Chapter 35 Metabolism of Lipids and Whale oil, extracted from blubber, is used to make soap, leather dressing, lubricants, and hydrogenated fats. Proteins Introduction to General, Organic, and Biochemistry, 10e John Wiley & Sons, Inc Morris Hein, Scott Pattison, and Susan Arena
Course 35.1 Metabolic Energy Sources: Organs Working Together for the Common Good 35.2 Fatty Acid Oxidation (Beta Oxidation) 35.3 Fat Storage and Utilization 35.4 Biosynthesis of Fatty Acids (Lipogenesis) 35.5 Ketone Bodies 35.6 Amino Acid Metabolism 35.7 Metabolic Nitrogen Fixation 35.8 Amino Acids and Metabolic Nitrogen Balance 2
Course 35.9 Amino Acids and Nitrogen Transfer 35.10 Nitrogen Excretion and the Urea Cycle 35.11 Acetyl-CoA, a Central Molecule in Metabolism Chapter 35 Summary 3
Metabolic Energy Sources: Organs Working Together for the Common Good Chapter Energy-providing chemicals are vital to every living cell. There are three different classes of biochemicals that serve to supply energy. carbohydrates fatty acids amino acids 4
Metabolic Energy Sources: Organs Working Together for the Common Good Chapter Fatty acids are an all-purpose energy supply and are more energy-rich than either carbohydrates or amino acids. Carbohydrates are the brain s only energy source and the body s only energy source under anaerobic conditions. Amino acids can be converted into either carbohydrate or fatty acids. The amino acids are also a major source of usable nitrogen for cells. 5
Metabolic Energy Sources: Organs Working Together for the Common Good Chapter A typical human body carries energy stored in various forms. A typical 70-kg man has fuel reserves that can provide about 161,800 kcal (677,000 kj) of energy. These supplies are distributed as given below. glucose and glycogen supply 1,800 kcal (7500 kj) fatty acids and triacylglycerols supply 136,000 kcal (569,000 kj) amino acids and protein supply 24,000 kcal (100,000 kj) 6
Metabolic Energy Sources: Organs Working Together for the Common Good Chapter Different energy-storage molecules are segregated into specific organs and tissues. Three especially important locations for storage are: adipose muscle liver Each location serves specific needs in the overall metabolic scheme. 7
Metabolic Energy Sources: Organs Working Together for the Common Good Chapter The liver is at the center of energy metabolism. In general, this organ maintains the blood levels of many nutrients. The liver: stores glycogen is the center for glucose synthesis (gluconeogenesis) converts fatty acids and amino acids to ketone bodies creates urea for excretion as part of amino acid metabolism 8
Metabolic Energy Sources: Organs Working Together for the Common Good Chapter Adipose tissue is the major repository for triacylglycerols. This tissue is responsible for supplying fatty acids to the bloodstream. Muscle tissue is a major source of protein that can be broken down for energy. These tissues cooperate differently depending on the human body s physiological state. During a meal, the tissues interact in one way, while during exercise they work together in another way. 9
Your Turn! Where is glycogen stored in the human body? The stomach The liver Adipose tissue The brain 10
Your Turn! Where is glycogen stored in the human body? The stomach The liver Adipose tissue The brain Glycogen is stored in the liver. 11
Your Turn! What is the major storage site for triacylglycerols in the human body? The kidneys The liver Adipose tissue Muscle tissue 12
Your Turn! What is the major storage site for triacylglycerols in the human body? The kidneys The liver Adipose tissue Muscle tissue Adipose tissue is the major storage site for triacylglycerols. 13
Your Turn! A typical 70-kg man has fuel reserves that can provide about 161,800 kcal of energy. What percentage of this is each of the following? glucose and glycogen fatty acids and triacylglycerols amino acids and protein 14
Your Turn! A typical 70-kg man has fuel reserves that can provide about 161,800 kcal of energy. What percentage of this is each of the following? Glucose and glycogen: Approximately 1,800 kcal of the total 161,800 kcal is provided by glucose and glycogen. This corresponds to 1.1%. 1,800 kcal 161,800 kcal x 100 = 1.1% 15
