Functional correlation of cyclooxygenases-1, 2 and 3 from amino acid sequences and three dimensional model structures

Abstract

COX-1, COX-2 and COX-3, three isoforms of cyclooxygenase are differentially expressed. We have analyzed the sequences of these cyclooxygenases and built the three dimensional model structures for human COX-1, COX-2 and canine COX-3 to characterize the function of cyclooxygenase isozymes based on the sequence and structure information. Sequence analysis reveals that COX-3 shares 90% homology with COX-1 and 60% with COX-2. The COX-1 model has, been compared with those of COX-2 and COX-3 and the active site regions have been analyzed. The major differences in the active sites of COX-1 and COX-2 are: Ile 523 in COX-1 is replaced by Val in COX-2, apart from a few mutations at the mouth of the active site. No such differences in the active sites are seen between COX-1 and COX-3 structures and the amino-acid residues that differ between COX-1 and COX-3 lie only on the surface of the protein. Therefore, it is hard to explain the specificity of acetaminophen towards COX-3. Further, the intron 1 of canine COX-1 gene that is retained in COX-3 mRNA transcript codes for a poly proline region that could be responsible for intermolecular interactions.