Metabolisms of Polar Lipids

Hello, everyone! I have returned with yet another dose of chemistry! I apologize if my posts seem a little lackluster as of late—it’s a little harder to muster up enthusiasm for this stuff while my little brothers are watching Netflix (read: A HORRIBLE ATTEMPT AT MAKING A TV SHOW OUT OF PACMAN) in the background. However, I have found a bubble of silence for now, and intend to use it for a small amount of studying before I dive back into my (already completed!) NaNoWriMo novel.

Onward!


In my previous posts on lipid metabolism, we’ve talked about what happens when you break apart triacylglycerides and use their constituent parts to generate energy. However, there is another class of lipids that perform a more interesting function than the TAGs that we hear so much about: the polar lipids!

Maintenance of the proper levels of polar lipids in our bodies is essential to proper cell membrane function, since, as we know, our cell membranes are made of lipid bilayers of polar lipids. Phosphatidylcholine is the predominant of these, followed by phosphatidylethanolamine and phosphatidylserine. Each of these fill slightly different roles as far as our body is concerned, so we have to keep them all in the proper ratios.

One way to keep these polar lipids in proper supply is simply to synthesize them from scratch. Although you might expect this to be pretty difficult, the net reaction is pretty easy to follow:

Polar Alcohol + DAG + ATP + CTP —> Phosphoglyceride + ADP + CMP + 2 Pi

There are a few things we can see from this net reaction. Firstly, we’re using a lot of chemical energy to put a polar alcohol and a diacylgylceride together to make a phosphoglyceride. Secondly, one of the phosphate groups from our energy sources has to end up in our final product (since we broke three phosphoanhydride bonds, but ended up with only two phosphates). Thirdly, we break both phosphoanhydride bonds in CTP.

Based on the amount of energy we’re consuming, we can only assume that this reaction is pretty spontaneous. That turns out to be a correct assumption, if my professor is to be believed. However, the reactants do beg a certain question: how and when do we use that energy?

Well, the first step of this synthesis consumes the first phosphoanhydride bond in the form of ATP. For example, in the synthesis of phosphatidylcholine, a kinase called choline kinase transfers a phosphate group from ATP to choline, generating phosphocholine and ADP. As you’d expect, this is a spontaneous reaction. The same thing happens if you want to make phosphatidylethanolamine: ethanolamine is activated with phosphate using ethanolamine kinase.

Once this takes place, the chemical energy in CTP is used to carry out the heavy lifting. The phosphoalcohols that we generated react with CTP, forming CDP-alcohols. Although these are CDP-alcohols, the enzyme that mediates this reaction, cytidine transferase, attaches CMP to the phosphoalcohol (meaning that the “CDP” designation includes the phosphate from the phosphoalcohol). The free energy lost in this transfer alone is not sufficient to drive this irreversibly in the forward direction, but since the PPi released when CMP is made is immediately cleaved into 2 Pi by other enzymes (a spontaneous reaction), the overall setup is still spontaneous.

Once we’ve made our CDP-alcohols (either CDP-ethanolamine or CDP-choline), the final transfer to DAG is made. The energy used in the previous reactions provides the energy needed to carry out this part of the synthesis; there is no use of ATP (or GTP or CTP or…) at this stage. Instead, a transferase enzyme mediates the attack of the hydroxyl group on the DAG by a phosphate group of the CDP-alcohol. CMP leaves, and a phosphoanhydride bond is cleaved in the process (making the reaction spontaneous).

Okay, okay, so that’s how we can make things like phosphatidylcholine and phosphatidylethanolamine from scratch. However, I implied up there that there was another way to keep polar lipid levels even, didn’t I? No, dear reader, I’m not accidentally carrying my terrible SciFi writing skills over to my science blog—there is, indeed, another method by which our bodies maintain lipid homeostasis.

Turns out, if our body finds itself in the pleasant predicament of having plenty of polar lipids but not enough of a specific type, it can interconvert different types of polar lipids. For example, for anyone out there with an explicit love of organic chemistry, transforming phosphatidylethanolamine into phosphatidylcholine is as easy as throwing in a methylating agent. Of course, methylation isn’t quite as simple in our bodies as it is in a test tube—fortunately, we can depend on SAM!

SAM, or S-adenosyl Methionine, is a powerful methylating agent found in the smooth ER of our liver cells. Three doses of SAM convert phosphatidylethanolamine into phosphatidylcholine in a very spontaneous reaction, producing three SAH (S-adenosylhomocysteine) in the process. The enzyme that mediates this transfer is called—deep breath now—phosphatidylethanolamine N-methyl-transferase. 

Now, what about our friend phosphatidylserine, who I mentioned at the beginning of this post but then sort of ignored? Well, turns out, using a base exchange enzyme, we can reversibly interconvert phosphatidylethanolamine and phosphatidylserine. Additionally, phosphatidylserine can be irreversibly transformed into phosphatidylethanolamine by decarboxylation using an enzyme called phosphatidylserine decarboxylase.

All right, so we’ve talked to a sufficient degree about the synthesis of phosphoglycerides such as the ones I mentioned above, but what about their breakdown? Is there a way to get rid of these suckers?

Well, of course, reader! Our bodies are thrifty, and they can find ways to recycle just about anything. In fact, because we have four different kinds of phospholipases (all bound to the inner face of the cytoplasmic membrane), we can make three different kinds of signalling molecules out of a phosphoglyceride like this!

Phospholipase A2 cleaves off the middle fatty acid from a phosphoglyceride. This is commonly an unsaturated fatty acid (often arachidonic acid) that serves as a signalling molecule. Phospholipase C and D, which cleave off the polar alcohol with and without its phosphate group, respectively, also liberate molecules that are used in cell signalling.

Pretty handy, huh? Sure, it’s not awe-inspiring, jaw-dropping stuff (ahem, ATP Synthase), but you can still see why it’s useful, right? That’s good, because, as cringy as talking about fat usually makes us, it’s pretty important that our body knows how to handle it. You know what else is a cringy subject that our body handles astoundingly well? You guessed it! The generation of urea!


Questions? Comments? Things that will motivate me to abandon all love for full nights of sleep in favor of study? There’s a nifty little box for that!

 

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