Biochemistry: A Short Course Second Edition Tymoczko Berg Stryer CHAPTER 27 Fatty Acid Degradation

Dietary Lipid (Triacylglycerol) Metabolism -In the small intestine, fat particles are coated with bile salts and digested by pancreatic lipases Two amphipathic bile salts that are cholesterol derivatives

Figure 27.1 Lipid degradation Dietary lipids are hydrolyzed by lipases in three steps to yield fatty acids and glycerol. The fatty acids are taken up by cells and used as a fuel. Glycerol also enters the liver, where it can be metabolized by the glycolytic or gluconeogenic pathways.

Epinephrine and glucagon stimulate breakdown of triacylglycerols stored in adipocytes. Protein kinase A phosphorylates perilipin and hormone-sensitive lipase. Phosphorylated perilipin activates adipocyte triacylglyceride lipase (ATGL), which breaks down lipids.

Upon entering the cell cytoplasm, fatty acids are activated by attachment to coenzyme A, catalyzed by the enzyme acyl-CoA synthetase, costing two ATP equivalents. After being activated by linkage to CoA, the fatty acid is transferred to carnitine, a reaction catalyzed by carnitine acyltransferase I, for transport into the mitochondria. A translocase transports the acyl carnitine into the mitochondria.

In the mitochondria, carnitine acyltransferase II transfers the fatty acid to CoA. The fatty acyl CoA is now ready to be degraded in the mitochondria by β-oxidation.

Figure 27.5 Beta Oxidation of Fatty Acids Repeat with shortened Acyl CoA Enters CAC

Figure 27.6 The first three rounds in the degradation of palmitate. Two carbon units are sequentially removed from the carboxyl end of the fatty acid.

The reaction for one round of β-oxidation is: The complete reaction for C 16 palmitoyl CoA is: Processing of the products of the complete reaction by cellular respiration would generate 106 molecules of ATP.

β-Oxidation of fatty acids with odd numbers of carbons generates propionyl CoA in the last thiolysis reaction. Propionyl carboxylase, a biotin enzyme, adds a carbon to propionyl CoA to form methylmalonyl CoA Succinyl CoA, a citric acid cycle component, is subsequently formed from methylmalonyl CoA by methylmalonyl CoA mutase, a vitamin B 12 requiring enzyme.

Figure 27.9 The conversion of propionyl CoA into succinyl CoA. Propionyl CoA, generated from fatty acids having an odd number of carbon atoms as well as from some amino acids, is converted into the citric acid cycle intermediate succinyl CoA.

Ketone bodies—acetoacetate, 3-hydroxybutyrate, and acetone—are synthesized from acetyl CoA in liver mitochondria and secreted into the blood for use as a fuel by some tissues such as heart muscle. 3-Hydroxybutyrate is formed upon the reduction of acetoacetate. Acetone is generated by the spontaneous decarboxylation of acetoacetate. In tissues using ketone bodies, 3-hydroxybutyrate is oxidized to acetoacetate, which is ultimately metabolized to two molecules of acetyl CoA.

Figure The formation of ketone bodies. The ketone bodies—acetoacetate, D -3-hydroxybutyrate, and acetone—are formed from acetyl CoA primarily in the liver. Enzymes catalyzing these reactions are (1) 3-ketothiolase, (2) hydroxymethylglutaryl CoA synthase, (3) hydroxymethylglutaryl CoA cleavage enzyme, and (4) D -3-hydroxybutyrate dehydrogenase. Acetoacetate spontaneously decarboxylates to form acetone. Ketone bodies are a crucial fuel source during starvation

Figure The utilization of D -3-hydroxybutyrate and acetoacetate as a fuel. D -3-Hydroxybutyrate is oxidized to acetoacetate with the formation of NADH. Acetoacetate is then converted into two molecules of acetyl CoA, which then enter the citric acid cycle.

Fats are converted into acetyl CoA, which is then processed by the citric acid cycle. Oxaloacetate, a citric acid cycle intermediate, is a precursor to glucose. However, acetyl CoA derived from fats cannot lead to the net synthesis of oxaloacetate or glucose because although two carbons enter the cycle when acetyl CoA condenses with oxaloacetate, two carbons are lost as CO 2 before oxaloacetate is regenerated.