The cyclooxygenase (COX) enzyme system is the major pathway catalyzing the conversion of arachidonic acid into prostaglandins (PGs).
Full Answer
What is the mechanism of action of cyclooxygenase (COX)?
Cyclooxygenase (COX) first oxidizes arachidonic acid to prostaglandin G2 and then peroxidizes it to prostaglandin H 2. COX exists as two isoforms: COX-1, which is constitutively active, and COX-2, which can be induced and mediates the inflammatory response.
How do cyclooxygenase isoenzymes catalyze the formation of prostaglandins?
The cyclooxygenase isoenzymes, COX-1 and COX-2, catalyze the formation of prostaglandins, thromboxane, and levuloglandins. The prostaglandins are autocoid mediators that affect virtually all known physiological and pathological processes via their reversible interaction with G-protein coupled membrane receptors.
What is the function of cyclooxygenase 1 and 2?
The cyclooxygenase isoforms (COX-1 and COX-2) are among the most thoroughly studied and best understood mammalian oxygenases. Possessing two separate but linked active sites, the COXs catalyze the bis-dioxygenation and subsequent reduction of arachidonic acid (AA) to prostaglandin (PG)G2and PGH2(Fig. 1A).
Is cyclooxygenase an oxidoreductase?
Cyclooxygenase (COX), also known as prostaglandin endoperoxide synthase, is a type of oxidoreductase enzyme that plays a key role in the formation of biological modulators such as prostaglandins (PGs), prostacylins and thromboxane from arachidonic acid [24].
What are cyclooxygenase pathways?
Abstract. The cyclooxygenase (COX) enzyme system is the major pathway catalyzing the conversion of arachidonic acid into prostaglandins (PGs).
What does the cyclooxygenase pathway produce?
The Cyclooxygenase Pathway Cyclooxygenase (COX) metabolism leads to the production of the five principal prostanoids via two distinct isozymes, COX-1 and COX-2.
What is the function of cyclooxygenase in the body?
The cyclooxygenase isoenzymes, COX-1 and COX-2, catalyze the formation of prostaglandins, thromboxane, and levuloglandins. The prostaglandins are autocoid mediators that affect virtually all known physiological and pathological processes via their reversible interaction with G-protein coupled membrane receptors.
What are COX-1 and COX-2 pathways?
Cyclooxygenases (COX-1 and COX-2) are key enzymes in the conversion of arachidonic acid to prostaglandins and other lipid mediators. Because it can be induced by inflammatory stimuli, COX-2 has been classically considered as the most appropriate target for anti-inflammatory drugs.
What is the role of cyclooxygenase during inflammation?
In the first, cyclooxygenase (COX) initiates the formation of prostaglandins and thromboxane. Inhibition of COX is one mechanism by which nonsteroidal anti-inflammatory drugs (NSAIDs) exert their potent analgesic and anti-inflammatory effects.
What is the difference between COX-1 and COX-2?
COX-1 is thought to be responsible for the production of prostaglandins associated with normal physiologic function and is found in such tissues as the stomach, kidney, and platelets. COX-2 was thought to be induced as the result of inflammation and responsible for producing prostaglandins such as prostaglandin E2.
What is cyclooxygenase in simple terms?
Definition of cyclooxygenase : an enzyme that catalyzes the conversion of arachidonic acid to prostaglandins and that has two isoforms of which one is involved in the creation of prostaglandins which mediate inflammation and pain.
Where is cyclooxygenase found in the body?
COX-1 was found in blood vessels, interstitial cells, smooth muscle cells, platelets and mesothelial cells. In contrast, COX-2 was found predominantly in the parenchymal cells of many tissues, with few exceptions, for example the heart.
How is COX activated?
Mechanism of the cyclooxygenase reaction Cyclooxygenase catalysis requires that the enzyme first be activated, a process dependent on the peroxidase activity. Two-electron reduction of a peroxide substrate results in the oxidation of the ferric heme to an oxo-ferryl porphyrin radical cation.
What is COX and LOX?
COX and LOX are the important enzymes for conversion of AA to eicosanoids [97]. These AA-derived eicosanoids play a vital role in eliciting immune responses, in inducing inflammation, and in resolution of inflammation. PUFAs compete with desaturases and elongases and reduce the levels of AA-derived eicosanoids.
What is the role of cyclooxygenase in endothelial cells?
Endothelial cell cyclooxygenase synthesizes prostacyclin, which inhibits aggregation and dilates vessels. Platelet cyclooxygenase forms thromboxane A2, a potent aggregating agent and vasoconstrictor. Aspirin irreversibly acetylates cyclooxygenase, rendering it inactive. Low doses of aspirin, 80 to 100 mg, easily overcome the finite amount of cyclooxygenase available in the nucleus-free platelets. However, endothelial cells can synthesize new cyclooxygenase. Thus, with low doses of aspirin, prostacyclin synthesis continues while thromboxane synthesis ceases, decreasing platelet activation and aggregation. High doses of aspirin inhibit the enzyme at both cyclooxygenase sites.