Your Turn! A typical 70-kg man has fuel reserves that can provide about 161,800 kcal of energy. What percentage of this is each of the following? Fatty acids and triacylglycerols: Approximately 136,000 kcal of the total 161,800 kcal is provided by fatty acids and triacylglycerols. This corresponds to 84.1%. 136,000 kcal 161,800 kcal x 100 = 84.1% 16
Your Turn! A typical 70-kg man has fuel reserves that can provide about 161,800 kcal of energy. What percentage of this is each of the following? Amino acids and proteins: Approximately 24,000 kcal of the total 161,800 kcal is provided by amino acids and proteins. This corresponds to 15%. 24,000 kcal 161,800 kcal x 100 = 15% 17
Fatty Acid Oxidation (Beta Oxidation) Fats are the most energy-rich class of nutrients. Most of the energy from fats is derived from their constituent fatty acids. Fats are broken down in a series of enzyme-catalyzed reactions that produce chemical energy in the form of ATP. In complete biochemical oxidation the carbon and hydrogen of a fat ultimately are combined with oxygen to form carbon dioxide and water. 18
Fatty Acid Oxidation (Beta Oxidation) Catabolism of fatty acids involves a process whereby their carbon chains are shortened, two carbon atoms at a time by successive removals of acetic acid units. The process involves the oxidation of the β-carbon atom and cleavage of the chain between the α and β carbons. A six-carbon fatty acid would therefore produce three acetic acid molecules as shown on the following slide... 19
Fatty Acid Oxidation (Beta Oxidation) 20
Fatty Acid Oxidation (Beta Oxidation) Beta oxidation, the two carbon chop, is accomplished in a series of five steps. 1. Activation (formation of thioester with CoA). 21
Fatty Acid Oxidation (Beta Oxidation) 2. Oxidation [dehydrogenation at carbons 2 and 3 (the α- and β- carbons)]. 3. Hydration (conversion to a secondary alcohol). 22
Fatty Acid Oxidation (Beta Oxidation) 4. Oxidation [dehydrogenation of carbon 3 (the β-carbon) to a keto group]. 5. Carbon-chain cleavage (reaction with CoA to produce acetyl-coa and an activated thioester of a fatty acid shortened by two carbons). 23
Fatty Acid Oxidation (Beta Oxidation) The thioester chain shortened by two carbon atoms repeats the reaction sequence of oxidation, hydration, oxidation, and cleavage to shorten the carbon chain by another two carbon atoms and produces another acetyl-coa. Eight molecules of acetyl-coa can be produced from one molecule of palmitic acid which contains sixteen carbon atoms. 24
Fatty Acid Oxidation (Beta Oxidation) ATP is not directly produced during fatty acid catabolism. ATP forms when the reduced coenzymes FADH 2 and NADH formed by beta oxidation are oxidized by the mitochondrial electron-transport system in concert with oxidative phosphorylation. Fatty acid oxidation is aerobic because FADH 2 and NADH can be reoxidized only when oxygen is present. 25
Fatty Acid Oxidation (Beta Oxidation) Fatty acid catabolism yields more energy than can be derived from glucose. A comparison of the ATPs produced from the 18 carbons of one stearic acid molecule and the 18 carbons of three glucose molecules is shown here. 26
Your Turn! The structure of capric acid is below. In this structure indicate: the first carbon atom to react with coenzyme-a in beta oxidation the beta carbon atom each carbon carbon bond that is broken when capric acid is converted to acetyl-coa during beta oxidation O CH 3 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 C OH 27
Your Turn! Beta carbon atom O CH 3 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 C OH Carbon atoms broken when converted to acetyl coenzyme-a First carbon atom to react with coenzyme-a in beta oxidation 28
Your Turn! Stearic acid contains eighteen carbon atoms. How many beta oxidation runs (steps 1 through 5) are needed to completely convert stearic acid to acetyl coenzyme-a? How many acetyl coenzyme-a molecules are produced during the complete oxidation? How many NADH and FADH 2 molecules are produced during the complete oxidation? 29
Your Turn! Stearic acid contains eighteen carbon atoms. How many beta oxidation runs (steps 1 through 5) are needed to completely convert stearic acid to acetyl coenzyme-a? Each beta oxidation run results in the cleavage of a carboncarbon bond in the stearic acid molecule. Eight carboncarbon bonds are broken in stearic acid during the complete oxidation. These bonds are broken during eight runs of beta oxidation. 30
