Chapter 24 Metabolic Pathways for Lipids and Amino Acids 24.1 Digestion of Triacylglycerols Copyright © 2007 by Pearson Education, Inc. Publishing as Benjamin Cummings

Digestion of Fats (Triacylglycerols) In the digestion of fats (triacylglycerols), Bile salts break fat globules into smaller particles called micelles in the small intestine. Pancreatic lipases hydrolyze ester bonds to form monoacylglycerols and fatty acids, which recombine in the intestinal lining. Fatty acids bind with proteins forming lipoproteins to transport triacylglycerols to the cells of the heart, muscle, and adipose tissues.

Digestion of Triacylglycerols Copyright © 2007 by Pearson Education, Inc. Publishing as Benjamin Cummings

Fat Mobilization Fat mobilization Breaks down triacylglycerols in adipose tissue. Forms fatty acids and glycerol. Hydrolyzes fatty acid initially from C1 or C3 of the fat. triacylglycerols + 3 H2O glycerol + 3 fatty acids Copyright © 2007 by Pearson Education, Inc. Publishing as Benjamin Cummings

Metabolism of Glycerol Glycerol from fat digestion Adds a phosphate from ATP to form glycerol-3-phosphate. Undergoes oxidation of the –OH group to dihydroxyacetone phosphate. Becomes an intermediate used in glycolysis and gluconeogenesis. Glycerol + ATP + NAD+ dihydroxyacetone phosphate + ADP + NADH + H+

Oxidation of Glycerol

Learning Check Give answers for the following questions on fat digestion. 1. What is the function of bile salts in fat digestion? 2. Why are the triacylglycerols in the intestinal lining coated with proteins to form chylomicrons? 3. How is glycerol utilized?

Solution 1. What is the function of bile salts in fat digestion? Bile salts break down fat globules allowing pancreatic lipases to hydrolyze the triacylglycerol. 2. Why are the triacylglycerols in the intestinal lining coated with proteins to form chylomicrons? The proteins coat the triacylglycerols to make water­ soluble chylomicrons that move into the lymph and bloodstream. 3. How is glycerol utilized? Glycerol adds a phosphate and is oxidized to an intermediate of the glycolysis and gluconeogenesis pathways.

Chapter 24 Metabolic Pathways for Lipids and Amino Acids 24.2 Oxidation of Fatty acids 24.3 ATP and Fatty Acid Oxidation Copyright © 2007 by Pearson Education, Inc. Publishing as Benjamin Cummings

Fatty Acid Activation Fatty acid activation Allows the fatty acids in the cytosol to enter the mitochondria for oxidation. Combines a fatty acid with CoA to yield fatty acyl CoA that combines with carnitine. Fatty acyl Copyright © 2007 by Pearson Education, Inc. Publishing as Benjamin Cummings

Transport of Fatty Acyl CoA Fatty acyl-CoA forms fatty acyl-carnitine that transports the fatty acyl group into the matrix. The fatty acyl group recombines with CoA for oxidation. Copyright © 2007 by Pearson Education, Inc. Publishing as Benjamin Cummings

Summary of Fatty Acid Activation Fatty acid activation is complex, but it regulates the degradation and synthesis of fatty acids. Fatty acyl Copyright © 2007 by Pearson Education, Inc. Publishing as Benjamin Cummings

Beta-Oxidation of Fatty Acids Fatty acyl CoA undergoes β oxidation in a cycle of four reactions. In reaction 1, oxidation Removes H atoms from the  and  carbons. Forms a trans C=C bond. Reduces FAD to FADH2.   Copyright © 2007 by Pearson Education, Inc. Publishing as Benjamin Cummings

Beta-Oxidation of Fatty Acids In reaction 2 of β oxidation, hydration Adds water across the trans C=C bond. Forms a hydroxyl group (—OH) on the  carbon.   Copyright © 2007 by Pearson Education, Inc. Publishing as Benjamin Cummings