Where is COX1 expressed?
It is also often upregulated in cancer cells, and is constitutively expressed in the kidney and brain. Both isoforms generate prostaglandins during an inflammatory response, while COX-1 activity is required for prostaglandin synthesis for tissue homeostasis.
What is the enzyme that converts arachidonic acid to prostaglandin H2?
Cyclooxygenase. Cyclooxygenase (COX) is a rate-limiting enzyme involved in the conversion of arachidonic acid to prostaglandin H2, which is the precursor of several molecules, including prostaglandins, prostacyclin, and thromboxanes. From: Handbook of Immunohistochemistry and in Situ Hybridization of Human Carcinomas, 2005.
What is the role of COX in platelet activation?
COX is the enzyme to catalyze arachidonic acid to generate prostaglandin H2, which is converted by downstream enzymes into other prostaglandins and thromboxanes. 67 Two COX isoforms (COX-I and II) have been identified; COX-I is constitutively expressed in nearly all tissues, but its activity is most strongly associated with prostaglandin production in gastric mucosa and thromboxane production in platelets. 68 Although there are multiple pathways of platelet activation, one of most potent agonists is thromboxane A2 (TXA2). 69 The thromboxane increases intracellular calcium via binding to its receptors on platelets, and this binding is also crucial for exposure of the GP IIb/IIIa receptor as well as the release of the dense and/or alpha granule contents (e.g., P-selectin) ( Figure 79.2 ). Therefore, the inhibition of COX-I is known to lessen platelet activation via several mechanisms, including the suppression of thromboxane production and P-selectin expression. In our study, the effects of 5-CQA on COX-I enzyme were investigated related to potential inhibition of P-selectin expression. 5-CQA was found to be a potent compound able to inhibit COX-I enzyme by more than 50% at the concentration of 0.05 μm. 65 On comparison to a well-known COX-I inhibitor (ibuprofen, aspirin), 5-CQA was able to inhibit COX-I as much as the two COX inhibitors. Although COX-I enzyme is primarily involved in platelet activation, the effects of 5-CQA on COX-II enzyme were also investigated in our study, because the COX-II enzyme is likely to be involved in many important physiological processes such as endothelial dysfunctions in diabetes, cardiovascular diseases, hypertension, and aging, and because the expression is induced/upregulated in response to inflammatory stimuli and elevates prostaglandin levels as part of the inflammatory response. 67 Similar to the COX-I inhibition, at the concentration of 0.05 μm, 5-CQA was also very potent compound able to inhibit COX-II enzyme by more than 50%. Compared to NS-398 (a COX-II specific inhibitor), 5-CQA was able to inhibit COX-II comparable to NS-398. These data suggest that 5-CQA found in coffee may be potent compounds to inhibit both COX-I and II enzymes. How are CHAs able to inhibit COX enzymes? There is not much information available about the potential mechanism. However, it is believed that CHAs can quench peroxide intermediates generated during the production of prostaglandin G 2 and prostaglandin H 2. 70 This assumption is in fact supported by kinetic data indicating that CHAs inhibit COX enzymes in an uncompetitive manner. Besides the direct inhibition of COX enzymes, another study showed that CHAs significantly decreased LPS-induced upregulation of COX-II at protein and mRNA levels in RAW 264.7 cells by suppressing the activation of nuclear factor-kappaB (NF-κB) and c-Jun-activator protein (AP-1) pathway. 71 Taken together, the data suggest that CHAs may inhibit COX-I and II enzymes, and they even suppress COX-II induction by inhibiting redox-sensitive transcriptional factors such as NF-κB.
How do prostaglandins affect tubular reabsorption?
As prostaglandins also promote natriuresis by interfering with tubular sodium reabsorption, and blunt the effects of antidiuretic hormone on the tubular reabsorption of water, inhibition of prostaglandin production by NSAIDs results in salt and water retention, with resultant hypertension and oedema.
What enzymes catalyze the hydroxylation and oxygenation of arachidonic acid?
Cyclooxygenases catalyze the hydroxylation and oxygenation of arachidonic acid that leads to the generation of endoperoxides (or PGH2 ). Subsequent processing by a number of enzymes converts PGH 2 into the biologically active spectrum of prostaglandins.
What is Cox-2 in PCA?
