Comparative investigation of ligand binding of heme-containing dioxygenases by computer modeling.

Abstract

Heme-containing enzymes are typically used as catalysts of oxidation-reduction reactions. These enzymes range from monooxygenases and dioxygenases to peroxidases and catalases to oxidases and dehydrogenases. Mechanistic aspects of these enzymes, including heme chemistry, have been extensively studied. Cyclooxygenase (COX), a heme-containing dioxygenase, has a cyclooxygenase activity and an associated peroxidase activity. COX shows similarity in the organization of the peroxidase active site to the other peroxidases. Cyclooxygenase active site, to which arachidonic acid binds, is on the proximal side of the heme and is the main target of explosive research interest, which results in great success. In plants, pathogen-inducible oxygenase (PIOX), another heme-containing enzyme, generates a potent lipid mediator by oxygenating 14-20 fatty acid substrates. COX and PIOX exhibit catalytic and structural similarities. The ligand-protein interactions of COX and PIOX have been characterized by crystallographic and mutagenic studies. Interestingly, the orientation of the fatty acid substrate inside the PIOX active site is different from the case of COX because of the α-dioxygenation of a cognate substrate by PIOX. This paper analyzes the characteristics of the substrate binding of mammalian and plant heme-containing dioxygenases using computer-aided modeling.