Beta-Oxidation of Fatty Acids In reaction 3 of β oxidation, a second oxidation Oxidizes the hydroxyl group. Forms a keto group on the  carbon.   Copyright © 2007 by Pearson Education, Inc. Publishing as Benjamin Cummings

Beta()-Oxidation of Fatty Acids In Reaction 4 of β- oxidation, acetyl CoA is cleaved By splitting the bond between the  and  carbons. To form a shortened fatty acyl CoA that repeats steps 1 - 4 of -oxidation. Copyright © 2007 by Pearson Education, Inc. Publishing as Benjamin Cummings

Learning Check Match the reactions of -oxidation with each: 1) oxidation 1 2) hydration 3) oxidation 2 4) acetyl CoA cleaved A. Water is added. B. FADH2 forms. C. A two-carbon unit is removed. D. A hydroxyl group is oxidized. E. NADH forms.

Solution Match the reactions of -oxidation with each: 1) oxidation 1 2) hydration 3) oxidation 2 4) acetyl CoA cleaved A. 2 Water is added. B. 1 FADH2 forms. C. 4 A two-carbon unit is removed. D. 3 A hydroxyl group is oxidized. E. 3 NADH forms.

Beta()-Oxidation of Myristic (C14) Acid Copyright © 2007 by Pearson Education, Inc. Publishing as Benjamin Cummings

Beta()-Oxidation of Myristic (C14) Acid (continued) 7 Acetyl CoA 6 cycles

Fatty Acid Length and -Oxidation The length of a fatty acid Determines the number of oxidations Determines the total number of acetyl CoA groups. Carbons in Acetyl CoA -Oxidation Cycles Fatty Acid (#C/2) (#C/2 –1) 12 6 5 14 7 6 16 8 7 18 9 8

Learning Check A. The number of acetyl CoA groups produced by the complete -oxidation of palmitic acid (C16 ): 1) 16 2) 8 3) 7 B. The number of oxidation cycles to completely oxidize palmitic acid (C16 ):

Solution A. The number of acetyl CoA groups produced by the complete -oxidation of palmitic acid (C16 ): 2) 8 (16 C/2 = 8) B. The number of oxidation cycles to completely oxidize palmitic acid (C16 ): 3) 7 (16 C/2 -1 = 7)

ATP and -Oxidation Activation of a fatty acid requires 2 ATP One cycle of oxidation of a fatty acid produces 1 NADH 3 ATP 1 FADH2 2 ATP Acetyl CoA entering the citric acid cycle produces 1 Acetyl CoA 12 ATP

ATP for Lauric Acid C12 ATP production for lauric acid (12 carbons): Activation of lauric acid -2 ATP 6 Acetyl CoA 6 acetyl CoA x 12 ATP/acetyl CoA 72 ATP 5 Oxidation cycles 5 NADH x 3ATP/NADH 15 ATP 5 FADH2 x 2ATP/FADH2 10 ATP Total 95 ATP

Learning Check 1) 108 ATP 2) 146 ATP 3) 148 ATP The total ATP produced from the -oxidation of stearic acid (C18) is 1) 108 ATP 2) 146 ATP 3) 148 ATP

Solution 2) 146 ATP Activation -2 ATP 9 Acetyl CoA x 12 ATP 108 ATP The total ATP produced from the -oxidation of stearic acid (C18) is: 2) 146 ATP Activation -2 ATP 9 Acetyl CoA x 12 ATP 108 ATP 8 NADH x 3 ATP 24 ATP 8 FADH2 x 2 ATP 16 ATP 146 ATP

Chapter 24 Metabolic Pathways for Lipids and Amino Acids 24.4 Ketogenesis and Ketone Bodies Copyright © 2007 by Pearson Education, Inc. Publishing as Benjamin Cummings

Ketone Bodies If carbohydrates are not available Body fat breaks down to meet energy needs. Keto compounds called ketone bodies form. Ketone bodies Copyright © 2007 by Pearson Education, Inc. Publishing as Benjamin Cumming

Ketogenesis In ketogenesis Large amounts of acetyl CoA accumulate. Two acetyl CoA molecules combine to form acetoacetyl CoA. Acetoacetyl CoA hydrolyzes to acetoacetate, a ketone body. Acetoacetate reduces to -hydroxybutyrate or loses CO2 to form acetone, both ketone bodies.