Your Turn! Stearic acid contains eighteen carbon atoms. How many acetyl coenzyme-a molecules are produced during the complete oxidation? Stearic acid contains eighteen carbon atoms which corresponds to nine two-carbon fragments which are used to form nine acetyl coenzyme-a molecules. 31
Your Turn! Stearic acid contains eighteen carbon atoms. How many NADH and FADH 2 molecules are produced during the complete oxidation? Each beta oxidation run produces one NADH molecule and one FADH 2 molecule. Eight beta oxidation runs are required to convert stearic acid to acetyl coenzyme-a. Therefore eight NADH molecules and eight FADH 2 molecules are produced during the complete oxidation. 32
Fat Storage and Utilization Fats (triacylglycerols) are stored primarily in adipose tissue. Fat tends to accumulate under the skin (subcutaneous fat), in the abdominal region and around some internal organs. Fat deposited around internal organs acts as a shock absorber, or cushion. Subcutaneous fat acts as an insulating blanket. 33
Fat Storage and Utilization Fat is the major reserve of potential energy. It is metabolized continuously. The plasma triacylglycerols are broken down and the resulting free fatty acids are transported into the adipose cells. The fatty acids are then converted back to triacylglycerols. When the body needs energy from fat, adipose cell enzymes hydrolyze triacylglycerols and the fatty acids are exported to other body tissues. 34
Biosynthesis of Fatty Acids (Lipogenesis) The biosynthesis of fatty acids from acetyl-coa is called lipogenesis. Acetyl-CoA can be obtained from the catabolism of carbohydrates, fats, and proteins. After fatty acids are synthesized, they combine with glycerol to form triacylglycerols which are stored in adipose tissue. 35
Biosynthesis of Fatty Acids (Lipogenesis) Lipogenesis is not a reversal of beta oxidation. The following are the major differences between these two processes. Beta oxidation occurs in the mitochondria, but fatty acid anabolism (lipogenesis) occurs in the cytoplasm. Lipogenesis requires a set of enzymes that are different from the enzymes used in the catabolism of fats. 36
Biosynthesis of Fatty Acids (Lipogenesis) In the anabolic pathway (lipogenesis), the growing fatty acid chain bonds to a special Acyl Carrier Protein, ACP- SH. Coenzyme A is the carrier in fatty acid catabolism. A preliminary set of reactions involving malonyl-coa occurs for each two-carbon addition cycle in the synthesis. Malonyl-CoA is synthesized from acetyl-coa and carbon dioxide. 37
Biosynthesis of Fatty Acids (Lipogenesis) The biosynthesis of a fatty acid occurs by the addition of successive two-carbon units starting with acetyl-coa in a five-step reaction sequence. 1. Acetyl-CoA and malonyl-coa bond to separate acyl carrier proteins (ACP). 38
Biosynthesis of Fatty Acids (Lipogenesis) 2. Acetyl-ACP and malonyl-acp condense with loss of carbon dioxide (decarboxylation). 39
Biosynthesis of Fatty Acids (Lipogenesis) 3. Reduction [hydrogenation of carbon 3 (the β-keto group)]. 4. Dehydration (formation of a double bond between carbons 2 and 3). 40
Biosynthesis of Fatty Acids (Lipogenesis) 5. Reduction (hydrogenation of carbons 2 and 3). 41
Biosynthesis of Fatty Acids (Lipogenesis) The next cycle begins with the reaction of butyryl-acp and malonyl-acp and continues by adding two-carbon units. The synthesis of palmitic acid is a follows. Nearly all naturally occurring fatty acids have even numbers of carbon atoms because catabolism and anabolism proceed by two-carbon increments. 42
Your Turn! The biosynthesis of fatty acids is called lipogenesis. What process is responsible for the catabolism of large fatty acid molecules into smaller carbon units? Glycolysis Beta oxidation The citric acid cycle Oxidative phosphorylation 43
Your Turn! The biosynthesis of fatty acids is called lipogenesis. What process is responsible for the catabolism of large fatty acid molecules into smaller carbon units? Glycolysis Beta oxidation The citric acid cycle Oxidative phosphorylation Beta oxidation is the process where fatty acids molecules are broken down to smaller carbon units. 44
