Chapter Twenty-One Lipid Metabolism

Lipids are Involved in Generation and Storage of Energy The oxidation of fatty acids (FA)in triacylglycerols are the principal storage form of energy for most organisms Their carbon chains are in a highly reduced form The energy yield per gram of fatty acid oxidized is greater than that per gram of carbohydrate oxidized

Catabolism of Lipids Lipases catalyze hydrolysis of bonds between fatty acid and the rest of triacylglycerols Phospholipases catalyze hydrolysis of bonds between fatty acid and the rest of phosphoacylglycerols May have multiple sites of action

Fatty Acid Activation Fatty acid oxidation begins with activation A thioester bond is formed between the carboxyl group of the FA and the thiol of CoA-SH

Liberation of Fatty Acids from Triacylglycerols

-Oxidation -Oxidation: a series of reactions that cleaves carbon atoms two at a time from the carboxyl end of a fatty acid The complete cycle of one -oxidation requires four enzymes Reaction 1: Oxidation of the , carbon-carbon single bond to a carbon-carbon double bond Reaction 2: Hydration of the carbon-carbon double bond Reaction 3: Oxidation of the -hydroxyl group to a carbonyl group Reaction 4: Cleavage of the carbon chain by a reverse Claisen reaction

-Oxidation (Cont’d)

b-Oxidation Gives Rise to Nine 2-Carbon Units

Summary Fatty acids are activated and transported to the mitochondrial matrix for further catabolism The breakdown of fatty acids takes place in the mitochondrial matrix and proceeds by successive removal of two-carbon units as acetyl-CoA Each Cleavage of a two-carbon moiety requires a four-step reaction sequences called -oxidation

Ketone Bodies Formation of ketone bodies occurs when the amount of acetyl-CoA produced is excessive compared to the amount of oxaloacetate available to react with it Intake high in lipids and low in carbohydrates Diabetes not suitably controlled Starvation Ketone bodies are: acetone, -hydroxybutyrate, and acetoacetate Formed principally in liver mitochondria Can be used as a fuel in most tissues and organs

Ketone Bodies (Cont’d) Summary: • If an organism has an excess of acetyl-CoA, it produces ketone bodies. • This situation can arise from an excessive intake of fats compared to carbohydrates, or from diabetes.

Fatty Acid Biosynthesis Biosynthesis is not exact reversal of oxidation Biosynthetic reactions occur in the cytosol

Fatty Acid Biosynthesis (Cont’d) Carboxylation of acetyl-CoA occurs in the cytosol Catalyzed by acetyl-CoA carboxylase Biotin is the carrier of the carboxyl group Malonyl-CoA is key intermediate that is produced

Biosynthesis of Palmitate from Acetyl- and Malonyl-CoA ACP : acetyl carrier protein

Biosynthesis of Palmitate from Acetyl- and Malonyl-CoA

Sites of Fatty Acid Metabolism in an Animal Cell

Comparison of FA Degradation and Biosynthesis Summary • Acetyl-CoA is transported to the cytosol and converted to malonyl-CoA • The biosynthesis of FA proceeds by the addition of 2-carbon units to the hydrocarbon chain. The process is catalyzed by the fatty-acid synthase complex Comparison of FA Degradation and Biosynthesis

Cholesterol Biosynthesis All carbon atoms of cholesterol and steroids synthesized from it are derived from the two-carbon acetyl group of acetyl-CoA Involves many reaction steps Involvement of isoprene units are key to the biosynthesis of steroids and other biomolecules known as terpenes

Overall View of Cholesterol Biosynthesis

Squalene to Cholesterol

Cholesterol as a Precursor Cholesterol is the precursor for a number of steroid hormones

Role of Cholesterol in Heart Disease Lipids are transported in the blood stream by lipoproteins Cholesterol and its fatty acid esters are packaged into several classes of lipoproteins for transport

The LDL Particle

The Fate of Cholesterol

Summary The biosynthesis of cholesterol proceeds by the condensation of five-carbon isoprenoid units Isoprenoid units in turn are derived from the reaction of three acetyl-CoA units Once cholesterol is formed, it serves as a precursor for other steroids Cholesterol must be packaged for transport in the bloodstream. Some of these forms of cholesterol play a role in heart disease