CYCLOOXYGENASE 1 AND 2 (COX-1 AND COX-2)
Eicosanoids

Author: daniele viarisio
Date: 27/09/2007

Description

DEFINITION

Cyclooxygenase is an enzyme (EC 1.14.99.1) 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

THE GENE

DatabaseLink
WikigenesPTGS1PTGS2
GeneCards"PTGS1":"PTGS2":
Your Favorite Gene Sigma"PTGS1":"PTGS2":

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

mRNA synthesis
protein synthesis

post-translational modifications
degradation

CELLULAR FUNCTIONS

cellular localization,
biological function

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.
  • Enzymes
DatabaseLink
BRENDA - The Comprehensive Enzyme Information System"URL":
KEGG Pathways"URL":
Human Metabolome Database"URL":
  • Cell signaling and Ligand transport
  • Structural proteins

REGULATION

DIAGNOSTIC USE

A major mechanism for the regulation of prostaglandin synthesis occurs at the level of cyclooxygenase, also known as prostaglandin-endoperoxide synthase (PTGS; EC 1.14.99.1). 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

COX-1COX-2
Size of gene22 kb8.3kb
Number of exon1110
Size of mRNA2.8 kb4.6 kb
Coding nucleotides1797 bp1812 bp
Number of amino acids576 aa604 aa
5'-Flankng regionno TATA box, GC rich, Sp1NF-kB, NF-IL6, CRE, E-box, TATA box
3'-UTR0.7 kb2 kb AUUUA rich element
Style of expressionConstitutiveInducible

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

Comments
2020-04-13T22:49:29 - Gianpiero Pescarmona

COX-2 is involved in vascular oxidative stress and endothelial dysfunction of renal interlobar arteries from obese Zucker rats. 2015

COX-2 activity is in turn upregulated by ROS.

COX-2 and iNOS are critical in advanced glycation end product-activated chondrocytes in vitro. 2009

Meanwhile, the upstream molecules regulating COX-2/iNOS activation, such as AP-1, NF-kappaB, extracellular signal regulated protein kinase (ERK) and c-jun N-terminal kinase (JNK), were activated by AGE.

Structure of COX-1 and COX-2 Enzymes and Their Interaction With Inhibitors, 1999

Abstract
Cyclooxygenase (COX) is the central enzyme in the biosynthetic pathway to prostaglandins (PGs) from arachidonic acid (AA). This protein was purified more than 20 years ago and cloned in 1988. A few years later another protein with COX activity was identified and called COX-2. Although the isoforms of COX are derived from different genes of different size and give rise to distinct mRNA sequences, the proteins are highly homologous in sequence and in three-dimensional structure. They also contain the same two catalytic sites, a peroxidase and a COX site, use the same substrate, AA, and form the same product. The detailed structures of the active COX sites in the isoforms are almost identical. Nevertheless, there are very important biological differences between COX-1 and COX-2. The latter is a highly inducible protein, absent from most tissues in normal conditions but increasing rapidly in response to inflammatory stimuli such as bacterial endotoxin, cytokines, or growth factors. Furthermore, there are differences in substrate binding and, particularly, in inhibitor binding sites that allow the isoforms to be inhibited differentially. This difference is therapeutically significant and selective inhibitors of COX-2 exhibit antiinflammatory potency without the gastric and renal toxicities of the aspirin-like drugs. Selective COX-2 inhibitors may also have important effects on cell growth, development, or survival, reflecting the location of COX-2 on the nuclear membrane of cells. Although much is known of the structure of the isoforms, all the questions have not yet been answered. The new therapeutic possibilities offered by selective inhibitors of COX-2 will encourage a continuing and more detailed analysis of the structures and functions of these closely related proteins.

Overexpression of inducible nitric oxide synthase and cyclooxygenase-2 in rat zinc-deficient lung: involvement of a NF-κB dependent pathway, 2006

… Several agents that produce oxidative stress induce iNOS and cyclooxygenase type 2
(COX-2) expression [14], [15] … Total protein thiol groups were determined as described by Sedlak
et al … As it is shown in (Table 2), protein thiols were significantly lower (about 22%) than in the …

Inhibition of platelet activation by 2-mercaptopropionylglycin in vitro and in Vivo. 1988

Abstract
2-mercaptopropionylglycin (2-MPG), a cell membrane penetrating thiol, was evaluated for its antithrombotic potential using in vitro and in vivo tests. 2-MPG was found to inhibit agonist-induced platelet aggregation and serotonin release as well as prostaglandin/thromboxane synthesis in platelet-rich plasma. Administration of 2-MPG to rats resulted in an inhibition of laser-induced thrombus formation in mesenteric vessels. When plasma was incubated with 2-MPG and then used for determination of various standard coagulation parameters, significant prolongation of the clotting times were observed.

