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3-D enzyme model provides new tool for anti-inflammatory drug development

Researchers develop first computer models of phospholipase A2 enzymes extracting their substrates out of the cell membrane, an early step in inflammation

Phospholipase A2 (PLA2) enzymes are known to play a role in many inflammatory diseases, including asthma, arthritisand atherosclerosis. It then stands to reason that PLA2 inhibitors could represent a new class of anti-inflammatory medication. To better understand PLA2 enzymes and help drive therapeutic drug development, researchers at University of California, San Diego School of Medicine developed 3D computer models that show exactly how two PLA2 enzymes extract their substrates from cellular membranes. The new tool is described in a paper published online the week of Jan. 26 by the Proceedings of the National Academy of Sciences.

“This is the first time experimental data and supercomputing technology have been used to visualize an enzyme interacting with a membrane,” said Edward A. Dennis, PhD, Distinguished Professor of Pharmacology, chemistry and biochemistry and senior author of the study. “In doing so, we discovered that binding the membrane triggers a conformational change in PLA2 enzymes and activates them. We also saw several important differences between the two PLA2 enzymes we studied — findings that could influence the design and development of specific PLA2 inhibitor drugs for each enzyme.”

The computer simulations of PLA2 enzymes developed by Dennis and his team, including first author Varnavas D. Mouchlis, PhD, show the specific molecular interactions between PLA2 enzymes and their substrate, arachidonic acid, as the enzymes suck it up from cellular membranes.

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