Your Turn! How many NADP + molecules would be produced during the biosynthesis of stearic acid, a fatty acid with eighteen carbon atoms? 45
Your Turn! How many NADP + molecules would be produced during the biosynthesis of stearic acid, a fatty acid with eighteen carbon atoms? Eight runs through the cycle are needed to produce stearic acid. Two NADP + molecules are produced during each cycle (one molecule for each reduction reaction). As a result sixteen NADP + molecules are produced. 46
Ketone Bodies Humans can obtain energy from more than one source. Recall that carbohydrates are the only energy source that can be used for rapid muscle contraction (anaerobic work) and is generally the only energy source for the brain. Ketone bodies are used as an energy source when the supply of carbohydrate runs low. There are three different ketone bodies. 47
Ketone Bodies Acetoacetic acid and β-hydroxybutyric acid are important metabolic energy sources. Acetone is a side product that is often exhaled. These molecules are water soluble (like glucose) but are metabolized aerobically (like fat). 48
Ketone Bodies As blood-glucose levels drop blood ketone body concentrations rise. Meanwhile, the brain slowly changes its metabolism to use ketone bodies instead of glucose for energy. This creates a condition called ketosis. One common cause of ketosis is starvation where dietary carbohydrates are absent. Another common cause is diabetes mellitus where cells lose access to glucose. When the blood concentration of ketone bodies increases, the blood also becomes more acidic. This serious condition is called ketoacidosis. 49
Your Turn! Which ketone bodies are important sources of energy? Acetoacetic acid β-hydroxybutyric acid Acetone None of these molecules are important sources of energy 50
Your Turn! Which ketone bodies are important sources of energy? Acetoacetic acid β-hydroxybutyric acid Acetone None of these molecules are important sources of energy Both acetoacetic acid and β-hydroxybutyric acid are important sources of energy. 51
Amino Acid Metabolism Amino acids serve an important and unique role in cellular metabolism. They are the building blocks of proteins and also provide most of the nitrogen for other nitrogencontaining compounds. The metabolism of the carbon structures of amino acids is complex because of the variety of amino acid structures and because of the presence of nitrogen. The cell uses different metabolic pathways to metabolize the amino acids. 52
Metabolic Nitrogen Fixation Nitrogen is an important component of many biochemicals. In the biosphere only a few procaryotes have the metabolic machinery necessary to use atmospheric nitrogen. The conversion of diatomic nitrogen to a biochemically useful form is termed nitrogen fixation. The process by which nitrogen is circulated and recirculated from the atmosphere through living organisms and back to the atmosphere is known as the nitrogen cycle. 53
Metabolic Nitrogen Fixation Nitrogen fixation occurs by three general routes. 1. Bacterial action Certain bacteria are capable of converting N 2 into nitrates. 2. High temperature The high temperature of lightning flashes causes substantial amounts of nitrogen oxide in the atmosphere. 3. Chemical fixation Chemical processes have been devised for making nitrogen compounds directly from atmospheric nitrogen. 54
Metabolic Nitrogen Fixation The nitrogen cycle is shown here. About 60% of all newly-fixed nitrogen comes from bacteria. Biological nitrogen supplies depend on a small number of nitrogen-fixing microorganisms. 55
Amino Acids and Metabolic Nitrogen Balance Chapter Protein is digested and absorbed to provide the amino acid dietary requirements. Once absorbed, an amino acid can be: incorporated into a protein used to synthesize other nitrogen-containing compounds deaminated to a keto acid, which can be used to synthesize other compounds or be oxidized to provide energy. 56
Amino Acids and Metabolic Nitrogen Balance Chapter Absorbed amino acids enter the amino acid pool. One particularly important nitrogen pool is composed of the proteins in all the body s tissues. Amino acids continually move back and forth between the amino acid pool and the tissue proteins. 57
