The Lp-PLA2 is bound to the monolayer in two different ways. Credit: UC San Diego Health Sciences
There is a lot of information about the role of the Membrane-associated proteins in cellular processes. The mechanism of action of the Lp-PLA2 is unknown, but it has an important role in cardiovascular health. The 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.
The findings will be published in the online issue of the National Academy of Sciences.
Lp-PLA2 works on lipoproteins in the bloodstream. The lipoprotein particles are made up of a spherical layer of cholesterol and fat. The free radicals attracted by the oxidation of the phospholipids in this outer layer contributes to plaque build up and cardiovascular disease.
Lp-PLA2 extracts the oxidations from the lipoprotein membrane and releases them to be further metabolized. Understanding how this process works will lead to new opportunities.
Edward A. Dennis, the senior author of the study and the Professor of Pharmacology, Chemistry and Biochemistry at the UC San Diego School of Medicine, said he was very pleased that they were able to go into much greater depth on how this enzyme works. The picture we got is worth a thousand words and was created using the latest advances in computationalmolecular dynamics simulations. We now have movies that show how this enzyme works at the atomic level, and that should help us figure out ways to inactivate it for health.
A typical lipoprotein has a conjugate bound to the monolayer. Credit: UC San Diego Health Sciences
This advanced approach revealed a specific region consisting of two alpha helices connected with a loop that acts as a gate to the active site. When Lp-PLA2 binding to the phospholipid membrane opens the gate and increases the volume of the active site, it's a closed gate.
Dennis' team showed which Lp-PLA2 has the greatest affinity for. They found a binding pocket distinct from known drug inhibitor binding pockets, which may serve as a new target for future therapeutic drugs.
The Dennis lab has been working on a unifying theory on the function of phospholipases for a long time. The group had previously introduced this concept of allosteric regulation of PLA2 enzymes, but had until this point only studied the enzymes that function on the cells. This study showed that a similar mechanism could be used to facilitate action on the pheline monolayers.
Dennis said it's amazing to see this wide variety of enzymes all show a similar action strategy. We've been studying this family of enzymes for over 50 years, and to finally have a complete picture of how they work is really satisfying.
The co-authors are from UC San Diego.
There is more information on the topic of allosteric regulation by membranes. There is a book titled "10.1073/pnas.
The National Academy of Sciences has a journal.
There is a computer model of blood enzyme that may lead to new drugs for cardiovascular disease.
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