Reactions of Ketogenesis Ketone bodies Copyright © 2007 by Pearson Education, Inc. Publishing as Benjamin Cummings

Ketosis Ketosis occurs In diabetes, diets high in fat, and starvation. As ketone bodies accumulate. When acidic ketone bodies lowers blood pH below 7.4 (acidosis). Copyright © 2007 by Pearson Education, Inc. Publishing as Benjamin Cummings

Ketone Bodies and Diabetes In diabetes Insulin does not function property. Glucose levels are insufficient for energy needs. Fats are broken down to acetyl CoA. Ketogenesis produces ketone bodies. Copyright © 2007 by Pearson Education, Inc. Publishing as Benjamin Cummings

Learning Check In ketogenesis, match the type of reaction with 1) oxidation 2) reduction 3) decarboxylation A. acetoacetate produces acetone B. acetoacetate produces β-hydroxybutyrate

Solution In ketogenesis, match the type of reaction with 1) oxidation 2) reduction 3) decarboxylation A. acetoacetate produces acetone 3 B. acetoacetate produces β-hydroxybutyrate 2

Chapter 24 Metabolic Pathways for Lipids and Amino Acids 24.5 Fatty Acid Synthesis Copyright © 2007 by Pearson Education, Inc. Publishing as Benjamin Cummings

Lipogenesis: Fatty Acid Synthesis Is the synthesis of fatty acids from acetyl CoA. Occurs in the cytosol. Uses reduced coenzyme NADPH (NADH with a phosphate group). Requires an acyl carrier protein (ACP). Copyright © 2007 by Pearson Education, Inc. Publishing as Benjamin Cummings

Synthesis of Malonyl CoA For fatty acid synthesis, Acetyl CoA combines with bicarbonate to form malonyl CoA. ATP hydrolysis provides energy. O acetyl CoA || carboxylase CH3—C—S—CoA + HCO3- + ATP acetyl CoA O O || || -O—C—CH2—C—S—CoA + ADP + Pi + H+ malonyl CoA

Acetyl and Malonyl Acyl Carrier Proteins (ACP) Active forms of acetyl ACP and malonyl-ACP are produced by combining with acyl carrier proteins (ACP). O O ║ ║ CH3—C—S—CoA + HS-ACP CH3—C—S—ACP + HS-CoA acetyl-ACP O O || || -O—C—CH2—C—S—CoA + HS-ACP -O—C—CH2—C—S—ACP + HS-CoA malonyl-ACP

Fatty Acid Synthesis: Condensation and Reduction In reactions 1 and 2 of fatty acid synthesis Condensation (1) by a synthase combines acetyl-ACP with malonyl-ACP to form acetoacetyl-ACP (4C) and CO2. Reduction(2) converts a ketone to an alcohol using NADPH. Copyright © 2007 by Pearson Education, Inc. Publishing as Benjamin Cummings

Fatty Acid Synthesis: Dehydration and Reduction In reactions 3 and 4 of fatty acid synthesis Dehydration(3) forms a trans double bond. Reduction (4) converts the double bond to a single bond using NADPH. Copyright © 2007 by Pearson Education, Inc. Publishing as Benjamin Cummings

Fatty Acid Synthesis (Lipogenesis) Cycle Repeats continues as Malonyl-ACP combines with the four-carbon butyryl-ACP to form a six-carbon-ACP. The carbon chain lengthens by two carbons each cycle. Copyright © 2007 by Pearson Education, Inc. Publishing as Benjamin Cummings

