Harper's Biochemistry Chapter 14 - Overview of Metabolism & the Provision of Metabolic Fuels.PDF

S E C T I O N Metabolism of IV Carbohydrates Overview of Metabolism C H A P T E R...

S E C T I O N Metabolism of IV Carbohydrates Overview of Metabolism C H A P T E R & the Provision of Metabolic Fuels Owen P. McGuinness, PhD 14 OBJ E C TI VE S Explain what is meant by anabolic, catabolic, and amphibolic metabolic pathways. After studying this chapter, Describe the movement of carbohydrates, lipids, and amino acids between you should be able to: organs, and metabolism within organs at the subcellular level. Describe the ways cells can modulate flux of metabolites through metabolic pathways. Describe how the movement (storage and release) of substrates is regulated in the fed and fasting states. BIOMEDICAL IMPORTANCE “crossroads” of metabolism. They can participate in both ana- bolic and catabolic functions, for example, the citric acid cycle Metabolism is the term used to describe the interconversion (see Chapter 16). of chemical compounds in the body. It includes the pathways Knowledge of normal metabolism is essential for an taken by individual molecules in a specific cell, the interrela- understanding of abnormalities that underlie disease. tionships of pathways in cells and between cells in an organ Normal metabolism requires that the metabolism in cells as well as between organs, and the regulatory mechanisms can not only perform their normal resting or basal metabolic that regulate the flow of metabolites through the pathways. functions but they can adapt to a changing environment. This Metabolic pathways fall into three categories. (1) Anabolic includes appropriate adaptation to periods of feasting, fasting, pathways are involved in the synthesis of larger and more starvation, and exercise, as well as pregnancy and lactation. complex compounds from smaller precursors—for example, Abnormal metabolism may result from nutritional deficiency, the synthesis of protein from amino acids and the synthesis caloric excess, enzyme deficiency or inappropriate regulation, of triacylglycerol and glycogen from carbohydrates. Anabolic abnormal secretion of hormones, or the actions of drugs and pathways are endothermic and thus require reducing equiva- toxins. lents or ATP to support the pathways. (2) Catabolic pathways A 70-kg adult human being requires about 8 to 12 MJ are involved in the breakdown of larger molecules, commonly (1920-2900 kcal) from metabolic fuels each day, depend- involving oxidative reactions. They are exothermic, produc- ing on physical activity. Caloric requirements increase as the ing reducing equivalents, and, mainly via the respiratory chain size of the animal increases. For any given size when animals (see Chapter 13), ATP. (3) Amphibolic pathways occur at the are growing, they have a proportionally higher requirement to allow for the energy cost of growth. This energy require- This was adapted from chapter in 30th edition by David A. Bender, ment is met by our diet. For humans the caloric content of our PhD, & Peter A. Mayes, PhD, DSc diet is derived from carbohydrates (40-60%), lipids (mainly 133 134 SECTION IV Metabolism of Carbohydrates triacylglycerol, 30-40%), and protein (10-15%), as well as alcohol. replacement protein synthesis are mobilized. This net pro- The mix of carbohydrate, lipid, and protein being oxidized tein breakdown will lead to protein wasting, emaciation, and, varies, depending on the actual composition of the diet (ie, you eventually, death (see Chapter 43). burn what you eat), whether the subject is in the fed or fasting state, and on the duration and intensity of physical work. There is a constant requirement for metabolic fuels through- OVERVIEW OF SUBSTRATE out the day. The resting or basal metabolic rate accounts for METABOLISM IN FASTING ~60% of daily energy expenditure in humans. Physical activity accounts for a variable amount to total daily energy expendi- & FEASTING ture as exercise can increase the metabolic rate by 40 to 50% After an overnight fast the liver is the main source of glucose over the basal or resting metabolic rate. Metabolism is not (~9 g/hr in humans). (Figure 14–1). The glucose is derived constant in a given individual in a 24-hour period; we cycle from hepatic glycogen stores (via glycogenolysis) and synthe- between anabolism and catabolism. In a weight stable person sis of new glucose (via gluconeogenesis). In humans over 60% these processes on average are equal; we are in net zero energy (~6 g/hr) of the glucose released by the liver is metabolized balance. Most people consume their daily intake of metabolic by the central nervous system (which is largely dependent fuels in two or three meals, so there is net anabolism where on glucose) and red blood cells (which are wholly reliant on we store reserves of carbohydrate (glycogen in liver and mus- glucose). Adipose tissue releases nonesterified fatty acids by cle), lipid (triacylglycerol in adipose tissue), and labile protein hydrolysis of stored triglycerides. These fatty acids are the pri- stores. During the period following a meal we mobilize and mary oxidizable fuel for many tissues (heart, muscle, liver). catabolize those stores when there is no intake of food. The liver can also synthesize ketone bodies from fatty acids If the intake of calories exceeds energy expenditure, the to export to muscle and other tissues for oxidation. As liver surplus is stored, either as glycogen (liver and muscle) or as glycogen reserves deplete, amino acids arising from net muscle triacylglycerol in adipose tissue. If this persists, it will lead to protein breakdown with prolonged fasting and lactate derived the development of obesity and its associated health hazards. from hydrolysis of stored muscle glycogen provide carbons By contrast, if the intake of metabolic fuels is consistently to support gluconeogenesis and thus provide glucose to the lower than energy expenditure (long-term energy deficit), the glucose-dependent tissues (see Chapter 19). limited reserves