Structure, distribution, activity and common inhibitors of COX1 and COX2
| COX1 | COX2 | Reference | |
|---|---|---|---|
| Gene size | 22 kb | 8.3 kb | Vane et al., 1998 |
| aa Sequence length | 576 | 587 | Smith et al., 2000 |
| Active site size | Smaller | Larger | Morita, 2002 |
| aa Substitutions causing differences in active site size | Ile523 | Val523 | Smith et al., 2000 |
| Ile434 | Val434 | ||
| His513 | Arg513 | ||
| Enzyme activity | Largely constitutive | Largely inducible | Morita, 2002 |
| Enzyme regulation and activation | High concentration of hydroperoxide required; negative allosteric regulation and decreased activity at low AA concentrations | 10-fold lower hydroperoxide concentration required; greater activity and prostanoid synthesis than COX1 at low AA concentrations | Davidge, 2001 |
| Substrate selectivity | AA, dihomo-γ-linolenic acid | AA, dihomo-γ-linolenic acid, other fatty acids (e.g., eicosapentoic acid, linolenic acid) | Vane et al., 1998 |
| Tissue distribution | Constitutively expressed in most tissues; can be induced in ECs in response to shear stress, VEGF, and thrombin | Inducible expression especially in ECs by many stimulants such as inflammatory cytokines, LPS, hypoxia, and LDL; can be constitutively expressed in certain tissues (e.g. lung, kidney, brain) | Smith et al., 2000; Davidge, 2001; Morita, 2002 |
| Subcellular distribution | ER and nuclear membrane | Mainly nuclear membrane | Morita, 2002 |
| COX-deficient mice phenotypes | COX1(−/−) mice survive, but display platelet disaggregation, increased cerebral infarct volume, delayed labor with decreased offspring survival | COX2(−/−) mice develop nephropathy and may die early; display failure of ductus arteriosus closure; decreased cerebral infarct volume; defective ovulation, fertilization, implantation, and decidualization | Davidge, 2001; Loftin et al., 2002a,b; Morita, 2002 |
| COX inhibitors | |||
| Glucocorticoids | No effect | Inhibition | Vane et al., 1998; Morita, 2002 |
| Aspirin | Complete inhibition | Incomplete inhibition of AA metabolism (transformed to active metabolite 15R-HETE) | |
| Higher selectivity (IC50, 1.67 μM) | Lower selectivity (IC50, 278 μM) | ||
| NSAIDS (IC50) | |||
| Indomethacin | 0.028 μM | 1.68 μM | |
| Diclofenac | 1.57 μM | 1.1 μM | |
| Selective COX2 inhibitors (IC50) | |||
| Celecoxib | 15 μM | 0.04 μM | |
| Meloxicam | 4.8 μM | 0.43 μM |
LDL, low-density lipoprotein; LPS, lipopolysaccharide.