Cyclooxygenase is an enzyme (EC 188.8.131.52) that is responsible for formation of important biological mediators called prostanoids, including prostaglandins, prostacyclin and thromboxane. It exists in two forms: COX-1 and COX-2
CHEMICAL STRUCTURE AND IMAGES
When relevant for the function
- Primary structure
- Secondary structure
- Tertiary structure
- Quaternary structure
Protein Aminoacids Percentage
COX-1 has lower asparagine and higher proline, glycine and leucine (less proliferation and more protein synthesis??)
SYNTHESIS AND TURNOVER
The expression of both isoforms is regulated differently. The COX1 gene is expressed constitutively in almost all cells. In fact, it is involved in immediate prostanoid biosynthesis and plays an important role in intercellular communication and modulation of local homeostatic functions.
The inducible COX-2 is instead a result of pro-inflammatory stimuli and is involved in delayed synthesis of prostanoids. Pro-inflammatory stimuli such as IL1 and the endotoxin LPS can cause a rapid and intense induction of COX2 in various cell types such as macrophages, fibroblasts and endothelial cells of blood vessels.
- PTGS1 is involved in production of prostaglandins for cellular housekeeping functions,
- PTGS2 is associated with biologic events such as injury, inflammation, and proliferation.
- Cell signaling and Ligand transport
- Structural proteins
A major mechanism for the regulation of prostaglandin synthesis occurs at the level of cyclooxygenase, also known as prostaglandin-endoperoxide synthase (PTGS; EC 184.108.40.206). The first rate-limiting step in the conversion of arachidonic acid to prostaglandins is catalyzed by PTGS. Two isoforms of PTGS have been identified: PTGS1 (COX1; OMIM 176805 ) and a mitogen-inducible form, PTGS2 (OMIM 600262 ).
The genes that codify for the two isoforms are located on different chromosomes.
The COX-1 map on 9q32-q33.3 and OMIM
The COX-2 map on 1q25.2-q25.3 and OMIM
This localization clearly indicate that these genes are not genetically linked.
Other differencens between the isoforms are listed below
|Size of gene||22 kb||8.3kb|
|Number of exon||11||10|
|Size of mRNA||2.8 kb||4.6 kb|
|Coding nucleotides||1797 bp||1812 bp|
|Number of amino acids||576 aa||604 aa|
|5'-Flankng region||no TATA box, GC rich, Sp1||NF-kB, NF-IL6, CRE, E-box, TATA box|
|3'-UTR||0.7 kb||2 kb AUUUA rich element|
|Style of expression||Constitutive||Inducible|
In this link it is possible to compare the amino acids composition of the two isoforms.
Green: the same quantity of amino acids in both isoforms
Blue: higher relative quantity of the highlighted amino acid
Yellow: lower relative quantity of the highlighted amino acid
The major difference in the sequence of the two isoforms is in the regulatory region. Infact COX-1 is constitutively expressed in many tissues and cells and its gene does not possess a canonical TATA or CAAT box. These features are consistent with those of an hosuekeeping gene. Sp1 has been shown to contribute to constitutive expression of COX-1 and mutation in this regulatory sequence sgnificantly reduced to 40-50% that of wild-type. COX-1 is preferentially expressed at high levels in specific cells and tissues, including vascular endothelia, monocytes, platelets, renal collecting tubules, and seminal vesicles.
Inducers of COX-1 gene expression
On the other hand COX-2 gene posses a lot of regulation sequences, mainly because this isoform is different induced and expressed in different cell types. As indicated below, COX-2 transcription can be promoted in response to:
* proinflammatory factors like IL-1, TNFalpha, INFgamma, LPS and TPA
* hormones like FSH, LH and estrogen
* growth factors like EGF, PDGF and FGF
* oncogenes like v-Sarc and v-Ras
Inducers of COX-2 gene expression
Role of COX-2 in cancer