of fat and carbohydrate get exhausted forc- In the fed state, after a meal in which there is an ample ing the organism to oxidize amino acids. The amino acids supply of carbohydrate, the metabolic fuel for most tis- arising from protein turnover that are normally reused for sues switches to glucose (see Figure 14–1). In response to a FASTING FEASTING Intestine Intestine Glucose Brain Brain Glucose Liver FFA Liver FFA Adipose Adipose Tissue Tissue Muscle Muscle FIGURE 14–1 Overview of Glucose and lipid flux in overnight fasted and fed humans. In the fasted setting liver is the source of the glucose and a large fraction of the glucose production is taken up by the brain. Adipose releases nonesterified fatty acids (FFA) that are used by the liver and skeletal muscle. In the fed state, the intestine becomes the source of glucose. The liver switches to a glucose consumer, while brain glucose uptake is unaltered. Lipolysis is suppressed and muscle and adipose tissue glucose uptake is increased and muscle fatty acid uptake is decreased.  CHAPTER 14 Overview of Metabolism & the Provision of Metabolic Fuels 135 carbohydrate-rich meal the liver switches to a glucose con- Carbohydrate Protein Fat sumer storing the majority of the glucose carbon as glyco- gen, with a small amount used for lipid synthesis. In contrast, Digestion and absorption glucose uptake by the brain and red blood cells is unaltered (~6 g/hr). The release of fatty acids from adipose tissue lipol- Simple sugars Fatty acids ysis is suppressed and tissues primarily reliant on fatty acid (mainly glucose) Amino acids + glycerol oxidation switch to glucose in part due to the decrease in fatty acid supply and increased glucose availability. Any dietary glu- Catabolism cose not taken up by the liver is taken up by peripheral tissues for oxidation or storage. It is stored in muscle as glycogen or in adipose tissue as triacylglycerol. Acetyl-CoA The formation and mobilization of reserves of triacylglyc- erol and glycogen, and the extent to which tissues take up and oxidize glucose, are largely controlled by the hormones insulin and glucagon that are made in the endocrine pancreas. Their Citric acid 2H ATP effects can also be modulated by other neural and/or endo- cycle crine signals (eg, sympathetic nervous system, growth hor- mone). Plasma glucose concentration is a tightly controlled variable. Because of the absolute dependency of the central 2CO2 nervous system on glucose; we have neuroendocrine systems to protect against low blood glucose (ie, hypoglycemia). FIGURE 14–2 Outline of the pathways for the catabolism of carbohydrate, protein, and fat. All these pathways lead to the production of acetyl-CoA, which is oxidized in the citric acid cycle, ultimately yielding ATP by the process of oxidative phosphorylation. PATHWAYS TO PROCESS THE MAJOR PRODUCTS OF OUR DIET Glucose and its metabolites also take part in other pro- The composition of the diet we eat dictates the general cesses. Glucose can be stored as a polymer called glycogen in metabolism of an organism. There is a need to process the skeletal muscle and liver (see Chapter 18). It can be diverted major products in the diet (carbohydrate, lipid, and protein) to the pentose phosphate pathway, an alternative to part of into their basic components. These are mainly glucose, fatty the pathway of glycolysis (see Chapter 20). This pathway is a acids and glycerol, and amino acids, respectively. If the com- source of reducing equivalents (NADPH) for fatty acid syn- position of the diet changes (eg, high carbohydrate vs low thesis (see Chapter 23) and the source of ribose for nucleotide carbohydrate) metabolic pathways can adapt to metabolize and nucleic acid synthesis (see Chapter 33). In the glycolytic the nutrient. In ruminants (and, to a lesser extent, other her- pathway triose phosphate intermediates can give rise to the bivores), dietary cellulose is fermented by symbiotic micro- glycerol moiety of triacylglycerols. Pyruvate can provide for organisms to short-chain fatty acids (acetic, propionic, butyric), the synthesis of intermediates in the citric acid cycle that can and metabolism in these animals is adapted to use these fatty provide the carbon skeletons for the synthesis of nonessential acids as major substrates. The products of digestion when com- or dispensable amino acids (see Chapter 27). Acetyl-CoA pletely oxidized go to a common product, acetyl-CoA, which derived from pyruvate is the precursor for the synthesis of is then oxidized by the citric acid cycle (see Chapter 16) fatty acids (see Chapter 23) and cholesterol (see Chapter 26) (Figure 14–2). and hence of all the steroid hormones synthesized in the body. Some tissues can synthesize glucose from precursors such as lactate, amino acids, and glycerol by the process of gluconeo- Carbohydrate Metabolism Is Centered genesis (see Chapter 19). This is important for suppling glu- on Oxidation & Storage of Glucose cose when dietary carbohydrate is low or inadequate. Glucose is metabolized by all tissues and is an important energy source for many (Figure 14–3). Glucose is first metab- olized to glucose-6-phosphate by hexokinase and from there Lipid Metabolism Is Concerned Mainly it can go to many fates. It can be metabolized to pyruvate by With Fatty Acids & Cholesterol the pathway of glycolysis (see Chapter 17). In aerobic tissues The long-chain fatty acids are either derived from dietary lipid the pyruvate can be metabolized to acetyl-CoA, which can or synthesized from acetyl-CoA derived from carbohydrate enter the citric acid cycle for complete oxidation to CO2 and or amino acids (lipogenesis). Fatty acids may be oxidized to H2O. The citric acid cycle is linked to the formation of ATP in acetyl-CoA (β-oxidation) or esterified with glycerol, forming the process of oxidative phosphorylation (see Figure 13–2). triacylglycerol as the body’s main fuel reserve. Stored triacyl- Glycolysis can also occur anaerobically (in the absence of oxygen) glycerol (adipose tissue) can be mobilized (lipolysis) to release where pyruvate is converted to the end product lactate. nonesterified fatty acids and glycerol. 