Membrane-associated proteins play a critical role in cellular processes. Lipoprotein-associated phospholipase A2 (Lp-PLA2) is one such protein with a vital role in cardiovascular health. Researchers at the University of California San //Diego School of Medicine used state-of-the-art experimental and computational tools to show how the enzyme interacts with the membrane and extracts its specific substrates.
‘Understanding how oxidized phospholipids from the lipoprotein membrane and releases their fatty acids to helps to identify new therapeutics agents against cardiovascular disease.’
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The findings are publishing in the online issue of Proceedings of the National Academy of Sciences.Read More..
Lp-PLA2 works on lipoproteins in the bloodstream, including common forms like low- and high-density lipoprotein (LDL and HDL). These lipoprotein particles are made up of a spherical layer of phospholipids surrounding a drop of fat and cholesterol esters.
Over time, the phospholipids in this outer layer become oxidized, attracting free radicals and further oxidation, contributing to plaque buildup and cardiovascular disease.
Lp-PLA2 extracts these oxidized phospholipids from the lipoprotein membrane and releases their fatty acids further metabolized. Understanding exactly how these process works creates new opportunities for therapeutics against cardiovascular disease.
“I am very pleased that we were able to go into much greater depth on how this enzyme works than ever before,” said Edward A. Dennis, PhD, senior author of the study and Distinguished Professor of Pharmacology, Chemistry, and Biochemistry at UC San Diego School of Medicine.
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This advanced 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.
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Dennis’ team, led by first author Varnavas D. Mouchlis, PhD, also showed which oxidized phospholipid substrates Lp-PLA2 have the greatest affinity. They further identified a binding pocket distinct from known drug inhibitor binding pockets, which may serve as a new target for future therapeutic drugs.
The research group had previously introduced the concept of membrane-facilitated allosteric regulation of PLA2 enzymes but had until this point only studied enzymes that function on phospholipid bilayers .
This study confirmed that a similar mechanism could be used to facilitate phospholipase action on phospholipid monolayers, such as those on lipoproteins.
“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.”
Source-Medindia