Synthesis of Glycerophospholipids – Membrane Lipid Metabolism

by Kevin Ahern, PhD

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    00:01 It's safe to say that without a lipid bilayer, a cell is not a cell.

    00:05 In this lecture, I will cover the metabolism of the primary molecules involved in making up the lipid bilayer of the cell membrane.

    00:12 This will include a discussion of the glycerophospholipids and also the synthesis of the sphingolipids.

    00:19 Now the glycerophospholipids are, as I said, one of the major components of the cell membrane.

    00:24 You can see how they come about or how their name comes about by virtue of the fact that in the middle, as you see here, they have a glycerol backbone.

    00:32 On the right side, they have a phospho component containing phosphate that is very polar.

    00:37 And on the left they contain the lipid part of the glycerophospholipids which are two fatty acids attached to the glycero.

    00:43 Now this compound is very amphiphilic meaning that it has a portion of it that is very polar and another portion of it that's non-polar.

    00:51 Now this schematic structure of a glycerophospholipid that I show on the screen here I would carry forward into the next slide.

    00:57 Please note the "X" at the lower right; because, this is the point of attachment for other molecules to make the finish glycerophospholipid.

    01:04 Now you can see on the right, that schematic structure, and you can see the X in the box that I have indicated here.

    01:10 If the X is a hydrogen then the molecule that we are talking about is phosphatidic acid.

    01:15 Now phosphatidic acid is not a significant component of the lipid bilayer.

    01:20 But it actually is a precursor for the synthesis of the other molecules below.

    01:25 If X is a serine, as you can see here then the compound that results is phosphatidylserine, serine of course is an amino acid.

    01:33 If the X is an ethanolamine we have a phosphatidylethanolamine.

    01:38 If the X is a choline, we have a phosphatidylcholine.

    01:41 And finally if the X is inositol we have a phosphatidylinositol.

    01:45 Now in contrast to the other additions that were above phosphatidylinositol, the inositol itself does not ionize but it is a very polar compound, thanks to the hydroxyl groups that are on it.

    01:57 Glycerophospholipids synthesis overlaps the synthesis of fats, as we shall see.

    02:02 Now the starting point for both fats and glycerophospholipids is the molecule you see on the screen, glycerol-3-phosphate.

    02:09 The glycerol-3-phosphate is added a fatty acid in an ester bond at position 1 by the enzyme acyltransferase 1 as you can see.

    02:18 We saw this also in fat synthesis to create lysophosphatidic acid.

    02:24 The lysophosphatidic acid gains a fatty acid on the second carbon of the glycerol just like fat synthesis to create the phosphatidic acid that we are already talking about.

    02:35 Now you can see the phosphatidic acid at the very top of the structure and that is just mearing what we brought into this original structure.

    02:42 The synthesis of additional phosphatidyl compounds now can proceed by two different mechanisms and these are very general in nature as you will see.

    02:52 Both mechanisms involve the use of what's called an activated intermediate.

    02:57 An activated intermediate is a molecule that has a high energy bond that uses the energy of that bond to donate a part of itself to something else as we shall see.

    03:08 Now the two general mechanisms you will see have some parallel, although, they sort of flip things around.

    03:15 The first method I will show you is starting with a molecule that is activated through the phosphatidyl compound.

    03:23 Now this material is called CDP-diacylglycerol.

    03:28 The CDP portion of this molecule, of course, comes from the nucleotide CTP which is used in the synthesis of RNA.

    03:35 And the rest of this is the phosphatidic acid that we had synthesized as of the last image on the screen.

    03:41 So if we take phosphatidic acid and combine it with CTP, we make this molecule.

    03:46 We split out in the process a pyrophosphate that's the PPi on the side.

    03:51 We started with 4 phosphates, one on phosphatidic acid and three on CTP. We end up with 4 phosphates.

    03:59 Two in the CDP-diacylglycerol and two in the pyrophosphate.

    04:05 Now the phosphatidyl portion is shown here again for your orientation; because, that's the part that will be carried forward into the synthesis of the phosphatidyl compound.

    04:15 The CTP splits off not as CDP but rather as CMP.

    04:20 So it leaves behind one of its phosphates to the phosphatidyl compound.

    04:28 Okay, we can see a reaction here for example with inositol.

    04:31 CDP-diacylglycerol plus inositol yields phosphatidylinositol plus the CMP, that I said will split off.

    04:40 Now this reaction requires the energy of that high energy bond of the activated intermediate of CDP-diacylglycerol.

    04:49 Thanks to the energy of that bond, the two molecules can be joined together that is the phosphatidyl compound and the inositol.

    04:56 This reaction does not require energy from ATP; because, the energy comes from the activated intermediate that was created previously.

    05:06 Now the second mechanism for the synthesis of glycerophospholipids sort of flips around that use of the activated intermediate, as we shall see.

    05:14 So, first of all, here is a compound that we wanna add to the phosphatidyl part as an X on the figure on the upper right. This is ethanolamine.

    05:24 In order to do this is what we do is we activate ethanolamine using the CDP.

    05:29 Now before we activated the phosphatidyl compound with the CDP.

    05:33 In order to active the ethanolamine we first put a phosphate onto it to make phosphorylethanolamine. Now that phosphorylethanolamine is a substrate for making CDP-ethanolamine. Now the way this is occurring is, of course, we have one phosphate on the phosphorylethanolamine.

    05:52 We have three phosphates on the CTP and when we will combine the two what we end up with is CDP-ethanolamine and we split out pyrophosphate just like we did in the phosphatidyl material.

    06:04 This CDP-ethanolamine is also an activated intermediate.

    06:08 So now the energy for creating the joined compound is going to come from this activated intermediate.

    06:16 So we see during the process of this activation that the CMP will split off exactly like we saw the CMP split off of phosphatidic acid earlier.

    06:25 The ethanolamine, meanwhile, will add two what would be diacylglycerol, as we should see, to make the phosphatidyl compound.

    06:35 So here is the CDP-ethanolamine here.

    06:37 Here is diacylglycerol. Now this is not phosphatidic acid in this case but rather is a phosphatidic acid minus the phosphate; because, the phosphate here is coming from the activated intermediate.

    06:50 When we put these two together we make phosphatidylethanolamine and CMP. So we have split off the CMP and once again we came in with two phosphate on the activated intermediate.

    07:03 One of them, got carried forward into making the final phosphatidylethanolamine.

    07:08 So these two mechanisms that I have described, either activating the phosphatidic acid or activating the molecule added to it are general ways in which glycerophospholipids are synthesized in cells.

    About the Lecture

    The lecture Synthesis of Glycerophospholipids – Membrane Lipid Metabolism by Kevin Ahern, PhD is from the course Lipid Metabolism.

    Included Quiz Questions

    1. It mostly proceeds through phosphatidic acid
    2. It begins with palmitic acid and serine
    3. It creates molecules with three fatty acids
    4. It starts with addition of a fatty acid to glycerol
    1. Phosphatidyl compounds differ in what is attached to the phosphate
    2. An activated intermediate involving GDP is involved
    3. The phosphatidyl part of the name refers to the diacylglycerol
    4. A phosphate must be removed to form the final product

    Author of lecture Synthesis of Glycerophospholipids – Membrane Lipid Metabolism

     Kevin Ahern, PhD

    Kevin Ahern, PhD

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