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UNE Biochemistry Unit 2 Exam
Terms in this set (24)
Fuel Oxidation and the Generation of Adenosine Triphosphate
These energy transformations can be divided into three principal phases: (1) oxidation of fuels (fat, carbohydrate, and protein), (2) conversion of energy from fuel oxidation into the high-energy phosphate bonds of adenosine triphosphate (ATP), and (3) use of ATP phosphate bond energy to drive energy-requiring processes.
Energy transformations in fuel metabolism.
When ATP energy is transformed into cellular responses, such as muscle contraction, ATP is cleaved to ADP and Pi. In cellular respiration, O2 is used for regenerating ATP from oxidation of fuels to CO2.
The first two phases of energy transformation are part of cellular respiration, the overall process of using O2 and energy derived from oxidizing fuels to generate ATP. We need to breathe principally because our cells require O2 to generate adequate amounts of ATP from the oxidation of fuels to CO2. Cellular respiration uses >90% of the O2 we inhale.
Phase 1 of respiration
In phase 1 of respiration, energy is conserved from fuel oxidation by enzymes that transfer electrons from the fuels to the electron-accepting coenzymes nicotinamide adenine dinucleotide (NAD+) and flavin adenine dinucleotide (FAD), which are reduced to NADH and FAD(2H), respectively (Fig. IV.2). The pathways for the oxidation of most fuels (glucose, fatty acids, ketone bodies, and many amino acids) converge in the generation of the activated 2-carbon acetyl group in acetyl coenzyme A (acetyl-CoA). The complete oxidation of the acetyl group to CO2 occurs in the tricarboxylic acid (TCA) cycle, which collects the energy mostly as NADH and FAD(2H).
Phase 2 of cellular respiration
In phase 2 of cellular respiration, the energy derived from fuel oxidation is converted to the high-energy phosphate bonds of ATP by the process of oxidative phosphorylation (see Fig. IV.2). Electrons are transferred from NADH and FAD(2H) to O2 by the electron-transport chain, a series of electron-transfer proteins that are located in the inner mitochondrial membrane. Oxidation of NADH and FAD(2H) by O2 generates an electrochemical potential across the inner mitochondrial membrane in the form of a transmembrane proton gradient (Δp). This electrochemical potential drives the synthesis of ATP from adenosine diphosphate (ADP) and inorganic phosphate (Pi) by a transmembrane enzyme called ATP synthase (or F0F1ATPase).
Phase 3 of cellular respiration
In phase 3 of cellular respiration, the high-energy phosphate bonds of ATP are used for processes such as muscle contraction (mechanical work), maintaining low intracellular Na+ concentrations (transport work), synthesis of larger molecules such as DNA in anabolic pathways (biosynthetic work), or detoxification (biochemical work). As a consequence of these processes, ATP is either directly or indirectly hydrolyzed to ADP and Pi or to adenosine monophosphate (AMP) and pyrophosphate (PPi).
Cellular respiration occurs in the mitochondria
Cellular respiration occurs in mitochondria (Fig. IV.3). The mitochondrial matrix, which is the compartment enclosed by the inner mitochondrial membrane, contains almost all of the enzymes for the TCA cycle and oxidation of fatty acids, ketone bodies, and most amino acids. The inner mitochondrial membrane contains the protein complexes of the electron-transport chain and ATP synthase, the enzyme complex that generates ATP from ADP and Pi. Some of the subunits of these complexes are encoded by mitochondrial DNA, which resides in the matrix. ATP is generated in the matrix, but most of the energy-using processes in the cell occur outside of the mitochondrion. As a consequence, newly generated ATP must be continuously transported to the cytosol by protein transporters in the impermeable inner mitochondrial membrane and by diffusion through pores in the more permeable outer mitochondrial membrane.
Oxidative metabolism in mitochondria.
The inner mitochondrial membrane forms infoldings, called cristae, which enclose the mitochondrial matrix. Most of the enzymes for the TCA cycle, the β-oxidation of fatty acids, and for mitochondrial DNA synthesis are found in the matrix. ATP synthase and the protein complexes of the electron-transport chain are embedded in the inner mitochondrial membrane. The outer mitochondrial membrane is permeable to small ions, but the inner mitochondrial membrane is impermeable.
The rates of fuel oxidation and ATP use are tightly coordinated through feedback regulation of the electron-transport chain and the pathways of fuel oxidation.
Thus, if less energy is required for work, more fuel is stored as glycogen or fat in adipose tissue. The basal metabolic rate (BMR), caloric balance, and ΔG (the change in Gibbs free energy, which is the amount of energy available to do useful work) are quantitative ways of describing energy requirements and the energy that can be derived from fuel oxidation. The various types of enzyme regulation described in Chapter 9 are all used to regulate the rate of oxidation of different fuels to meet energy requirements.
Fatty acids are a major fuel in the body.
After eating, we store excess fatty acids and carbohydrates that are not oxidized as fat (triacylglycerols) in adipose tissue. Between meals, these fatty acids are released and circulate in blood bound to albumin. In muscle, liver, and other tissues, fatty acids are oxidized to acetyl-CoA in the pathway of β-oxidation. NADH and FAD(2H) generated from β-oxidation are reoxidized by O2 in the electron-transport chain, thereby generating ATP (see Fig. IV.2). Small amounts of certain fatty acids are oxidized through other pathways that convert them to either oxidizable fuels or urinary excretion products (e.g., peroxisomal β-oxidation).
