Model insight into blood enzyme Lp-PLA2 could aid cardiovascular health

Admin on 24 / 03 / 2022 under #blood_enzyme #lipoprotein #biomarker

A new study in the US has used a computer model to reveal the mechanism of action of lipoprotein-associated phospholipase A2 – a biomarker for cardiovascular disease.

Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a type of membrane-associated protein that plays a key role in cardiovascular health; yet until now, details of its processes have been lacking.

According to a new report published in Proceedings of the National Academy of Sciences, however, researchers at the University of California San Diego School of Medicine have garnered new understanding of the mechanism of action of these important proteins. Using state-of-the-art experimental and computational tools, the scientists have shown precisely how the enzyme interacts with the membrane and extracts its specific substrates.

Lp-PLA2 extracts oxidised phospholipids from the lipoprotein membrane and releases their fatty acids to be metabolised, thus removing the attraction of free radicals that contribute to plaque buildup and cardiovascular disease. The scientists’ model has shown exactly how this process works and it is hoped that new therapeutic opportunities for cardiovascular disease will open up.

Commenting on the value of this new insight, Edward A Dennis PhD, Distinguished Professor for Pharmacology, Chemistry and Biochemistry at US San Diego School of Medicine and senior author of the study, said: “I am very pleased that we were able to go into much greater depth on how this enzyme works than ever before. Using the latest advances in lipidomics and computational molecular dynamics simulations, we got a picture which is worth a thousand words. We now have movies that show how this enzyme works at the atomic level, and that should help us figure out ways to activate or inactivate the enzyme as necessary for health.”

According to the report, their approach revealed a specific peptide region consisting of two alpha helices connected with a loop that acts as a gate to the enzyme’s active site. This gate is usually ‘closed’ but when Lp-PLA2 binds to the phospholipid membrane, it undergoes an allosteric conformational change that opens the gate and increases the volume of the active site.

The study also revealed which oxidised phospholipid substrates Lp-PLA2 has the greatest affinity for and identified a new distinct drug inhibitor binding pocket – a potential new target for therapeutics.

“PLA2 enzymes have all sorts of important functions in inflammation, digestion, brain health, and more, so it’s amazing to see this wide variety of enzymes all show a similar action strategy,” said Dennis. “We’ve been studying this superfamily of enzymes for almost 50 years, so to finally have this complete picture of how they work is really satisfying, and the whole field advances.”