The use of N-(2-mercaptopropionyl)-glycine (MPG) for preparation and storage of platelets. 1988

Abstract
The SH group containing drug MPG which inhibits platelet aggregation in a reversible manner was used as a cytoprotective substance in some experiments on preparation and storage of human platelets for transfusion. In vitro (n = 6): concentration, morphology score, HSR and aggregation of stored platelets were measured after simulating in vitro the post transfusional conditions by resuspension of stored platelets in fresh drawn plasma (pH 7.4, 37 degrees C). In vivo (n = 2): Autologous platelets stored for 48 h at 22 degrees C were labelled with 111In and retransfused. The results obtained from platelets prepared and stored in plasma containing MPG were compared with those obtained from control platelets without MPG.

The role of the GSH-disulfide status in the reversible and irreversible aggregation of human platelets, 1983

Abstract
Disturbance of cellular SH/SS status of blood platelets by diminution of the level of reduced glutathione is very sensitively reflected in changes of the in vitro aggregation. Additionally, disulfide-linked protein polymers are formed. One of these polymers participates in mediating platelet disaggregation.

Platelet cyclic guanosine monophosphate production during menstrual cycle in healthy women, 2002

Abstract
The incidence of cardiovascular disease among women during their reproductive years is considerably less than in men and this difference decreases after menopause. Since in cultured endothelial cells and in platelets E2 increases nitric oxide (NO) production, it is possible that their cardioprotective effect may be mediated by NO. The aim of this study was to evaluate platelet cyclic guanosine monophosphate (cGMP), as a marker of NO production, during menstrual cycle. Fifteen women aged 26–40 yr were studied to evaluate: LH, FSH, E2, P and cGMP on the 5th follicular and 22nd luteal day of the cycle and during the ovulatory period. Platelet cGMP was evaluated in basal condition (3-isobuthyl 1-methylxanthine- IBMX) and with ionomycine (IONO) and sodium nitroprusside (SNP). Results: LH, FSH, E2 and P demonstrated the typical patterns of ovulatory cycle. During follicular and luteal IBMX, SNP and IONO phase were homogeneous while they increased during the ovulatory period. A correlation between IBMX cGMP and E2 (p<0.002, rs=0.456) was found. In conclusion the data show an increase in platelet cGMP during the ovulatory period and a correlation between E2 and cGMP suggesting that E2 modulates NO production. The cardioprotective effect of E2 may be, at least in part, mediated by the increase in NO production.

Thrombocytopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: A meta-analysis. 2020

Abstract
Background: Coronavirus disease 2019 (COVID-19) is a novel infectious disease with lack of established laboratory markers available to evaluate illness severity. In this study, we investigate whether platelet count could differentiate between COVID-19 patients with or without severe disease. Additionally, we evaluate if thrombocytopenia is associated with severe COVID-19.
Methods: An electronic search in Medline, Scopus and Web of Science was performed to identify studies reporting data on platelet count in COVID-19 patients. A meta-analysis was performed, with calculation of weighted mean difference (WMD) of platelet number in COVID-19 patients with or without severe disease and odds ratio (OR) of thrombocytopenia for severe form of COVID-19.
Results: Nine studies with 1779 COVID-19 patients, 399 (22.4%) with severe disease, were included in the meta-analysis. The pooled analysis revealed that platelet count was significantly lower in patients with more severe COVID-19 (WMD -31×109/L; 95% CI, from -35 to -29×109/L). A subgroup analysis comparing patients by survival, found an even lower platelet count was observed with mortality (WMD, -48×109/L; 95% CI, -57 to -39×109/L. In the four studies (n=1427) which reported data on rate of thrombocytopenia, a low platelet count was associated with over fivefold enhanced risk of severe COVID-19 (OR, 5.1; 95% CI, 1.8-14.6).
Conclusions: Low platelet count is associated with increased risk of severe disease and mortality in patients with COVID-19, and thus should serve as clinical indicator of worsening illness during hospitalization.

Keywords: Coronavirus, COVID-19; Platelets; Thrombocytopenia.

Copyright © 2020 Elsevier B.V. All rights reserved.

Conflict of interest statement
Declaration of Competing Interest The authors declared that there is no conflict of interest.

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