136 SECTION IV Metabolism of Carbohydrates Diet Glucose Glycogen Glucose 3CO2 phosphates Pentose phosphate pathway Glycolysis Triose Ribose RNA phosphates phosphate DNA Pyruvate Lactate Triacylglycerol acid o in s CO2 Am Acetyl-CoA Fatty Protein acids Cholesterol Amino acids Citric FIGURE 14–4 Overview of fatty acid metabolism showing acid the major pathways and end products. The ketone bodies are cycle acetoacetate, 3-hydroxybutyrate, and acetone (which is formed non- enzymically by decarboxylation of acetoacetate). 2CO2 backbone is to be used for other processes the alpha amino nitrogen must be removed (deamination), metabolized in the FIGURE 14–3 Overview of carbohydrate metabolism show- liver to urea, and excreted by the kidney. The carbon skeletons ing the major pathways and end products. Gluconeogenesis is not that remain after transamination may (1) be oxidized to CO2 shown. in the citric acid cycle, (2) be used to synthesize glucose (gluconeogenesis, see Chapter 19), fatty acids (see Chapter 28), Acetyl-CoA formed by β-oxidation of fatty acids may or (3) form ketone bodies. undergo three fates (Figure 14–4): Several amino acids are also the precursors of other com- pounds, for example, purines, pyrimidines, hormones such as 1. Oxidized to CO2 + H2O via the citric acid cycle epinephrine and thyroxine, and neurotransmitters. 2. Synthesis of cholesterol and other steroids 3. Synthesize ketone bodies (acetoacetate and 3-hydroxybu- tyrate) in the liver (see Chapter 22) METABOLIC PATHWAYS AT THE ORGAN & CELLULAR LEVEL At the whole organism level substrates are moved between Much of Amino Acid Metabolism organs that can either remove or add substrates to the blood Involves Transamination perfusing the organ. The concentrations of the substrates The amino acids are required for protein synthesis entering and leaving tissues and organs can be measured to (Figure 14–5). The essential or indispensable amino acids help describe how substrates move between organs. Within must be supplied in the diet, since they cannot be synthe- each organ substrates can be followed as they transverse the sized in the body. The nonessential or dispensable amino plasma membrane and enter the metabolic pathways. Depend- acids, which are supplied in the diet, can also be formed from ing on the specific pathway it could all occur in the cytosol metabolic intermediates by transamination using the amino (eg, glycolysis) or be compartmentalized in subcellular organ- group from other amino acids (see Chapter 27). If the carbon elles (eg, citric acid cycle in the mitochondrion).  CHAPTER 14 Overview of Metabolism & the Provision of Metabolic Fuels 137 Diet protein Nonprotein Tissue protein Amino acids nitrogen derivatives T R A N S A M I N AT I O N Carbohydrate (glucose) Ketone bodies Amino nitrogen in glutamate Acetyl-CoA DEAMINATION Citric NH3 acid cycle Urea 2CO2 FIGURE 14–5 Overview of amino acid metabolism showing the major pathways and end products. The Anatomical Location of see Chapter 18) and the synthesis of glucose from metabolites such as lactate, glycerol, and amino acids (gluconeogenesis; an Organ & the Blood Circulation see Chapter 19). Integrates Metabolism The liver is a consumer of many dietary amino acids. Like When food is digested in the intestine the substrates are either glucose only a fraction of the total absorbed amino acids are directly taken up and enter the portal vein or are packaged removed by the liver. The remaining are removed by periph- and secreted into the lymphatic system. The portal vein sends eral tissues. In the liver they are substrates for the synthesis of all of the absorbed substrates to the liver. Depending on the the major plasma proteins (eg, albumin, fibrinogen). A sig- substrate, the liver can take up a small or large fraction of that nificant fraction is deaminated. While the carbon backbone which is delivered into the portal vein with the remaining of amino acids can be oxidized, the nitrogen is converted to allowed to pass into the systemic circulation. Substrates that urea, transported to the kidney and excreted (see Chapter 28). enter the lymphatic circulation coalesce into a common tho- The remaining amino acids are taken up by peripheral tissues racic duct which bypasses the liver and drains its contents into primarily for protein synthesis. the systemic circulation. The main dietary lipids (Figure 14–7) are triacylglycerols Amino acids resulting from the digestion of dietary pro- that are hydrolyzed to monoacylglycerols and fatty acids in the tein and glucose resulting from the digestion of carbohydrates gut, then reesterified in the intestinal mucosa. Here they are are absorbed via the hepatic portal vein. The liver has the role packaged with protein (ie, apolipoproteins) and secreted into the of regulating the blood concentration of these water-soluble lymphatic system and thence into the bloodstream as chylomi- metabolites (Figure 14–6) by removing a variable portion of crons, the largest of the plasma lipoproteins (see Chapter 25). these substrates before they enter the systemic circulation. The Chylomicrons also contain other lipid-soluble nutrients from uptake of glucose and amino acids is a regulated process. the diet, including vitamins A, D, E, and K (see Chapter 44). In the case of glucose, in the fed state ~10 to 15% of the Unlike glucose and amino acids absorbed from the small intes- absorbed glucose is taken up by the liver (see Figure 14–1). tine, chylomicron triacylglycerol is not taken up directly by The majority is used to synthesize glycogen (glycogenesis, see the liver. It is first metabolized by tissues that have lipoprotein Chapter 18). A small fraction is used for fatty acid synthesis lipase, which hydrolyzes the triacylglycerol, releasing fatty acids (lipogenesis, see Chapter 23) and the remainder is broken that are incorporated into tissue lipids or oxidized as fuel. The down by glycolysis to generate pyruvate that can be oxidized chylomicron remnants are cleared by the liver. The other major in the citric acid cycle for pyruvate oxidation. The glucose not source of long-chain fatty acids is synthesis (lipogenesis) from taken up by the liver is oxidized by the brain and many other carbohydrate, in adipose tissue and the liver (see Chapter 23). tissues including skeletal muscle. Between meals, the liver rap- Adipose tissue triacylglycerol is the main fuel reserve of the idly switches to a producer of glucose. It is the primary source body. It is hydrolyzed (lipolysis) and glycerol and nonesteri- of glucose in the fasted setting (see Figure 14–1). The glucose fied (free) fatty acids are released into the circulation. Glycerol is derived from two sources; stored glycogen (glycogenolysis; is used as a substrate for gluconeogenesis (see Chapter 19). 