Biochemistry 401 Lecture 28 Today we re going to continue our discussion of lipid metabolism We re going to talk about triacylglycerols and membrane lipids We re going to discuss the synthesis of triacylglycerols phospholipids and glycolipids and then we ll finish with aberrant lipid synthesis and disease So let s first talk about the nature of membrane lipids Membrane lipids are amphipathic They have a hydrophilic region and a hydrophobic region The hydrophilic region is the head group Head groups extend outward from the membrane to make contact with the aqueous solution whereas the hydrophobic region generally hydrophobic fatty acid tails extend inward toward the center of the membrane away from aqueous solution Membrane lipids have a great deal of variety both in the nature of the head groups and the hydrophobic region Let s look at the classification of membrane lipids There are three major classes of membrane lipids These are sterols phospholipids and glycolipids Now in animals the sterol is cholesterol and this is the ring structure that s shown here in the upper left Now phospholipids and glycolipids are organized into these groups because of their polar head group Phospholipids contain a phosphate group to which is attached an alcohol Glycolipids on the other hand contain one or more sugars as their polar head group Phospholipids contain one or more fatty acids and this depends on the type of platform that s used A glycerol backbone such as is shown in the upper right hand corner will have two fatty acids esterified to the backbone whereas a sphingosine phospholipid shown in the middle will have one fatty acid attached to the amino group of the sphingosine backbone Now in animals glycolipids are exclusively formed on a sphingosine backbone and therefore they will have one fatty acid tail attached to the sphingosine at the amino group but in plants there are some glycolipids that also have a glycerol backbone and in this case we ll have two fatty acids attached to the glycerol backbone and one or more sugars as the polar head group Now sphingosine is shown here It has three basic characteristics a long hydrocarbon tail that helps to anchor it into the membrane an amino group which serves as the point of attachment for the other fatty acid and a terminal hydroxyl that s shown on the far right and this is the place where the phosphate group or the sugar is going to be added We re going to look at the synthesis of each of these classes of membrane lipids We re going to talk about cholesterol synthesis in another lecture but in this lecture we re going to talk about the synthesis of phospholipids and glycolipids Here is a chart that shows the classification of membrane lipids in plants and animals and it s here to help you study So now let s talk about the synthesis of triacylglycerols and phosphoglycerolipids These are going to use an activated precursor phosphatidate This is an activated diacylglycerol precursor It consists of a glycerol backbone to which are attached two fatty acids These are attached to carbon number one and carbon number two through ester linkages At carbon number three there is a phosphate group And so another name for this and so another name for phosphatidate is diacylglycerol 3 phosphate Now if you ll notice the fatty acid attached to carbon number one is saturated and the fatty acid attached to carbon number two is unsaturated and generally this is what we see Phosphatidate is an important precursor so let s look at how it s synthesized This is a pretty complex slide and we re going to break it down The synthesis of phosphatidate occurs in the endoplasmic reticulum of liver cells and it happens by two main pathways by the de novo pathway and the salvage pathway Now the de novo pathway requires glycerol 3 phosphate and free fatty acids The glycerol 3 phosphate is produced either from dihydroxyacetone phosphate or from glycerol And so I have a question for you what kind of reaction would it take to be able to go from dihydroxyacetone phosphate which is a phosphorylated three carbon ketone sugar to glycerol 3 phosphate and again how do we go from glycerol to glycerol three phosphate What sort of an enzyme would do this reaction We re going to reduce dihydroxyacetone phosphate in order to make glycerol three phosphate and the source of the electrons is NADH and we re also going to add a proton If you figured this out very good Another question where did we see this before This is part of the glycerol 3 phosphate shuttle It s one of the ways to get reducing equivalents into the mitochondrial matrix and so this cytoplasmic enzyme also is used to produce glycerol 3 phosphate for the production of triacylglycerols and glycerophospholipids Okay now what about taking glycerol and producing glycerol 3 phosphate How is that This is a simple kinase reaction We re going to phosphorylate glycerol at position three to make glycerol 3 phosphate That s pretty simple So in adipose tissue diagrammed on the left triacylglycerols are catabolized to release free fatty acids and glycerol Now he glycerol travels in the blood to the liver and in liver cells the glycerol kinase produces glycerol 3 phosphate So why do we have to transport the glycerol all the way to the liver The activity of glycerol kinase in the adipose tissue is very slight compared to what s in the liver In fact in the liver cells glycerol kinase is 200 to 600 times more active than in adipose tissue So now that we have glycerol 3 phosphate and we produced free fatty acids from the breakdown of triacylglycerol in the adipose tissue or in the diet we can then transport those intermediates to the liver and in the endoplasmic reticulum of liver cells we can synthesize phosphatidate We re going to add two fatty acids the first one at position one and the second one at position two These fatty acids aren t just fatty acids on their own They re activated fatty acids Each one is a fatty acyl CoA and the enzyme that catalyzes these reactions is glycerol phosphate acyltransferase and this name makes sense because this process transfers a fatty acyl group from the thiol ester of coenzyme A to form an oxygen ester first to make lysophosphatidate and then finally to make phosphatidate You do not have to remember the name of the intermediate lysophosphatidate And so at the end of these two acylations we end up with the acylated activated glycerol intermediate phosphatidate And in the endoplasmic reticulum of the liver
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