Fatty Acid Synthesis (Lipogenesis) Cycle Completed Is completed when palmitoyl ACP reacts with water to give palmitate (C16) and free ACP. Copyright © 2007 by Pearson Education, Inc. Publishing as Benjamin Cummings

Summary of Lipogenesis Copyright © 2007 by Pearson Education, Inc. Publishing as Benjamin Cummings

Fatty Acid Length In fatty acid synthesis Shorter fatty acids undergo fewer cycles. Longer fatty acids are produced from palmitate using special enzymes. Unsaturated cis bonds are incorporated into a 10-carbon fatty acid that is elongated further.

Regulation of Fatty Acid Synthesis In fatty acid synthesis A high level of blood glucose and insulin stimulates glycolysis and pyruvate oxidation. More acetyl CoA is available to form fatty acids.

Comparing -Oxidation and Fatty Acid Synthesis TABLE 24.1 Copyright © 2007 by Pearson Education, Inc. Publishing as Benjamin Cummings

Learning Check Match each with the description below: 1) mitochondria 2) cytosol 3) glucagon 4) insulin 5) acetyl ACP 6) malonyl ACP A. Site of fatty acid synthesis. B. Site of -oxidation. C. Starting material for lipogenesis. D. Compound added to elongate acyl-ACP. E. Activates -oxidation. F. Activates lipogenesis.

Solution Match each with the description below: 1) mitochondria 2) cytosol 3) glucagon 4) insulin 5) acetyl ACP 6) malonyl ACP A. 2 Site of fatty acid synthesis. B. 1 Site of -oxidation. C. 5,6 Starting material for lipogenesis. D. 6 Compound added to elongate acyl-ACP. E. 3 Activates -oxidation. F. 4 Activates lipogenesis.

Chapter 24 Metabolic Pathways for Lipids and Amino Acids 24.6 Digestion of Proteins 24.7 Degradation of Amino Acids Copyright © 2007 by Pearson Education, Inc. Publishing as Benjamin Cummings

Digestion of Proteins The digestion of proteins (stage 1) Begins in the stomach where HCl in stomach acid activates pepsin to hydrolyze peptide bonds. Continues in the small intestine where trypsin and chymotrypsin hydrolyze peptides to amino acids. Is complete as amino acids enter the bloodstream for transport to cells.

Digestion of Proteins Copyright © 2007 by Pearson Education, Inc. Publishing as Benjamin Cummings

Learning Check Match the end products of digestion with the types of food: 1. amino acids 2. fatty acids and glycerol 3. glucose A. fats B. proteins C. carbohydrates

Solution Match the end products of digestion with the types of food: 1. amino acids 2. fatty acids and glycerol 3. glucose A. fats 2. fatty acids and glycerol B. proteins 1. amino acids C. carbohydrates 3. glucose

Proteins in the Body Proteins provide Amino acids for protein synthesis. Nitrogen atoms for nitrogen-containing compounds. Energy when carbohydrate and lipid resources are not available. Copyright © 2007 by Pearson Education, Inc. Publishing as Benjamin Cummings

Transamination In transamination Amino acids are degraded in the liver. An amino group is transferred from an amino acid to an -keto acid, usually -ketoglutarate. The reaction is catalyzed by a transaminase or aminotransferase. A new amino acid, usually glutamate, and a new -keto acid are formed.

