Cyclooxygenase-1
| Cyclooxygenase-1 | ||
|---|---|---|
|
Existing structural data : 1cqe , 1diy , 1ebv , 1eqg , 1eqh , 1fe2 , 1ht5 , 1ht8 , 1igx , 1igz , 1pge , 1pgf , 1pgg , 1prh , 1pth , 1q4g , 1u67 , 2ayl |
||
| Properties of human protein | ||
| Mass / length primary structure | 576 amino acids | |
| Secondary to quaternary structure | Homodimer | |
| Cofactor | Heme b | |
| Isoforms | COX-1, COX-3 | |
| Identifier | ||
| Gene names | PTGS1 ; COX1; COX3; PCOX1; PGG / HS; PGHS-1; PGHS1; PHS1; PTGHS | |
| External IDs | ||
| Enzyme classification | ||
| EC, category | 1.14.99.1 , dioxygenase | |
| Response type | Oxidation + peroxidation | |
| Substrate | Arachidonic acid + AH 2 + 2 O 2 | |
| Products | Prostaglandin H 2 + A + H 2 O | |
| Occurrence | ||
| Homology family | Prostaglandin synthase | |
| Parent taxon | Jaws | |
The prostaglandin synthase-1 or cyclooxygenase-1 (short: COX-1 ) is an enzyme that arachidonic acid to the two-step eicosanoid prostaglandin H2 oxidized . COX-1 is therefore indispensable for the production of prostaglandin E2 , which regulates gastric acid production and controls inflammatory reactions everywhere in the body , and is responsible for the production of thromboxane A2 in platelets and thus for the aggregation process in blood clotting and vasoconstriction . In contrast to COX-2 , COX-1 is found in all tissue types and its inhibition therefore also affects the whole body. Both are cyclooxygenases , which in turn belong to the large family of pathogen-inducible oxygenases (PIOXs).
Only non - specific non -steroidal anti-inflammatory drugs such as acetylsalicylic acid , which inhibit all cyclooxygenases, are available to inhibit the enzyme . Aspirin can also block COX-1 in lymphocytes in low doses without harming the stomach, for example. An inhibition of the inflammatory signaling pathways without side effects in the whole body is otherwise only possible through specific COX-2 inhibition.
Occurrence in the organism
Cyclooxygenases are located inside the endoplasmic reticulum (ER), inside the nuclear envelope and in the Golgi apparatus and adhere to the inside of the membranes of these cell compartments .
COX-1 occurs in the following cells and organs, among others:
- Only COX-1 occurs in blood platelets that induce clotting .
- COX-1 is found in endothelial cells of normal blood vessels (while COX-2 is found in endothelial cells of proliferating blood vessels, inflamed tissues, and atherosclerotic lesions).
- COX-1 occurs in the renal cortex and especially in the renal medulla. There above all prostaglandin E2 and prostacyclin are formed, which above all increase the kidney blood flow and thus also the glomerular filtration rate . COX-1-inhibiting NSAIDs can therefore have harmful side effects on kidney function in the case of certain underlying diseases ( heart failure , cirrhosis of the liver , kidney failure ) or in the case of overdosing.
- COX-1 occurs throughout the brain, but especially in the frontal lobe; it is believed to be involved in complex integrative functions between the autonomic nervous system and sensor technology.
Biosynthesis and structure
Cyclooxygenase-1 is encoded on chromosome 9q32-q33.3 as the PTGS1 gene (PTSG1 = prostaglandin G / H synthase 1, a synonym for COX1). In contrast to the cyclooxygenase-2 gene, it is a large gene (> 28 kb) with eleven exons , the transcription of which is ubiquitous and probably poorly regulated. The 4,982 base long mRNA is converted into the 576 amino acid enzyme through translation and post-translational modification .
Probably before the time that vertebrates evolved, their path of development separated from cyclooxygenase-2 through gene duplication and followed its own evolutionary path. General structural aspects of COX-1 are described under cyclooxygenases .
A splicing variant called COX3 - cyclooxygenase 3 can arise from the PTSG1 gene . This was first described in 2002, but is not functional in humans. One intron less is expressed in the PTSG1 gene . In dogs this leads to a 31 amino acids (corresponding to 93 base pairs ) shorter and enzymatically active cyclooxygenase. However, due to a frameshift mutation , the non-expressed intron is 94 base pairs long in mice and humans and this results in a completely different protein structure that has no cyclooxygenase activity. In addition to these two forms, a further nine splicing variants are described.
Biological function
Catalyzed reaction
+ 2 O 2 + AH 2 → 
→ 
+ A + H 2 O
Other functions
COX-1 appears to influence the formation of new blood vessels; this was discovered in colon cancer cells in the laboratory.
pharmacology
- Because when cyclooxygenase is inhibited, more arachidonic acid is available for the lipoxygenase pathway , which results in the formation of leukotrienes , which increase inflammation and anaphylaxis , inhibitors of cyclooxygenase can trigger an asthma attack .
- Acetylsalicylic acid (aspirin) leads to a transacetylation at the serine in position 530 in the catalytic center of the cyclooxygenase, which renders the enzyme inoperable until it is regenerated. Cyclooxygenase-1 is 10–100 times more sensitive than cyclooxygenase-2 .
- Competitively acting NSAIDs compete in the cyclooxygenase center for the binding site for the arachidonic acid . Ibuprofen binds very quickly and is quickly washed out again, diclofenac or indomethacin have a slower binding behavior.
history
From 1972 it was speculated that there was more than one cyclooxygenase . In 1988 the genome and primary protein structure for human cyclooxygenase-1 was sequenced. In 1994 the tertiary and quaternary structure became known. Since then, the essential similarities and differences in structure, origin, occurrence, function and regulation of the two cyclooxygenases have been examined and clarified more and more closely.
Individual evidence
- ↑ a b c Simmons, DL et al. (2004): Cyclooxygenase isozymes: the biology of prostaglandin synthesis and inhibition. In: Pharmacol. Rev. Vol. 56, pp. 387-437. PMID 15317910
- ^ Regina Botting: COX-1 and COX-3 inhibitors . Thrombosis Research 2003, Volume 110, Double Issue 5-6, June 15, 2003, pages 269,272; doi: 10.1016 / S0049-3848 (03) 00411-0 ; PMID 14592546
- ↑ ENSEMBL entry
- ↑ M. Tsujii et al .: Cyclooxygenase regulates angiogenesis induced by colon cancer cells. Cell 93 / - / 1998 . Pp. 705-716. PMID 9630216