Amino Acids and Metabolic Nitrogen Balance Chapter In a healthy, well-nourished adult the amount of nitrogen excreted is equal to the amount of nitrogen ingested. The nitrogen pools within the body remain constant and such a person is said to be in nitrogen balance. A fasting or starving person excretes more nitrogen than is ingested. Such a person is said to be in negative nitrogen balance. Tissue protein breaks down to supply more amino acids to the amino acid pool. These amino acids are used as an energy source and nitrogen is excreted. 58
Your Turn! All amino acids that are ingested by humans are used to make protein molecules. True False 59
Your Turn! All amino acids that are ingested by humans are used to make protein molecules. True False Some amino acids are incorporated into protein but some are used to synthesize other nitrogen-containing compounds and others are oxidized to provide energy. 60
Amino Acids and Nitrogen Transfer Amino acids are important in metabolism as carriers of usable nitrogen. If an amino acid is not directly incorporated into tissue proteins, its nitrogen may be incorporated into various molecules. When an amino acid is used for some purpose other than protein synthesis, the amino acid carbon skeleton is separated from the amino acid nitrogen. 61
Amino Acids and Nitrogen Transfer A process called transamination is responsible for most of the nitrogen transfer to and from amino acids. Transamination is the transfer of an amino group from an α-amino acid to an α-keto acid. Transamination involves many different molecules with each different transamination requiring a different enzyme (transaminase). 62
Amino Acids and Nitrogen Transfer Examples of transamination reactions are shown below. 63
Amino Acids and Nitrogen Transfer Note that in both transamination reactions L-glutamic acid is converted to α-ketoglutaric acid. Most transamination reactions use L-glutamic acid. L-Glutamic acid plays a central role in cellular nitrogen transfer. 64
Amino Acids and Nitrogen Transfer Transamination is the first step in the conversion of the carbon skeletons of amino acids to energy-storage compounds. Amino acids that are used to produce glucose are termed glucogenic amino acids. Most amino acids are glucogenic but some amino acids converted to acetyl-coa are called ketogenic amino acids... 65
Amino Acids and Nitrogen Transfer 66
Amino Acids and Nitrogen Transfer L-Glutamic acid is the center of the amino acid pool. Other amino acids can either add nitrogen to or remove nitrogen from this compound. 67
Amino Acids and Nitrogen Transfer L-Glutamic acid can also accept a second nitrogen atom to form L-glutamine. This reaction reduces the basicity (and toxicity) of ammonia to the cell. 68
Amino Acids and Nitrogen Transfer L-Glutamine serves as a safe package for transporting nitrogen. In the human body, L-glutamine is the major compound for transferring nitrogen from one cell to another via the bloodstream. 69
Nitrogen Excretion and the Urea Cycle Under normal conditions adult humans excrete 6 18 g of nitrogen per day. Mammals excrete the water-soluble compound urea. Urea synthesis in mammals follows a pathway called the urea cycle which takes place in the liver. The urea cycle uses ATP to make urea from ammonia, bicarbonate, and L-aspartic acid. 70
Nitrogen Excretion and the Urea Cycle First, ammonium ion is produced from L-glutamic acid in an oxidation reduction reaction. 71
Nitrogen Excretion and the Urea Cycle Then the ammonium ion reacts with the hydrogen carbonate ion and ATP to form carbamoyl phosphate. 72
Nitrogen Excretion and the Urea Cycle Finally carbamoyl phosphate enters the urea cycle ultimately forming urea and fumaric acid. The overall reaction of the urea cycle is shown here. 73
Carbamoyl phosphate enters the urea cycle after it is formed. The detailed urea cycle is shown here. 74
Nitrogen Excretion and the Urea Cycle The cell must expend energy in the form of ATP to produce urea. The formation of a nontoxic nitrogen excretion product is essential. Also notice that one nitrogen atom in each urea molecule comes from L-glutamic acid and the other nitrogen atom comes from L-aspartic acid, which may have gained its nitrogen from L-glutamic acid by transamination. L-Glutamic acid is central to nitrogen-transfer reactions and is also the major contributor to nitrogen excretion. 75