138 SECTION IV Metabolism of Carbohydrates Plasma proteins Liver Urea Protein Amino acids CO2 Glucose Amino acids Glycogen Protein Urea Lactate Amino acids Alanine, etc Portal vein Erythrocytes Glucose CO2 Glucose phosphate Kidney Urine Glycogen Diet Glucose Carbohydrate Blood plasma Amino acids Protein Muscle Small intestine FIGURE 14–6 Uptake and fate of major carbohydrate and amino acid substrates and metabolites. Note: Brain and adipose tissue are not depicted. NEFA CO2 Glucose Fatty acids Ketone bodies E st polysis erificatio Li n Blood TG Plasma CO2 Liver LPL Fatty VL acids DL E st polysis erificatio Fatty Lipoprotein Glucose TG Li acids LPL E C n st hy polysis TG lom erificatio icr ons Muscle Li n TG Diet MG + Adipose TG TG fatty acids tissue Small intestine FIGURE 14–7 Uptake and fate of major lipid substrates and metabolites. (LPL, lipoprotein lipase; MG, monoacylglycerol; NEFA, non- esterified fatty acids; TG, triacylglycerol; VLDL, very low-density lipoprotein.)  CHAPTER 14 Overview of Metabolism & the Provision of Metabolic Fuels 139 The fatty acids are transported bound to serum albumin; they THE FLUX THROUGH METABOLIC are taken up by most tissues (but not brain or erythrocytes) and either esterified to triacylglycerols for storage or oxidized PATHWAYS MUST BE REGULATED as a fuel. In the liver, newly synthesized triacylglycerol, triac- IN A CONCERTED MANNER ylglycerol from chylomicron remnants (see Figure 25–3) and Regulation of the overall flux through a pathway is important nonesterified (free) fatty acids from adipose tissue are pack- as it allows a cell to respond to a changing environment. The aged in very low-density lipoprotein (VLDL) and secreted regulation could be dictated by changes in overall substrates into the circulation. This triacylglycerol undergoes a fate simi- available to the cell as well as by endocrine signals that stimulate lar to that of chylomicrons. Fatty acids can be partially oxi- or inhibit specific metabolic pathways to subserve the needs of dized in the liver in the fasting setting to form ketone bodies the organism. For example, storing glycogen in the liver in the (ketogenesis, see Chapter 22). Ketone bodies are exported to fed state and mobilizing it in the fasted setting. This control is extrahepatic tissues, where they provide an alternative fuel in achieved by one or more key reactions in the pathway catalyzed prolonged fasting and starvation. by regulatory enzymes and/or transport systems that shuttle Skeletal muscle’s primary fuel is fatty acids in the fasted metabolites across the plasma membrane or between intracellu- setting. In the fed state muscle glucose uptake increases markedly lar compartments. The physicochemical factors that control the as its preferred substrate fatty acid decreases (see Figure 14–1). rate of an enzyme-catalyzed reaction, such as substrate concen- The glucose is oxidized to CO2 (aerobic) or anaerobically con- tration, are of primary importance in the control of the overall verted to lactate. A large fraction (>50%) is stored as glycogen rate of a metabolic pathway (see Chapter 9). in the fed state. Skeletal muscle synthesizes muscle protein from plasma amino acids. Muscle accounts for approximately 50% of body mass and consequently represents a considerable store of Nonequilibrium Reactions Are protein that can be drawn upon to supply amino acids for gluco- Potential Control Points neogenesis and be oxidized in skeletal muscle in starvation (see In a reaction at equilibrium, the forward and reverse reactions Chapter 19). In long term fasting ketones can be a significant occur at equal rates, and there is therefore no net flux in either contributor to muscle substrate oxidation. direction. A↔C↔D At the Subcellular Level, Glycolysis If this were a closed system and we added a fixed quantity of Occurs in the Cytosol & the Citric Acid “A”, the reaction would proceed to the right to make “C and Cycle in the Mitochondria D” until a new equilibrium was reached where the forward Compartmentation of pathways in separate subcellular com- and reverse reactions are equal. The final concentration of A, partments or organelles permits integration and regulation of C, and D would be determined by the absolute amount of A metabolism. Not all pathways are of equal importance in all added and the properties of the enzymes. In vivo, there is a cells. Figure 14–8 depicts the subcellular compartmentation net flux from left to right because there is a continuous sup- of metabolic pathways in a liver parenchymal cell. ply of substrate A and continuous removal of product D. The The liver performs many anabolic processes simultane- in vivo pathway is in a “steady state” if the rates of the reactions ously (gluconeogenesis, lipogenesis, VLDL synthesis, and are constant and the concentration of the substrates, products, protein synthesis) each of these are energy requiring (ATP, and intermediates are constant. In practice, there are normally NADH, NADPH). The central role of the mitochondrion is one or more nonequilibrium reactions in a metabolic path- immediately apparent, since it acts as the focus of carbohy- way, where the reactants are present in concentrations that are