Synthesis of lipids and N-containing molecules 1

Published on April 19, 2020 Reviewed on November 27, 2022   40 min

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Greetings. Welcome to this Lecture 21 in our Principles of Biochemistry lecture series. My name is Jerry Feigenson, I'm a professor in the Department of Molecular Biology and Genetics at Cornell University in the USA. In the last lecture, Lecture 20, you learned about biosynthesis. We compared synthesis of a new sugar, gluconeogenesis, to glycolysis. We looked at what's called substrate cycling, along with the Calvin cycle, and the anabolic reactions of photosynthesis.
In this first part, you're going to learn about the synthesis of the unstable 3-carbon malonyl group, which is the first step in lipid synthesis. You're going to see how fatty acid synthesis occurs in the remarkable fatty acid synthase complex, which channels intermediates from one active site to the next. Finally, we will see that to synthesize either fat or membrane phospholipid, first a molecule called phosphatidic acid is made. In the second part, we will look at liver synthesis of lipoproteins. Those lipoproteins deliver cholesterol esters and fat to tissues. Finally, we will look at the synthesis of nitrogen containing molecules.
First, let us look at the synthesis of fatty acids. Let's compare fatty acid breakdown to fatty acid biosynthesis. So first we can just look at these over all equations for fatty acid breakdown by Beta oxidation and biosynthesis. Let's look at the overall equation for Beta oxidation. We could've chosen any length of fatty acid, but here I'm choosing the 16-carbon palmitoyl. So palmitoy-CoA, 7FAD, 7NAD, 7CoAs breakdown to 8 acetyl-CoAs, and FADH_2 and NADH. When we compare those reactions to biosynthesis reactions, we notice a big difference right away. First of all, there are seven malonyl CoAs required for synthesis of a palmitic acid. There's no malonyl in the breakdown, so they're not the reverse of similar reactions. And there's NADPH in biosynthesis of palmitic acid. So we see some differences right away just looking at the overall equations. Now, here's another difference. Where does Beta oxidation occur? Beta oxidation occurs in mitochondria in their matrix. Biosynthesis of fatty acids, we say that occurs in the cytosol. Now here, this is a jargon use of the term cytosol. Here, cytosol means not inside an organelle. And in particular for fatty acid synthesis, fatty acid synthesis occurs on the surface of the smooth endoplasmic reticulum. You'll also notice the rough endoplasmic reticulum. Those little dots on the surface of the rough endoplasmic reticulum are ribosomes. Proteins are synthesized on those ribosomes. Smooth endoplasmic reticulum does not have the ribosomes. It's on the surface of the smooth endoplasmic reticulum that lipid synthesis occurs. It occurs with water soluble precursors, acetyl-CoA, and malonyl-CoA, both water-soluble. So on the smooth endoplasmic reticulum, lipid synthesis occurs from water-soluble precursors. But the product lipid is membrane soluble and it goes right into that smooth endoplasmic reticulum membrane. Let's summarize these differences or this comparison of fatty acid breakdown and fatty acid synthesis. We can say that fatty acid biosynthesis is not the reversal of any steps of Beta oxidation. So this is very different from glycolysis compared to gluconeogenesis, which are the reversal of each others steps, at most of the steps. But here in animal cells, the location is different. Beta oxidation is in the mitochondrial matrix, biosynthesis is in the cytosol. No enzymes in common. All the enzymes of Beta oxidation are different from the enzymes of synthesis of fatty acid. The electron carriers in Beta oxidation are NADH and FADH_2, whereas in biosynthesis, it's NADPH that is the electron carrier. There is a key role for this molecule malonyl-CoA in biosynthesis. We're going to see an important principle here. The 3-carbon malonyl is unstable, it is reactive, and it is used, we could say instead of the stable two carbon acetyl, to add two carbon units. And we will see that in a moment.

Synthesis of lipids and N-containing molecules 1

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