Title : Human
cyclooxygenase-2 is a sequence
homodimer that functions as a conformational
heterodimer
Abstract :
- Prostaglandin endoperoxide H synthases 1 and 2, also known as cyclooxygenases (COXs) 1 and 2 , convert arachidonic acid (AA) to prostaglandin endoperoxide H(2)
- Prostaglandin endoperoxide H synthases are targets of nonspecific nonsteroidal anti-inflammatory drugs and COX COX-2 -specific inhibitors called coxibs
- PGHS-2 is a sequence homodimer
- Each monomer has a peroxidase and a COX active site
- We find that human PGHS-2 functions as a conformational heterodimer having a catalytic monomer (E(cat)) and an allosteric monomer (E(allo))
- Heme binds tightly only to the peroxidase site of E(cat), whereas substrates, as well as certain inhibitors (e.g. celecoxib), bind the COX site of E(cat)
- E(cat) is regulated by E(allo) in a manner dependent on what ligand is bound to E(allo)
- Substrate and nonsubstrate fatty acids ( FAs ) and some COX inhibitors (e.g. naproxen) preferentially bind to the COX site of E(allo)
- AA can bind to E(cat) and E(allo), but the affinity of AA for E(allo) is 25 times that for E(cat)
- Palmitic acid, an efficacious stimulator of human PGHS-2 , binds only E(allo) in palmitic acid/murine PGHS-2 co-crystals
- Nonsubstrate FAs can potentiate or attenuate actions of COX inhibitors depending on the FA and whether the inhibitor binds E(cat) or E(allo)
- Our studies suggest that the concentration and com position of the free FA pool in the environment in which PGHS-2 functions in cells, the FA tone, is a key factor regulating PGHS-2 activity and its responses to COX inhibitors
- We suggest that differences in FA tone occurring with different diets will likely affect both base-line prostanoid synthesis and responses to COX inhibitors
Output (sent_index, trigger,
protein,
sugar,
site):
Output(Part-Of) (sent_index,
protein,
site):
- 4. COX, site
- 6. COX, site
- 6. peroxidase, site
- 8. COX, site
*Output_Site_Fusion* (sent_index,
protein,
sugar,
site):