drate, lipid, and amino acid metabolism as well as a site for far from equilibrium. In attempting to reach equilibrium, large generation of energy to support these processes. It contains the losses of free energy occur, making this type of reaction essen- enzymes of the citric acid cycle (see Chapter 16), β-oxidation tially irreversible. Such a pathway has both flow and direction. of fatty acids and ketogenesis (see Chapter 22), as well as the The enzymes catalyzing nonequilibrium reactions are usually respiratory chain and ATP synthase (see Chapter 13). present in low concentration and are subject to a variety of Glycolysis (see Chapter 17), the pentose phosphate pathway regulatory mechanisms. However, most reactions in metabolic (see Chapter 20), and fatty acid synthesis (see Chapter 23) all pathways cannot be classified as equilibrium or nonequilib- occur in the cytosol. Gluconeogenesis (see Chapter 19) requires rium, but fall somewhere between the two extremes. movement of molecules between cellular compartments. Sub- strates such as lactate and pyruvate, which are formed in the The Control of Flux Through Many cytosol, enter the mitochondrion to yield oxaloacetate that then has to be moved to the cytosol to generate phosphoenolpyru- Pathways Is Distributed vate, which serves as a precursor for the synthesis of glucose. The flux-generating reaction can be identified as a non- The membranes of the endoplasmic reticulum con- equilibrium reaction in which the Km of the enzyme is con- tain the enzyme system for triacylglycerol synthesis (see siderably lower than the normal concentration of substrate. Chapter 24), and the ribosomes are responsible for protein The first reaction in glycolysis, catalyzed by hexokinase (see synthesis (see Chapter 37). Figure 17–2), would be considered such a flux-generating step 140 SECTION IV Metabolism of Carbohydrates FIGURE 14–8 Intracellular location and overview of major metabolic pathways in a liver parenchymal cell. (AA →, metabolism of one or more essential amino acids; AA ↔, metabolism of one or more nonessential amino acids.) because its Km for glucose of 0.05 mmol/L is well below the nor- the control of glucose uptake then shifts to hexokinase. The mal blood glucose concentration of 3 to 5 mmol/L. However, product of the hexokinase reaction is glucose-6-phosphate. glucose must first be transported into the cell by transporters. Glucose-6-phosphate is an allosteric inhibitor of hexokinase. In some tissues, transport activity is very low in the resting If the downstream pathway does not have the capacity to effi- state relative to the activity of hexokinase. Thus intracellular ciently metabolize the additional glucose-6-phosphate when glucose concentration is kept relatively low because of the transport activity is increased, glucose-6-phosphate will high affinity of hexokinase and the relatively low rate of glu- increase and serve as a brake on hexokinase. Then hexokinase cose uptake allowed by the transport system. Thus in this set- activity will limit how much glucose uptake is increased even ting transport activity is an important (it could be considered though transport activity is markedly enhanced. The pres- rate limiting) determinant of glucose uptake and subsequent ence of allosteric inhibition allows downstream reactions to metabolism. In the presence of insulin (a hormone made by indirectly serve an important controlling influence on the flux the endocrine pancreas) transport activity increases so trans- through the pathway. Thus, there is rarely one enzyme control- port is no longer a significant barrier to glucose uptake. Thus, ling flux through a pathway. Rather the control is distributed;  CHAPTER 14 Overview of Metabolism & the Provision of Metabolic Fuels 141 this distribution of control can vary depending on the physi- a biosynthetic pathway inhibits the enzyme catalyzing the first ologic setting. This distribution of control allows for fine- reaction in the pathway. Other control mechanisms depend on tuning of metabolic flux under differing physiologic states. the action of hormones responding to the needs of the body as a whole; they may act rapidly by altering the activity or cellular localization of existing enzyme molecules or slowly changing ALLOSTERIC & HORMONAL enzyme content by altering the rate of enzyme synthesis (see Chapter 42). SIGNALS CONTROL OF ENZYME-CATALYZED REACTIONS MANY METABOLIC FUELS In the metabolic pathway shown in Figure 14–9, ARE INTERCONVERTIBLE A↔B→C↔D Carbohydrate in excess of requirements for immediate energy- yielding metabolism and formation of glycogen reserves in reactions A ↔ B and C ↔ D are equilibrium reactions and muscle and liver can readily be used for synthesis of fatty B → C is a nonequilibrium reaction. The flux through this acids, and hence triacylglycerol in both adipose tissue and pathway can be regulated by the availability of substrate A. liver (whence it is exported in very low-density lipoprotein). This depends on its supply from the blood, which in turn The rate of lipogenesis in human beings is dependent on the depends on either food intake or key reactions that release carbohydrate content of the diet and total caloric intake. In substrates from tissue reserves (glycogen and triglycerides) Western countries dietary carbohydrates provide ~50% of into the bloodstream. For example, glycogen phosphorylase energy intake. In less-developed countries, carbohydrate may in liver (see Figure 18–1) can mobilize liver glycogen and provide 60 to 75% of energy intake. However, the total intake hormone-sensitive lipase in adipose tissue can mobilize adi- of food is so low that there is little surplus for lipogenesis. A high pose tissue triglycerides (see Figure 25–8). It also depends on intake of fat inhibits lipogenesis in adipose tissue and liver. the transport of substrate A into the cell. Muscle and adipose Despite the relatively higher fat intake in Western countries tissue glucose transport from the bloodstream increases in lipogenesis is significant because total caloric