Cox-2 is the inducible form of cyclo-oxygenase and catalyzes the conversion of arachidonic acid to prostaglandins. Cox-2 is expressed by inflammatory cells, such as macrophages, and can be induced by TNF and EGF. 36 The prostaglandins and eicosanoids produced can have a major role in the development of human cancers but the role is not as firmly established in PCa. 37 There is over-expression of Cox-2 in PCa and PIN compared to normal or hyperplastic prostate. 38,39 In vitro Cox-2 inhibitors inhibit PCA growth and increase apoptosis in PCa cell lines. 40 Cox-2 may play a role in more advanced T3 or T4 cancers. 41
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What enzyme is responsible for the biosynthesis of prostaglandins?
Cyclooxygenases (COX) catalyze the transformation of arachidonic acid into prostaglandin H2 (PGH2), the first step in the biosynthesis of prostanoids (prostaglandins, prostacyclin, and thromboxane). While COX-1 is a constitutive enzyme, COX-2 is expressed under pathological conditions such as inflammation or cancer proliferation, ...
What are the inhibitors of prostacyclin synthetase?
Hitherto, only two inhibitors of prostacyclin formation have been reported: 15-hydroperoxyarachidonic acid (15-HPAA, Gryglewski et al., 1976) and nicotine ( Wennmalm 1978a, b ).
How is arachidonic acid converted into PG endoperoxides?
Arachidonic acid is converted into PG endoperoxides by cyclo-oxygenase for which a number of specific inhibitors exist, the chief of which are the aspirin-like drugs ( Ferreira et al, 1971; Smith and Willis, 1971; Vane, 1971 ). Specific inhibitors of thromboxane synthetase have also been described ( Blackwell et al, 1978; Moncada et al, 1977c; Gorman et al, 1977b) and treatment with these should achieve an anti-thrombotic effect, with a prolonged bleeding time and inhibition of thrombus formation, whereas inhibition of prostacyclin synthetase should lead to a prothrombotic state.
What enzyme converts arachidonic acid to prostanoids?
Cyclooxygenase-2. COX-2 is the readily inducible, rate-limiting enzyme for the conversion of arachidonic acid to prostanoids in most cells and tissues that have been activated by inflammatory cytokines, trophic hormones, or tumor promoters ( 346–349 ).
What is the chemical structure of COX-2 inhibitors?
Chemical structures of some COX-2 inhibitors. A key structural feature that characterizes celecoxib and valdecoxib is the presence of a primary sulfonamide moiety; rofecoxib possesses instead the isosteric and isoelectronic methyl sulfone group in its structure.
When was Celecoxib first approved?
Celecoxib (Celebrex) and rofecoxib (Vioxx) were the first two coxibs approved by the FDA and launched in 1999. Valdecoxib (Bextra, Pfizer-Pharmacia) was approved by the FDA and launched in 2002. Figure 17.4.
Is COX1 or COX2 a developmental regulation?
Both COX-1 and COX-2 are subject to developmental regulation, and interference with their developmental expression may condition adult phenotypes [ 22 ]. COX-1 and COX-2 are expressed in a spatially and temporaly segregated manner during thymic development, where they influence T-cell maturation [ 23 ].
What are the roles of COX-2 PGs in the kidney?
During normal physiological conditions, PGs play important roles in the regulation of renal hemodynamic and homeostasis of body water and sodium balance.
Where is COX1 expressed?
COX-1 is the dominant isoform to be expressed in glomerular mesangial cells, arteriolar endothelial cells, as well as in cortical and medullary collecting ducts in the kidney of bovine, rabbi t, guinea pig, rat, and mouse [8], [9].
What is the rate limiting enzyme responsible for the first 2 steps in the synthesis of PGs?
Cyclooxygenase (COX) is the rate-limiting enzyme that is responsible for the first 2 steps in the synthesis of PGs. The COX enzyme exists in 2 isoforms, COX-1 and COX-2. These 2 isoforms have a comparable molecular mass of 71 and 73 kDa, respectively, but their expression and distribution within the renal tissue are different.
What enzyme converts arachidonic acid into prostaglandins?
The cyclooxygenase (COX) enzyme system is the major pathway catalyzing the conversion of arachidonic acid into prostaglandins (PGs). PGs are lipid mediators implicated in a variety of physiological and pathophysiological processes in the kidney, including renal hemodynamics, body water and sodium balance, and the inflammatory injury characteristic ...
Where is PGE2 produced?
PGE2 in the kidney. Although PG production occurs in all tissues, the kidney is a rich source, particularly with PGE2 being the major renal PG metabolite. PGE2 can be generated by all renal cells which are characterized by the presence of PGE2 synthases—the enzyme responsible for the production of PGE2.
Is COX2 expressed in kidneys?
In response to inflammatory states, however, COX-2 may be expressed in many more cells and different cell types within the kidney [16].
Do mice with COX2 have nephropathy?
In contrast, mice with gene disruption of COX-2 have severe nephropathy, and the kidneys appear pale and smaller than those of the wild-type littermates. In the earlier states, the kidneys show small immature glomeruli in the subcapsular region with enlarged glomeruli outside of this hypoplastic area.