A Transamination Reaction NH3+ O alanine | || aminotransferase CH3—CH—COO- + -OOC—C—CH2—CH2—COO- alanine -ketoglutarate O NH3+ || | CH3—C—COO- + -OOC—CH—CH2—CH2—COO- pyruvate glutamate

Oxidative Deamination Removes the amino group as an ammonium ion from glutamate. Provides -ketoglutarate for transamination. NH3+ glutamate | dehydrogenase -OOC—CH—CH2—CH2—COO- + NAD+ + H2O glutamate O || -OOC—C—CH2—CH2—COO- + NH4+ + NADH -ketoglutarate

Learning Check Write the products from the transamination of -ketoglutarate by aspartate. NH3+ | -OOC—CH—CH2—COO- aspartate O || -OOC—C—CH2—CH2—COO- -ketoglutarate

Solution Write the products from the transamination of -ketoglutarate by aspartate. O || -OOC—C—CH2—COO- oxaloacetate NH3+ | -OOC—CH—CH2—CH2—COO- glutamate

Chapter 24 Metabolic Pathways for Lipids and Amino Acids 24.8 Urea Cycle O || H2N—C—NH2 urea

Urea Cycle The urea cycle Detoxifies ammonium ion from amino acid degradation. Converts ammonium ion to urea in the liver. O || H2N—C—NH2 urea Provides 25-30 g urea daily for urine formation in the kidneys.

Carbamoyl Phosphate Carbamoyl phosphate is formed In the mitochondria, when ammonium ion reacts with CO2 from the citric acid cycle, 2 ATP, and water. carbomyl phosphate synthetase NH4+ + CO2 + 2ATP + H2O O O || || H2N—C—O—P—O- + 2ADP + Pi | O- carbamoyl phosphate

Reaction 1 Transfer of Carbamoyl Group In reaction 1 of the urea cycle, The carbamoyl group is transferred to ornithine to form citrulline. Citrulline moves across the mitochondrial membrane into the cytosol. Copyright © 2007 by Pearson Education, Inc. Publishing as Benjamin Cummings

Reaction 2 Condensation with Aspartate In reaction 2 of the urea cycle, That takes place in the cytosol, citrulline combines with aspartate. Hydrolysis of ATP to AMP provides energy. The N in aspartate is part of urea. Cytosol Copyright © 2007 by Pearson Education, Inc. Publishing as Benjamin Cummings

Reaction 3 Cleavage of Fumarate In reaction 3 of the urea cycle, fumarate Is cleaved from argininosuccinate. Enters the citric acid cycle. Copyright © 2007 by Pearson Education, Inc. Publishing as Benjamin Cummings

Reaction 4 Hydrolysis Forms Urea In reaction 4 of the urea cycle, Arginine is hydrolyzed Urea forms. Ornithine returns to the mitochondrion to pick up another carbamoyl group to repeat the urea cycle. Copyright © 2007 by Pearson Education, Inc. Publishing as Benjamin Cummings

Urea Cycle Copyright © 2007 by Pearson Education, Inc. Publishing as Benjamin Cummings

Summary of Urea Cycle The urea cycle converts: Ammonium ion to urea Aspartate to Fumarate 3ATP to 2ADP, AMP, 4Pi NH4+ + CO2 + 3ATP + aspartate + 2H2O urea + 2ADP + AMP + 4Pi + fumarate

Learning Check Identify the site for each as: 1) mitochondrion 2) cytosol A. Formation of urea. B. Formation of carbamoyl phosphate. C. Aspartate combines with citrulline. D. Fumarate is cleaved. E. Citrulline forms.

Solution Identify the site for each as: 1) mitochondrion 2) cytosol A. 2 Formation of urea. B. 1 Formation of carbamoyl phosphate. C. 2 Aspartate combines with citrulline. D. 2 Fumarate is cleaved. E. 1 Citrulline forms.

Chapter 24 Metabolic Pathways for Lipids and Amino Acids 24.9 Fates of the Carbon Atoms from Amino Acids Copyright © 2007 by Pearson Education, Inc. Publishing as Benjamin Cummings

Carbon Atoms from Amino Acids When needed, carbon skeletons of amino acids are used to produce energy by forming intermediates of the citric acid cycle. Three-carbon skeletons alanine, serine, and cysteine pyruvate Four-carbon skeletons aspartate, asparagine oxaloacetate Five-carbon skeletons glutamine, glutamate, proline, arginine, histidine glutamate

Glucogenic and Ketogenic Amino Acids Amino acids are classified as Glucogenic if they generate pyruvate or oxaloacete, which can be used to synthesize glucose. Ketogenic if they generate acetoacetyl CoA or acetyl CoA, which can form ketone bodies or fatty acids.