intake exceeds response to the hormone insulin. energy demand requiring diversion of excess carbohydrate Flux is also determined by removal of the end product D calories to lipogenesis. and the availability of cosubstrates or cofactors. Enzymes cata- Fatty acids (and ketone bodies formed from them) cannot lyzing nonequilibrium reactions are often allosteric proteins be used for the synthesis of glucose. The reaction of pyruvate subject to the rapid actions of “feed-back” or “feed-forward” dehydrogenase, forming acetyl-CoA, is irreversible, and for control by allosteric modifiers, in immediate response to the every two-carbon unit from acetyl-CoA that enters the citric needs of the cell (see Chapter 9). Frequently, the end product of acid cycle, there is a loss of two carbon atoms as carbon dioxide Inactive Enz1 + + 2 Ca2+ – calmodulin cAMP 2 Cell membrane Active Enz1 A A B C D 1 Enz2 + – + or – Positive feedforward allosteric activation Negative feedback allosteric inhibition 3 Ribosomal synthesis of new enzyme protein + or – 4 Induction Nuclear production of mRNA Repression 5 + – FIGURE 14–9 Mechanisms of control of an enzyme-catalyzed reaction. Circled numbers indicate possible sites of action of hormones: ➀ alteration of membrane permeability; ➁ conversion of an inactive enzyme to an active enzyme, usually involving phosphorylation/dephosphorylation reactions; ➂ alteration of the rate translation of mRNA at the ribosomal level; ➃ induction of new mRNA formation; and ➄ repression of mRNA formation. ➀ and ➁ are rapid mechanisms of regulation, whereas ➂, ➃, and ➄ are slower. 142 SECTION IV Metabolism of Carbohydrates before oxaloacetate is reformed. This means that acetyl-CoA and carbon dioxide is produced. When glucose (C6H12O6) is (and hence any substrates that yield acetyl-CoA) can never be oxidized (C6H12O6 + 6O2 → 6CO2 + 6 H2O) for each mole of used for gluconeogenesis. The (relatively rare) fatty acids with glucose oxidized a mole of oxygen is consumed and mole of an odd number of carbon atoms yield propionyl-CoA as the carbon dioxide is released. The molar ratio of CO2 produced product of the final cycle of β-oxidation. Propionyl-CoA can and O2 consumed is called the respiratory quotient. For car- be a substrate for gluconeogenesis, as can the glycerol released bohydrates this ratio is one. For fatty acid and protein oxida- by lipolysis of adipose tissue triacylglycerol reserves. tion this ratio is less than one (Table 14–1). We can measure Most of the amino acids in excess of requirements for this ratio in expired air. This is called the respiratory exchange protein synthesis (arising from the diet or from tissue protein ratio. This ratio reflects the mixture of substrates being oxi- turnover) yield pyruvate, or four- and five-carbon intermedi- dized by all tissues. In a typical person this ratio averages ates of the citric acid cycle (see Chapter 29). Pyruvate can be ~0.85 in a 24-hour period for a person on a standard diet. For carboxylated to oxaloacetate, which is the primary substrate several hours after a carbohydrate-rich meal, while the prod- for gluconeogenesis, and the other intermediates of the cycle ucts of digestion are being absorbed, there is an abundant sup- also result in a net increase in the formation of oxaloacetate, ply of carbohydrate. Thus carbohydrate oxidation is the main which is then available for gluconeogenesis. These amino substrate being oxidized so the respiratory exchange ratio acids are classified as glucogenic. Two amino acids (lysine and increases toward 1. The process of storing excess calories as leucine) yield only acetyl-CoA on oxidation, and hence cannot glycogen and lipid is an energy requiring process and is called be used for gluconeogenesis, and four others (phenylalanine, the thermic effect of food, which can account for ~10% of tyrosine, tryptophan, and isoleucine) give rise to both acetyl- daily energy expenditure. As a person transitions to a fast the CoA and intermediates that can be used for gluconeogenesis. rate of glucose oxidation decreases and the rate of fat oxida- Those amino acids that give rise to acetyl-CoA are referred tion increases (this is observed as a decrease in the respiratory to as ketogenic. With prolonged fasting and starvation amino exchange ratio toward 0.7 reflecting a shift to fat oxidation; see acids are mobilized from muscle protein to provide substrates Table 14–1). for gluconeogenesis, oxidized by the liver to support liver Glucose uptake into muscle and adipose tissue is con- energy demands, and contribute to synthesis of ketone bodies. trolled by insulin, which is secreted by the β-islet cells of the pancreas in response to an increased concentration of glucose in the arterial blood. In the fasting state, the glucose trans- A SUPPLY OF OXIDIZABLE FUEL porter of muscle and adipose tissue (GLUT-4) is in intracellular IS PROVIDED IN BOTH THE FED vesicles. An early response to insulin is the migration of these & FASTING STATES vesicles to the cell surface, where they fuse with the plasma membrane, exposing active glucose transporters. These insulin- Glucose Is Always Required by the sensitive tissues only take up glucose from the bloodstream to any significant extent in the presence of the hormone. As Central Nervous System & Erythrocytes insulin secretion falls in the fasting state, the transporters are Erythrocytes lack mitochondria and hence are wholly reliant internalized, reducing glucose uptake. However, in skeletal on (anaerobic) glycolysis and the pentose phosphate path- muscle, the increase in cytoplasmic calcium ion concentra- way at all times. The brain normally metabolizes glucose but tion in response to nerve stimulation and subsequent muscle can metabolize ketone bodies. When ketone availability is contraction stimulates the migration of the vesicles to the cell high such as prolonged fasting, they can meet about 20% of surface and exposure of active glucose transporters whether its energy requirements; the remainder must be supplied by there is significant insulin