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A Bench to Bedside Quest
LPCAT Enzyme Identified in Plasma Membranes for the First Time

"LPCAT is the last major player of the three in which we were interested, and what we've found is that the story is much more complex than you'd think."
The plasma membrane, of which the RBC is a primary example, is composed of a bilayer of proteins embedded here and there amidst approximately 250 different types of phospholipids. The location of the proteins is very precise, however, with the lipid to protein composition being essential to normal membrane function.

"If you change something in your lipid bilayer, it will change the function of the plasma membrane," says Dr. Kuypers. "Any changes need to be reversed, or the house, so to speak, will fall down."

While there has been clear indication of repair and maintenance activity being undertaken in RBC plasma membranes, how it is being accomplished has led Dr. Kuypers and his colleagues on what Dr. Kuypers refers to as a Quest.

"When you show up in the morning and see the house is repaired, you know that the maintenance is going on, but you don't know by who or how it is done. So we set out a number of years ago on this quest of ours to identify the key players in this game."

To date, the hard labors of the Quest have proved fruitful, with Drs. Kuypers and Soupene already having identified in previous publications the two major players, acyl-CoA synthetase, and the so called flippase. Now in the latest PNAS publication, LPCAT has been added to the list, the protein responsible for incorporating fatty acid CoA into phospholipids during one of the last steps in the phospholipids repair which is necessary for normal membrane function. None of them turn out to be isolated players, however.

"Of the proteins we've identified, the first one, acyl-CoA synthetase, it's not just one guy, it's five guys, and if you look at LPCAT, it's also only the first member of a family we've identified that all work together to maintain lipid function."
"While all three of these players are different, they work as a community, and without each other, they are useless."

With the identification of the latest protein family in their belts, Drs. Kuypers and Soupene are not at the end of their Quest, however, but only about halfway there. Identification is just the first step in answering the question of how these proteins do their jobs.

"Now that we know who they are, we have to interrogate them in order to figure out first, what they do in detail, and second, how they do what they do," says Dr. Kuypers.

There are a variety of ways a researchers can undertake such interrogations, from cloning the proteins and putting them into different environments, to mutating them and determining how those mutations effect their function.

"You change the proteins in different ways and see what happens," Dr. Kuypers explains. "That's the next step in characterizing the nature of these players, so that's what we're doing now."
As exciting as the discovery process of the Quest is, Dr. Kuypers is quick to point out, however, that gaining knowledge about the RBC plasma membrane isn't an isolated exercise independent of the clinical world.

"Although it's basic research, everything we do here should have an application to human physiology, and in this case, understanding better how lipids are maintained in normal blood cells allows us to understand how they are NOT maintained properly in hemoglobinopathies like sickle cell disease or thalassemia," says Dr. Kuypers. "That's what will give us insight into these diseases, which can allow for new understanding of treatments, which can allow for a better quality of life for all these patients."

Creating novel treatments and increased quality of life is, after all, the real grail at the end of the quest. Thankfully for those patients at CHRCO's premier sickle cell and thalassemia center, as well as for patients across the globe, Drs. Kuypers and Soupene are dedicated to reaching the quest's end, enlightening the world of research along the way.

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Tuesday, May 17, 2011 8:19 AM

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