Amino Acid Pathways to Citric Acid Intermediates Ketogenic Glucogenic Copyright © 2007 by Pearson Education, Inc. Publishing as Benjamin Cummings

Amino Acid Pathways to Pyruvate and Oxaloacetate Copyright © 2007 by Pearson Education, Inc. Publishing as Benjamin Cummings

Glucogenic Amino Acids that Form Intermediates of the Citric Acid Cycle Copyright © 2007 by Pearson Education, Inc. Publishing as Benjamin Cummings

Learning Check Match each the intermediate with the amino acid that provides its carbon skeleton. 1) pyruvate 2) fumarate 3) -ketoglutarate A. cysteine B. glutamine C. aspartate D. serine

Solution Match each the intermediate with the amino acid that provides its carbon skeleton. 1) pyruvate 2) fumarate 3) -ketoglutarate A. 1 cysteine B. 3 glutamine C. 2 aspartate D. 1 serine

Learning Check Identify each as glucogenic (G) or ketogenic (K) A. alanine B. lysine C. phenylalanine D. aspartate E. glutamate

Solution Identify each as glucogenic (G) or ketogenic (K) A. G alanine B. K lysine C. K phenylalanine D. G aspartate E. G glutamate

Chapter 24 Metabolic Pathways for Lipids and Amino Acids 24.10 Synthesis of Amino Acids Copyright © 2007 by Pearson Education, Inc. Publishing as Benjamin Cummings

Sources of Amino Acids Essential amino acids must be obtained in the diet. Nonessential amino acids are synthesized in the body. TABLE 24.3 Copyright © 2007 by Pearson Education, Inc. Publishing as Benjamin Cummings

Synthesis of Amino Acids In humans, transamination of compounds from glycolysis or the citric acid cycle produces nonessential amino acids. Copyright © 2007 by Pearson Education, Inc. Publishing as Benjamin Cummings

Synthesis of Glutamine Glutamine is synthesized by adding another amino group to glutamate. NH3+ glutamine | synthetase -OOC—CH—CH2—CH2—COO- + NH3 + ATP glutamate NH3+ O | || -OOC—CH—CH2—CH2—C—NH2 + ADP + Pi glutamine

Learning Check Match each amino acid with the intermediate needed for its synthesis: 1) alanine 2) glutamate 3) aspartate A. pyruvate B. oxaloacetate C. -ketoglutarate

Solution Match each amino acid with the intermediate needed for its synthesis: 1) alanine 2) glutamate 3) aspartate A. 1 pyruvate B. 3 oxaloacetate C. 2 -ketoglutarate

Phenylketonurea (PKU) In phenylketonurea (PKU) The gene that converts phenylalanine to tyrosine is defective. Phenylalanine forms phenylpyruvate (transamination), which goes to phenylacetate (decarboxylation). High levels of phenylacetate cause severe mental retardation. A diet low in phenylalanine and high in tyrosine is recommended.

Phenylketonurea (PKU) Copyright © 2007 by Pearson Education, Inc. Publishing as Benjamin Cummings

Overview of Metabolism In metabolism Catabolic pathways degrade large molecules. Anabolic pathway synthesize molecules. Branch points determine which compounds are degraded to acetyl CoA to meet energy needs or converted to glycogen for storage. Excess glucose is converted to body fat. Fatty acids and amino acids are used for energy when carbohydrates are not available. Some amino acids are produced by transamination.

Copyright © 2007 by Pearson Education, Inc Copyright © 2007 by Pearson Education, Inc. Publishing as Benjamin Cummings