Your Turn! How many ATP molecules are used to make one molecule of urea starting from L-glutamic acid? 76
Your Turn! How many ATP molecules are used to make one molecule of urea starting from L-glutamic acid? Each L-glutamic acid molecules produces one NH 4+. Two ATP molecules are used to convert NH 4 + and HCO 3 - to carbamoyl phosphate and one ATP to convert L-aspartic acid to argininosuccinic acid. Three ATP molecules are used. 77
Your Turn! Which of the following explains why L-glutamic acid is important in nitrogen metabolism? Most transaminations use L-glutamic acid. Nitrogen atoms in urea come from L-glutamic acid. 78
Your Turn! Which of the following explains why L-glutamic acid is important in nitrogen metabolism? Most transaminations use L-glutamic acid. Nitrogen atoms in urea come from L-glutamic acid. Both choices are correct. 79
Acetyl Co-A, a Central Molecule in Metabolism Chapter As we have seen some compounds are very important in metabolism. Glucose is the central compound in carbohydrate metabolism. Glutamic acid is central to amino acid metabolism. Acetyl-CoA is especially important. It is central to the metabolism of fats, proteins, and carbohydrates. 80
Acetyl Co-A, a Central Molecule in Metabolism Chapter This is a simplified diagram showing acetyl-coa as the hub of protein, carbohydrate, and fat metabolism. 81
Acetyl Co-A, a Central Molecule in Metabolism Chapter Acetyl-CoA is a critical intermediate in the processes that form and break down both fats and amino acids. Essentially all compounds that enter the citric acid cycle must first be catabolized to acetyl-coa. 82
Acetyl Co-A, a Central Molecule in Metabolism Chapter Acetyl-CoA consists of a small two-carbon unit (an acetyl group) bonded to a thioester linkage bonded to a large organic coenzyme molecule, coenzyme A. This structure makes for an almost ideal central metabolic molecule... 83
Acetyl Co-A, a Central Molecule in Metabolism Chapter The small size and simple structure of the two-carbon acetyl fragment enable this molecule to be used to build a variety of diverse structures. The thioester causes both carbons in the acetyl fragment to be specially reactive. Coenzyme A acts as a kind of handle for the various enzymes that catalyze reactions of the acetyl group. 84
Chapter 35 Summary Glucose (and glycogen), fatty acids (and triacylglycerols), and amino acids (and proteins) are three sources of metabolic energy for humans. The liver, adipose, and muscle are especially important in energy metabolism. Fatty acid catabolism shortens the fatty acid chain successively by two carbon atoms at a time. Beta oxidation is a series of reactions whereby the first two carbon atoms of the fatty acid chain become the acetyl group in a molecule of acetyl-coa. 85
Chapter 35 Summary Complete fatty acid oxidation to carbon dioxide yields more energy than can be derived from glucose. Fatty acids are the energy-storage molecules of choice in the human body. Fats (triacylglycerols) are stored in the adipose tissue. The biosynthesis of fatty acids from acetyl-coa is called lipogenesis. Lipogenesis lengthens a fatty acid successively two carbons at a time. 86
Chapter 35 Summary Ketone bodies are produced as a partial substitute when the human body is low in glucose. Amino acids serve as building blocks for protein synthesis and also provide nitrogen for other nitrogencontaining biochemicals. Amino acid metabolism is very different from that for carbohydrates or fatty acids. Nitrogen fixation is the conversion of diatomic nitrogen to a biochemically usable form.the nitrogen cycle is a process were nitrogen is circulated between the 87 atmosphere and living organisms.
Chapter 35 Summary Protein is digested and absorbed to provide amino acid dietary requirements. Absorbed amino acids enter the amino acid pool. Transamination is the transfer of an amino group from an alpha amino acid to an alpha keto acid. Some amino acids are converted to glucose and some are converted to acetyl-coa. Nitrogen excretion occurs when there is an excess of nitrogen. Humans eliminate nitrogen in the form of urea. 88
Chapter 35 Summary Acetyl-CoA is at the hub of most common metabolic processes. 89