Enzymes called lipoxygenases stoke the fires of inflammatory diseases such as asthma, atherosclerosis, psoriasis, and inflammatory bowel disease. In today's issue of Nature Structural Biology, researchers describe the first clear structure of a mammalian lipoxygenase. With this and similar blueprints, pharmaceutical companies should have an easier time designing lipoxygenase inhibitor drugs to douse the immune system's response in such diseases.
All lipoxygenases perform the same task: They attach two oxygen atoms to the long tail of a cell membrane molecule called arachodonic acid. Until now, the only known lipoxygenase structure was from a soybean plant--of dubious help to drug designers. So Michelle Browner of the biotech company Roche Bioscience in Palo Alto, California, and colleagues at Roche and the University of California, San Francisco (UCSF), decided to pin down the structure of 12-lipoxygenase, a mammalian version of particular interest because of its suspected role in the arterial damage that leads to blood clots.
The team used the tried-and-tested technique of x-ray crystallography: They formed a rabbit version of the enzyme into a crystal and scattered x-rays off it to deduce its structure. The researchers found that the globular enzyme's most important feature was a boot-shaped pocket containing the machinery that attaches the oxygen. This confirmed previous ideas that the long tail of the arachadonic acid penetrates into the pocket and the oxygen is attached part way up the tail.
This model still isn't universally accepted, says Colin Funk, a structural biologist at the University of Pennsylvania, Philadelphia. "There's still a bit of debate about how [arachadonic acid] might go into the pocket," he says. Some researchers have evidence that, with certain lipoxygenases, the molecule can slide into the pocket head first rather than tail first. Nevertheless, the structure should be a windfall for drug designers, says team member Robert Fletterick of UCSF. With "a little chemistry and some trial and error," they should be able to design drugs which mimic arachdonic acid, but plug the pocket.