stimulation or not. Thus part of the glucose. The metabolic changes that occur in the fasting state increase in glucose uptake during exercise is independent of and starvation serve to preserve plasma glucose for use by the an increase in insulin. brain and red blood cells, and to provide alternative metabolic The transport capacity for glucose into the liver is high (lipids, amino acids) fuels for other tissues (Figure 14–10). In and is independent of insulin, thus transport does not control pregnancy, the fetus requires a significant amount of glucose, the rate of glucose uptake in the liver. The liver, however, has as does the mammary gland for synthesis of lactose during an isoenzyme of hexokinase (glucokinase) with a high Km, so lactation. that as the concentration of glucose increases and enters the liver hepatocyte, so does the rate of synthesis of glucose-6- In the Fed State, the Exogenous phosphate. Thus, when plasma glucose is elevated in the fed state the liver takes up glucose (see Figure 14–1). If it is in excess Metabolic Fuels Are Both Oxidized of the liver’s requirement for energy-yielding metabolism, it is & Stored used mainly for synthesis of glycogen. In both liver and skel- In response to a meal typically the caloric intake during the etal muscle, insulin, which increases in response to an increase period the food is absorbed exceeds the energy requirements in glucose acts to amplify glycogen synthesis by stimulating of the organism. The excess calories are stored either as glyco- glycogen synthetase and inhibiting glycogen phosphorylase. gen or lipid. When substrates are oxidized oxygen is consumed Some of the additional glucose entering the liver may also be  CHAPTER 14 Overview of Metabolism & the Provision of Metabolic Fuels 143 Glucose-6-phosphate Acyl-CoA Glycerol-3-phosphate Adipose tissue Triacylglycerol (TG) cAMP FFA Glycerol LPL Extrahepatic tissue (eg, FFA Blood Glycerol heart muscle) Glycerol Chylomicrons Gastro- LPL TG intestinal Oxidation (lipoproteins) tract NEFA NEFA Glucose Glucose Extra glucose drain (eg, diabetes, pregnancy, VLDL lactation) Ketone bodies FFA TG Glucose Liver Acyl-CoA Glycerol-3-phosphate Acetyl-CoA Glucose-6-phosphate esis g en eo on uc Citric Gl acid 2CO2 Amino acids, Glycogen cycle lactate FIGURE 14–10 Metabolic interrelationships among adipose tissue, the liver, and extrahepatic tissues. In tissues such as heart, meta- bolic fuels are oxidized in the following order of preference: fatty acids > ketone bodies > glucose. (LPL, lipoprotein lipase; NEFA, nonesterified fatty acids; VLDL, very low-density lipoproteins.) used for lipogenesis and hence triacylglycerol synthesis. In adi- adipose tissue and skeletal muscle, extracellular lipoprotein pose tissue, insulin stimulates glucose uptake. Glucose is used lipase is synthesized and activated in response to insulin; the to synthesize both the glycerol and fatty acid in triacylglycerol. resultant nonesterified fatty acids are largely taken up by the It inhibits intracellular lipolysis and the release of nonesterified tissue and used for synthesis of triacylglycerol, while the glyc- fatty acids by adipose tissue (see Figure 14–1). erol remains in the bloodstream. It is taken up by the liver and The products of lipid digestion enter the circulation as used for gluconeogenesis and glycogen synthesis or lipogen- chylomicrons, the largest of the plasma lipoproteins, which esis. Fatty acids remaining in the bloodstream are taken up are especially rich in triacylglycerol (see Chapter 25). In by the liver and reesterified. The lipid-depleted chylomicron 144 SECTION IV Metabolism of Carbohydrates TABLE 14–1 Energy Yields, Oxygen Consumption, & Carbon Dioxide Production in the Oxidation of Metabolic Fuels RQ (CO2 Produced/ Energy Yield (kJ/g) O2 Consumed (L/g) CO2 Produced (L/g) O2 Consumed) Energy (kJ)/L O2 (glucose) C6H12O6 + 6O2 → 6CO2 + 6 H2O Carbohydrate 16 0.829 0.829 1.00 ~20 (albumin) C72H112N2O22S + 77O2 → 63CO2 + 38 H2O +SO3 + 9CO(NH2)2 Protein 17 0.966 0.782 0.81 ~20 (triglyceride) C55H104O6 + 78O2 → 55CO2 + 52 H2O Fat 37 2.016 1.427 0.71 ~20 (ethanol) C2H5OH +3O2 → 2CO2 + 3 H2O Alcohol 29 1.429 0.966 0.66 ~20 remnants are cleared by the liver, and the remaining triacyl- The resulting glucose-6-phosphate is hydrolyzed by glucose- glycerol is exported, together with that synthesized in the liver, 6-phosphatase, and glucose is released into the bloodstream for in very low-density lipoprotein. use primarily by the brain and erythrocytes (see Figure 14–1). In healthy weight stable individuals the rates of tissue protein Muscle glycogen cannot contribute directly to plasma catabolism and anabolism are equal in a 24-hour period, thus glucose, since muscle lacks glucose-6-phosphatase, and the whole body protein stores are constant. While protein catabolism primary use of muscle glycogen is to provide a source of is relatively constant, the rate of protein synthesis does change glucose-6-phosphate and pyruvate potentially for energy-yielding through the 24-hour period. Protein synthesis falls during the metabolism in the muscle itself. However, acetyl-CoA formed fasting period and increases in the feeding period (a change of by oxidation of fatty acids in muscle inhibits pyruvate dehy- ~20-25%). It is only in cachexia associated with advanced can- drogenase, leading to an accumulation of pyruvate. Most of cer and other diseases that there is an increased rate of protein this is transaminated to alanine, at the expense of amino acids catabolism. The increased rate of protein synthesis in response to arising from breakdown of muscle protein or released as increased availability of amino acids and metabolic fuel is again a lactate. The alanine, lactate, and much of the keto acids result- response to insulin. Protein synthesis is an energy expensive pro- ing from this transamination are exported from muscle and are cess; it may account for up to 20% of resting energy expenditure taken up by the liver to support gluconeogenesis. In adipose after a meal, but only 9% in the fasting