Highlights Lecture #32 Spring 2017

Highlights Lipid Metabolism II

1. Fatty acids are synthesized in the cytoplasm and each step increases the size of the fatty acid by two carbons. Acetyl groups are shuttled out of the mitochondria using citrate. Thus, most fatty acids have even numbers of carbons. Many of the steps of fatty acid synthesis are CHEMICALLY similar to the reversal of beta oxidation.

2. Fatty acids in the process of being synthesized are attached to a molecule called ACP (acyl carrier protein) instead of CoA. Fatty acid biosynthesis begins with formation of a three carbon molecule called malony-CoA. This comes about from addition of a carboxyl group (biotin is a required coenzyme). The enzyme responsible for this reaction is acetyl-CoA carboxylase (note that this enzyme is DIFFERENT from fatty acid synthase below). Acetyl-CoA carboxylase is the only regulated enzyme in fatty acid biosynthesis and is activated by citrate and inhibited by palmitate. Malonyl-CoA is readily converted to malonyl-ACP.

3. In the next step of fatty acid biosynthesis, two carbons of the malonyl-ACP are joined to the growing fatty acid and the carboxyl group that was added is lost as carbon dioxide.

4. The remaining steps are the chemical reversal of the steps occurring in oxidation. Sequentially are reduction of the ketone, dehydration to create a double bond, and reduction of the double bond using electrons and protons from NADPH.

5. The enzyme responsible for fatty acid synthesis has multiple catalytic activities and is known as Fatty Acid Synthase. It contains all of the catalytic activities necessary to make fatty acids up to 16 carbons in size. Synthesis of longer fatty acids requires other enzymes and occurs in the endoplasmic reticulum.

6. 1. Fats are synthesized by putting fatty acids onto glycerol-3-phosphate. In the reactions, fatty acids are first esterified onto carbons 1 and 2 of the glycerol. This creates the molecule called phosphatidic acid, which is a branch point between synthesis of fats and glycerophospholipids.

7. In the direction of fat synthesis, the phosphate of phosphatidic acid is removed and replaced with a fatty acid, making a fat. In the direction of glycerophospholipid synthesis, the phosphate is replaced by the nucleotide CDP, creating CDP-diacylglycerol (an activated form of diacylglycerol). The CDP can be readily removed and replaced by other molecules, creating phosphatides (such as phosphatidyl serine, etc.).

8. Sphingolipids are made starting with a palmitoyl-CoA and serine. The ultimate product of this reaction is the molecule called sphingosine, that we have discussed before.

9. Acetyl-CoA is the starting point for synthesis of cholesterol. The pathway overlaps with that of ketone body synthesis at first, as two acetyl-CoAs are joined to form acetoacetyl-CoA, a four carbon molecule. Addition of another 2 carbons from a third acetyl-CoA creates HMG-CoA, a six carbon molecule. The next reaction in the synthesis pathway to cholesterol is catalyzed by HMG-CoA reductase. This enzyme is the major regulatory enzyme controlling synthesis of cholesterol in the body. HMG-CoA reductase is feedback inhibited by cholesterol, the end product of the pathway. HMG-CoA reductase is also the target of cholesterol-lowering drugs called the statins, which resemble HMG-CoA.

10. From mevalonate, the following moledules are formed – isoprenes (5 carbon molecules), geranyl-pyrophosphate (contains two isoprenes), farnesyl-pyrophosphate (contains three isoprenes), squalene (contains two farnesyl-pyrophosphates, lanosterol (rearranged form of cholesterol), and (after 19 steps), cholesterol.

11. Sphingolipids arise from joining of serine and palmitoyl-CoA.

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