COX-3
Encyclopedia
COX-3 is an enzyme
that is encoded by the PTGS1
(COX1) gene
, but is not functional in humans. COX-3 is the third and most recently discovered cyclooxygenase
(COX) isozyme
, the others being COX-1 and COX-2. The COX-3 isozyme is encoded by the same gene as COX-1, with the difference that COX-3 retains an intron
that is not retained in COX-1.
The other two cyclooxygenase isozymes are known to convert arachidonic acid
into prostaglandins and are the targets of nonsteroidal anti-inflammatory
drugs (NSAIDs).
differently. In dogs the resulting protein resembles the other two COX enzymes, but in mice
and humans it does not, owing to a frame-shift mechanism. This mechanism is due to the fact that the spliced intron has 93 bases in dogs, resulting in the loss of 93:3 = 31 amino acid
s in the COX-3 sequence, which apparently does not impair its functionality. In humans, the intron is 94 bases long, leading to a protein with a completely different amino acid sequence from those of COX-1 or COX-2. The expressed protein does not show COX activity, and it is unlikely to play a role in prostaglandin-mediated physiological responses.
and inflammation
. Even though COX-2 inhibitor
s are as active as traditional NSAIDs in inflammatory models, there were still some unexplained issues. For example, the widespread use of the newer generation of COX-2-selective compounds demonstrated that COX-2 also has other physiological roles, e.g. in the maintenance of fluid balance by the kidney
s. In addition, the COX-1/COX-2 model did not explain the properties of paracetamol
(acetaminophen): although its antipyretic
(fever reducing) and analgesic
(pain relieving) effects might be explained by inhibition of COX-2, it is not anti-inflammatory. Daniel L. Simmons
' group suggested this was because of the presence of a variant of COX-1, which they named COX-3, that would be especially sensitive to paracetamol and related compounds. If this enzyme were particularly expressed in the brain, it could explain both the characteristics of paracetamol, which has been reputed for some time of being a centrally-acting antipyretic
.
COX-3 was actually discovered in 2002, and been found to be selectively inhibited by paracetamol, phenacetin
, antipyrine, dipyrone, and some NSAIDs in rodent
studies.
A number of arguments counted against the COX-3 hypothesis: COX-2-selective inhibitors react weakly with the COX-3 enzymatic site, because the site is identical to that in COX-1, but they are as good at reducing fever as older NSAIDs. The fever response has also been clearly associated with a rapid induction of COX-2 expression and an associated increase in prostaglandin E2 production, with no role for COX-1 or a COX-1 gene product (e.g., COX-3). Finally, the sites of COX-3 expression do not appear to fit in well with those sites associated with fever, and the protein should be present within the hypothalamus
rather than the cerebral cortex
. All these considerations appeared to argue against COX-3 being the site of the antipyretic actions of NSAIDs and COX-2-selective agents. However, the results could be read as showing that paracetamol acts at a different site than the other NSAIDs and that more than one COX isoform contribute to the fever response.
Finally, the discovery of the frame-shift mechanism has made it highly unlikely that COX-3 plays a role in inflammation and fever in humans.
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
that is encoded by the PTGS1
PTGS1
Cyclooxygenase-1 , also known as prostaglandin G/H synthase 1, prostaglandin-endoperoxide synthase 1 or prostaglandin H2 synthase 1, is an enzyme that in humans is encoded by the PTGS1 gene.- History :...
(COX1) gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
, but is not functional in humans. COX-3 is the third and most recently discovered cyclooxygenase
Cyclooxygenase
Cyclooxygenase is an enzyme that is responsible for formation of important biological mediators called prostanoids, including prostaglandins, prostacyclin and thromboxane. Pharmacological inhibition of COX can provide relief from the symptoms of inflammation and pain...
(COX) isozyme
Isozyme
Isozymes are enzymes that differ in amino acid sequence but catalyze the same chemical reaction. These enzymes usually display different kinetic parameters Isozymes (also known as isoenzymes) are enzymes that differ in amino acid sequence but catalyze the same chemical reaction. These enzymes...
, the others being COX-1 and COX-2. The COX-3 isozyme is encoded by the same gene as COX-1, with the difference that COX-3 retains an intron
Intron
An intron is any nucleotide sequence within a gene that is removed by RNA splicing to generate the final mature RNA product of a gene. The term intron refers to both the DNA sequence within a gene, and the corresponding sequence in RNA transcripts. Sequences that are joined together in the final...
that is not retained in COX-1.
The other two cyclooxygenase isozymes are known to convert arachidonic acid
Arachidonic acid
Arachidonic acid is a polyunsaturated omega-6 fatty acid 20:4.It is the counterpart to the saturated arachidic acid found in peanut oil, Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega-6 fatty acid 20:4(ω-6).It is the counterpart to the saturated arachidic acid found in peanut oil,...
into prostaglandins and are the targets of nonsteroidal anti-inflammatory
Anti-inflammatory
Anti-inflammatory refers to the property of a substance or treatment that reduces inflammation. Anti-inflammatory drugs make up about half of analgesics, remedying pain by reducing inflammation as opposed to opioids, which affect the central nervous system....
drugs (NSAIDs).
