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.”
European Journal of Case Reports and Clinical Images is an international open-access journal publi
.png)
.jpg)
.gif)
