Even more stuff on membranes! I must sound like the biggest membrane fanatic right now :P This time the focus is on phospholipid synthesis, as well as mentioning the very important fact that the composition of phospholipids differs between the two sides of the membrane (hence the "asymmetry" in the title of this post).
Phospholipid Synthesis
Joy... a topic I've forgotten and need to revise.
Okay. Here goes.
The first step in phospholipid synthesis is synthesising diacylglycerol. I've already explained this part in my post on the metabolism of fatty acids.
The next step is to activate one of the head groups so that it can attach to diacylglycerol. Firstly, a phosphoryl group from ATP is attached, producing phosphorylcholine, phosphorylethanolamine etc. After that, CTP (cytidine triphosphate) activates the phosphorylated molecule, forming CDP-choline, CDP-ethanolamine etc. These activated head groups can then be added to diacylglycerol to form a phospholipid, releasing CMP in the process.
Another important point to note is that sometimes it is diacylglycerol rather than the head groups that is activated. In this case CTP activates phosphatidic acid (a precursor of diacylglycerol) to form CDP-diacylglycerol, which can then react with a head group such as phosphatidylglycerol or inositol to form cardiolipin or phosphatidylinositol, respectively.
Now that I've gone through the general steps in the process, let's have a look more closely at where it occurs and what enzymes are used. Phospholipid synthesis occurs on the cytoplasmic side of the smooth endoplasmic reticulum. Acyl transferases move activated acyl CoA groups onto 3-glycerol phosphate in the first step of phospholipid synthesis. A phosphatase then removes the phosphate group. Next, the activated head group is attached via an enzyme such as choline phosphotransferase (there are similar enzymes for other head groups).
Once a phospholipid is formed, it may remain on that side of the membrane, or move to the other layer of the membrane via the action of a flippase enzyme.
Interconversion of Phospholipids
While phospholipids can be formed from scratch, some phospholipids can also be formed from converting others.
One example is the formation of phosphatidylserine. Phosphatidylserine is formed from converting phosphatidylethanolamine.
Another example is the methylation of phosphatidylethanolamine to form phosphatidylcholine. (Choline is essentially phosphatidylethanolamine but with amine groups instead of hydrogen ions attached to the N atom.) The methyl groups here are donated from S-adenosylmethionine, which is converted to S-adenosylhomocysteine as a result.
Repair of Phospholipids
Sometimes, for one reason or another, one of the acyl chains in a phospholipid may break off, leaving a lysophospholipid. Another acyl CoA can come in here with the help of the enzyme acyltransferase, shedding its CoA in the process. This process enables fatty acids to change the composition of their phospholipids.
Phospholipid Shape
Different phospholipids have different shapes due to the sizes of their head groups and other factors. This can then affect membrane thickness and curvature.
For example, sphingomyelin molecules are long, straight somewhat cylindrical-shaped molecules that can pack closely together. Phosphatidylcholine is also somewhat cylindrical, but it is not quite as long or straight, so phosphatidylcholine molecules cannot pack as closely together without help from cholesterol. Longer, straighter molecules make for a thicker membrane than shorter molecules.
Another example is the difference in shape between phosphatidylcholine and phosphatidylethanolamine. Phosphatidylethanolamine has a smaller head group than phosphatidylcholine (remember, choline is simply ethanolamine but with three extra methyl groups), and thus phosphatidylethanolamine is more conical shaped whereas phosphatidylcholine is more cylindrical shaped. When several conical phosphatidylethanolamine molecules pack together, they can form a curve in the membrane. (Curves can also be induced by membrane-binding proteins.)
Membrane Transverse Asymmetry
As mentioned several times before, the two layers of the membrane can have different lipid compositions due to the action of flippases and so on. Generally sphingomyelin and phosphatidylcholine are in higher concentrations in the outer leaflet while most other phospholipids are in higher concentrations in the inner leaflet. Additionally, different types of membranes may have different lipid compositions.
Phospholipases
As suggested by their name, phospholipases catalyse the breakdown of phospholipids. Phospholipase A1 breaks down the ester bond between the first acyl chain and glycerol, phospholipase A2 breaks down the ester bond between the second acyl chain and glycerol, phospholipase C attacks the ester bond between glycerol and the phosphate group, and phospholipase D attacks the ester bond between the phosphate group and the head group. As for phospholipase B, I think that one pretty much does the same as A1 and A2 combined.
Phospholipids can be broken down to form signalling molecules, or precursors of signalling molecules. For example, arachidonic acid, one of the fatty acids that may be a component of a phospholipid, can form signalling molecules such as prostaglandins, thromboxanes and leukotrienes. Another example is the breakdown of phosphatidylinositol 4,5-biphosphate (essentially phosphatidylinositol with phosphate groups added to the fourth and fifth carbons of the ring) which, through the action of phospholipase C, can break down to diacylglycerol and inositol 1,4,5-triphosphate. Inositol 1,4,5-triphosphate can open calcium channels in the ER, which increases Ca2+ levels in the cell. Ca2+ then also helps to activate diacylglycerol, which activates protein kinase C, which goes on to phosphorylate target proteins in the cell.
Another note about phospholipase C is that it is often activated by extracellular signalling molecules. These molecules bind to receptors on the outsides of the cell, causing a conformational change in the receptor, which in turn activates other molecules on the inside. If I remember correctly, protein kinase C can be activated by G-protein receptors (receptors that activate special proteins called GTPases, which in turn activate other molecules) or by enzyme-coupled receptors. I'll probably go into this in greater depth when I start revising for Molecular Biology of the Cell.
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