This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Human lipoxygenases (LOX) play pivotal roles in the biosynthesis of leukotrienes and other biologically active eicosanoids. Specific inhibitors that can modulate the physiological and pathological effects of these potent signaling compounds are of high interest. Currently, there are no animal LOX structures that provide a model for how the substrate binds in the LOX active site, a model critical for the development of specific inhibitors. The overall goal of the investigations is to develop substrate-LOX models that can be used for the development of specific anti-LOX inhibitors. Specifically, we will: 1) model protein-substrate interactions in 8R-lipoxygenase. There is no crystal structure of a lipoxygenase in complex with its substrate arachidonic acid (AA) to reveal the structural basis for product specificity in this family of enzymes. The recent 1.85 ? resolution structure of 8R-LOX provides a strong foundation for model enzyme-substrate interactions. 2) """"""""Test"""""""" the generally applicability of this model to lipoxygenases of different product specificity. The results of our research will help understand the mechanism of substrate recognition in lipoxygenases and facilitate drug design to target lipoxigenases. We have used computational methods to find the candidate docking pockets in 8R-LOX for the substrate, arachidonic acid (AA). Analysis of various docking confirmations of AA is in process to identify the biding site. Further work will include identifying the active site of 8R-LOX for substrate AA and generating a model of how AA binds or interacts with 8R-LOX.
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