Transcription
COX-3 is transcribed from the PTGS1 (COX1) gene, but the resulting mRNA is splicedRNA splicing
In molecular biology and genetics, splicing is a modification of an RNA after transcription, in which introns are removed and exons are joined. This is needed for the typical eukaryotic messenger RNA before it can be used to produce a correct protein through translation...
differently. In dogs the resulting protein resembles the other two COX enzymes, but in mice
MICE
-Fiction:*Mice , alien species in The Hitchhiker's Guide to the Galaxy*The Mice -Acronyms:* "Meetings, Incentives, Conferencing, Exhibitions", facilities terminology for events...
and humans it does not, owing to a frame-shift mechanism. This mechanism is due to the fact that the spliced intron has 93 bases in dogs, resulting in the loss of 93:3 = 31 amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
s in the COX-3 sequence, which apparently does not impair its functionality. In humans, the intron is 94 bases long, leading to a protein with a completely different amino acid sequence from those of COX-1 or COX-2. The expressed protein does not show COX activity, and it is unlikely to play a role in prostaglandin-mediated physiological responses.
Discovery
The original COX-1/COX-2 model did not fully explain the immune responses of feverFever
Fever is a common medical sign characterized by an elevation of temperature above the normal range of due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering.As a person's temperature increases, there is, in...
and inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
. Even though COX-2 inhibitor
COX-2 inhibitor
COX-2 selective inhibitor is a form of non-steroidal anti-inflammatory drug that directly targets COX-2, an enzyme responsible for inflammation and pain. Targeting selectivity for COX-2 reduces the risk of peptic ulceration, and is the main feature of celecoxib, rofecoxib and other members of this...
s are as active as traditional NSAIDs in inflammatory models, there were still some unexplained issues. For example, the widespread use of the newer generation of COX-2-selective compounds demonstrated that COX-2 also has other physiological roles, e.g. in the maintenance of fluid balance by the kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
s. In addition, the COX-1/COX-2 model did not explain the properties of paracetamol
Paracetamol
Paracetamol INN , or acetaminophen USAN , is a widely used over-the-counter analgesic and antipyretic . It is commonly used for the relief of headaches and other minor aches and pains and is a major ingredient in numerous cold and flu remedies...
(acetaminophen): although its antipyretic
Antipyretic
Antipyretics ; an-tee-pahy-ret-iks; from the Greek anti, against, and pyreticus, are drugs or herbs that reduce fever. Normally, they will not lower body temperature if one does not have a fever. Antipyretics cause the hypothalamus to override an interleukin-induced increase in temperature...
(fever reducing) and analgesic
Analgesic
An analgesic is any member of the group of drugs used to relieve pain . The word analgesic derives from Greek an- and algos ....
(pain relieving) effects might be explained by inhibition of COX-2, it is not anti-inflammatory. Daniel L. Simmons
Daniel L. Simmons
Daniel L. Simmons is a professor of chemistry and the director of the Cancer Research Center at Brigham Young University . He was the discoverer of the COX-2 enzyme that is the target of celecoxib and other COX-2 inhibitors...
' group suggested this was because of the presence of a variant of COX-1, which they named COX-3, that would be especially sensitive to paracetamol and related compounds. If this enzyme were particularly expressed in the brain, it could explain both the characteristics of paracetamol, which has been reputed for some time of being a centrally-acting antipyretic
Antipyretic
Antipyretics ; an-tee-pahy-ret-iks; from the Greek anti, against, and pyreticus, are drugs or herbs that reduce fever. Normally, they will not lower body temperature if one does not have a fever. Antipyretics cause the hypothalamus to override an interleukin-induced increase in temperature...
.
COX-3 was actually discovered in 2002, and been found to be selectively inhibited by paracetamol, phenacetin
Phenacetin
Phenacetin is an analgesic, once widely used; its use has declined because of its adverse effects.-History:Phenacetin was introduced in 1887, and was used principally as an analgesic, and was one of the first synthetic fever reducers to go on the market...
, antipyrine, dipyrone, and some NSAIDs in rodent
Rodent
Rodentia is an order of mammals also known as rodents, characterised by two continuously growing incisors in the upper and lower jaws which must be kept short by gnawing....
studies.
A number of arguments counted against the COX-3 hypothesis: COX-2-selective inhibitors react weakly with the COX-3 enzymatic site, because the site is identical to that in COX-1, but they are as good at reducing fever as older NSAIDs. The fever response has also been clearly associated with a rapid induction of COX-2 expression and an associated increase in prostaglandin E2 production, with no role for COX-1 or a COX-1 gene product (e.g., COX-3). Finally, the sites of COX-3 expression do not appear to fit in well with those sites associated with fever, and the protein should be present within the hypothalamus
Hypothalamus
The Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions...
rather than the cerebral cortex
Cerebral cortex
The cerebral cortex is a sheet of neural tissue that is outermost to the cerebrum of the mammalian brain. It plays a key role in memory, attention, perceptual awareness, thought, language, and consciousness. It is constituted of up to six horizontal layers, each of which has a different...
. All these considerations appeared to argue against COX-3 being the site of the antipyretic actions of NSAIDs and COX-2-selective agents. However, the results could be read as showing that paracetamol acts at a different site than the other NSAIDs and that more than one COX isoform contribute to the fever response.
Finally, the discovery of the frame-shift mechanism has made it highly unlikely that COX-3 plays a role in inflammation and fever in humans.