant extent by COX - 2 inhibitors.

History

From 1972, it was speculated that there were more than a cyclooxygenase. 1992, the gene was sequenced and the primary structure of protein for the human cyclooxygenase -2. 1996-1999 the crystallographic structure has been elucidated that showed great similarity to the cyclooxygenase-1 at first glance. From 1999 there was the first cyclooxygenase -2- selective pharmacological agents. Since then, the major differences in structure, origin, occurrence, function and regulation of these two cyclooxygenases be investigated and cleared up more and more accurate.

Human Genome Organisation Mouse Genome Informatics Enzyme induction and inhibition COX-2 inhibitor Cellular compartment Endothelium
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