state. tissue, the decrease in insulin and increase in glucagon results in inhibition of lipogenesis, inactivation and internalization of lipoprotein lipase, and activation of intracellular hormone- Metabolic Fuel Reserves Are Mobilized sensitive lipase (see Chapter 25). This leads to release from in the Fasting State adipose tissue of increased amounts of glycerol (which is a There is a small fall in plasma glucose in the fasting state, and substrate for gluconeogenesis in the liver) and nonesterified then little change as fasting is prolonged into starvation. Plasma fatty acids, which are used by liver, heart, and skeletal muscle nonesterified fatty acids increase in fasting, but then rise little as their preferred metabolic fuel, so sparing glucose. more in starvation; as fasting is prolonged, the plasma concen- Although muscle preferentially takes up and metabolizes tration of ketone bodies (acetoacetate and 3-hydroxybutyrate) nonesterified fatty acids in the fasting state, it cannot meet all increases markedly (Table 14–2, Figure 14–11). of its energy requirements by β-oxidation. By contrast, the liver In the fasting state, as the concentration of glucose in the has a greater capacity for β-oxidation than is required to meet portal blood coming from the small intestine falls, insulin its own energy needs, and as fasting becomes more prolonged, secretion decreases, and skeletal muscle and adipose tissue take it forms more acetyl-CoA than can be oxidized. This acetyl- up less glucose. The increase in secretion of glucagon by α-cells CoA is used to synthesize the ketone bodies (see Chapter 22), of the pancreas inhibits glycogen synthetase, and activates gly- which are major metabolic fuels for skeletal and heart muscle cogen phosphorylase in the liver; mobilizing glycogen stores. and can meet up to 20% of the brain’s energy needs in states of TABLE 14–2 Plasma Concentrations of Metabolic Fuels (mmol/L) in the Fed & Fasting States Fed 40-h Fasting 7 Days Starvation Glucose 5.5 3.6 3.5 Nonesterified fatty acids 0.30 1.15 1.19 Ketone bodies Negligible 2.9 4.5  CHAPTER 14 Overview of Metabolism & the Provision of Metabolic Fuels 145 Plasma Plasma glucagon long-term fasting. In prolonged starvation, glucose may repre- ins sent less than 10% of whole body energy-yielding metabolism. u lin Were there no other source of glucose, liver and muscle glycogen would be exhausted after about 18 hours fasting. As fasting becomes more prolonged, an increasing amount of the amino acids released as a result of protein catabolism is utilized in the liver and kidneys for gluconeogenesis (Table 14–3). Relative change ac free CLINICAL ASPECTS ids fat ma as In prolonged starvation, as adipose tissue reserves are depleted, ty Pl there is a considerable increase in the net rate of protein catab- Blood glucose olism to provide amino acids, not only as substrates for gluco- neogenesis, but also as a metabolic fuel of many tissues. Death results when essential tissue proteins are catabolized and not s Liv replaced. In patients with cachexia as a result of release of die e rg cytokines in response to tumors and disease, there is marked e bo lyc eton og Blood k en increase in the rate of tissue protein catabolism, as well as a considerably increased metabolic rate, so they are in a state of advanced starvation. Again, death results when essential tissue 0 12–24 Hours of starvation proteins are catabolized and not replaced. The high demand for glucose by the fetus, and for lactose FIGURE 14–11 Relative changes in plasma hormones and synthesis in lactation, can lead to ketosis. This may be seen as metabolic fuels during the onset of starvation. mild ketosis with hypoglycemia in human beings; in lactating TABLE 14–3 Summary of the Major Metabolic Features of the Principal Organs Major Products Organ Major Pathways Main Substrates Exported Specialist Enzymes Liver Glycolysis, gluconeogenesis, Nonesterified fatty acids, Glucose, triacylglycerol Glucokinase, glucose-6- lipogenesis, β-oxidation, glucose (in fed state), lactate, in VLDL,a ketone phosphatase, glycerol kinase, citric acid cycle, glycerol, fructose, amino acids, bodies, urea, uric acid, phosphoenolpyruvate ketogenesis, lipoprotein alcohol bile salts, cholesterol, carboxykinase, fructokinase, metabolism, drug plasma proteins arginase, HMG-CoA synthase, metabolism, synthesis of HMG-CoA lyase, alcohol bile salts, urea, uric acid, dehydrogenase cholesterol, plasma proteins Brain Glycolysis, citric acid cycle, Glucose, amino acids, ketone Lactate, end products Those for synthesis and amino acid metabolism, bodies in prolonged starvation of neurotransmitter catabolism of neurotransmitters neurotransmitter synthesis metabolism Heart β-Oxidation and citric acid Nonesterified fatty acids, — Lipoprotein lipase, very active cycle Ketone bodies, lactate, electron transport chain chylomicron and VLDL triacylglycerol, some glucose Adipose Lipogenesis, esterification Glucose, chylomicron, and Nonesterified fatty Lipoprotein lipase, hormone- tissue of fatty acids, lipolysis (in VLDL triacylglycerol acids, glycerol sensitive lipase, enzymes of the fasting) pentose phosphate pathway Fast twitch Glycolysis Glucose, glycogen Lactate, (alanine and — muscle keto acids in fasting) Slow twitch β-Oxidation and citric acid Nonesterified fatty acids, lactate, alanine Lipoprotein lipase, very active muscle cycle ketone bodies, chylomicron, electron transport chain and VLDL triacylglycerol Kidney Gluconeogenesis Nonesterified fatty acids, Glucose with long-term Glycerol kinase, lactate, glycerol, glucose fasting phosphoenolpyruvate carboxykinase Erythrocytes Anaerobic glycolysis, Glucose Lactate Hemoglobin, enzymes of pentose phosphate pathway pentose phosphate pathway a VLDL, very low-density lipoprotein. 146 SECTION IV Metabolism of Carbohydrates cattle and in ewes carrying a twin pregnancy, there may be SUMMARY very pronounced ketoacidosis and profound hypoglycemia. The products of digestion provide the tissues with the building Ketogenic diets (low carbohydrate