Not all acetyl-CoA generated from β-oxidation enters the TCA cycle.
In the liver, acetyl-CoA generated from β-oxidation of fatty acids can also be converted to the ketone bodies acetoacetate and β-hydroxybutyrate. Ketone bodies are taken up by muscle and other tissues, which convert them back to acetyl-CoA for oxidation in the TCA cycle. They become a major fuel for the brain during prolonged fasting.
Amino acids derived from dietary or body proteins are also potential fuels that can be oxidized to acetyl-CoA or converted to glucose and then oxidized
These oxidation pathways, like those of fatty acids, generate NADH or FAD(2H). Ammonia, which can be formed during amino acid oxidation, is toxic. It is therefore converted to urea in the liver and excreted in the urine. There are more than 20 different amino acids, each with a somewhat different pathway for oxidation of the carbon skeleton and conversion of its nitrogen to urea. Because of the complexity of amino acid metabolism, use of amino acids as fuels is considered separately in Section VII.
Glucose is a universal fuel used to generate ATP in every cell type in the body
In glycolysis, 1 mol of glucose is converted to 2 mol of pyruvate and 2 mol of NADH by cytosolic enzymes. Small amounts of ATP are generated when high-energy pathway intermediates transfer phosphate to ADP in a process termed substrate-level phosphorylation. In aerobic glycolysis, the NADH produced from glycolysis is reoxidized by O2 via the electron-transport chain, and pyruvate enters the TCA cycle. In anaerobic glycolysis, the NADH is reoxidized by conversion of pyruvate to lactate, which enters the blood. Although anaerobic glycolysis has a low ATP yield, it is important for tissues with a low oxygen supply and few mitochondria (e.g., the kidney medulla) or tissues that are experiencing diminished blood flow (ischemia).
In glycolysis, glucose is converted to pyruvate. If the pyruvate is reduced to lactate, the pathway does not require O2 and is called anaerobic glycolysis (in red). If this pyruvate is converted instead to acetyl-CoA and oxidized in the TCA cycle, glycolysis requires O2 and is aerobic (in black).
The pathologic consequences of metabolic problems in fuel oxidation can be grouped into one of two categories: (1) lack of a required product or (2) excess of a substrate or pathway intermediate.
he product of fuel oxidation is ATP, and an inadequate rate of ATP production occurs under a wide variety of medical conditions. Extreme conditions that interfere with ATP generation from oxidative phosphorylation, such as complete oxygen deprivation (anoxia) or cyanide poisoning, are fatal. A myocardial infarction is caused by a lack of adequate blood flow to regions of the heart (ischemia), thereby depriving cardiomyocytes of oxygen and fuel. Hyperthyroidism is associated with excessive heat generation from fuel oxidation, and in hypothyroidism, ATP generation can decrease to a fatal level. Conditions such as malnutrition, anorexia nervosa, or excessive alcohol consumption may decrease availability of thiamine, Fe2+, and other vitamins and minerals required by the enzymes of fuel oxidation. Mutations in mitochondrial DNA or nuclear DNA result in deficient ATP generation from oxidative metabolism.
In contrast, problems arising from an excess of substrate or fuel are seen in diabetes mellitus, which may result in a potentially fatal ketoacidosis. Lactic acidosis occurs with a reduction in oxidative metabolism.
Bioenergetics refers to cellular energy transformations.
The ATP-ADP Cycle. In cells, the chemical bond energy of fuels is transformed into the physiologic responses that are necessary for life. The central role of the high-energy phosphate bonds of adenosine triphosphate (ATP) in these processes is summarized in the ATP-ADP (adenosine diphosphate) cycle (Fig. 19.1). To generate ATP through cellular respiration, fuels are degraded by oxidative reactions that transfer most of their chemical bond energy to NAD+ and FAD to generate the reduced form of these coenzymes: NADH and FAD(2H). When NADH and FAD(2H) are oxidized by O2 in the electron-transport chain, the energy is used to regenerate ATP in the process of oxidative phosphorylation. Energy available from cleavage of the high-energy phosphate bonds of ATP can be used directly for mechanical work (e.g., muscle contraction) or for transport work (e.g., a Na+ gradient generated by Na+,K+-ATPase). It can also be used for biochemical work (energy-requiring chemical reactions), such as anabolic pathways (biosynthesis of large molecules such as proteins) or detoxification reactions. Phosphoryl transfer reactions, protein conformational changes, and the formation of activated intermediates containing high-energy bonds (e.g., nucleotide-sugars) facilitate these energy transformations. Energy released from foods that is not used for work against the environment is transformed into heat.
Fuel oxidation is regulated to maintain ATP homeostasis ("homeo," same; "stasis," state). Regardless of whether the level of cellular fuel utilization is high (with increased ATP consumption) or low (with decreased ATP consumption), the available ATP within the cell is maintained at a constant level by appropriate increases or decreases in the rate of fuel oxidation. Problems in ATP homeostasis and energy balance occur in obesity, hyperthyroidism, and myocardial infarction.
Energy from Fuel Oxidation.
Fuel oxidation is exergonic: It releases energy. The maximum quantity of energy released that is available for useful work (e.g., ATP synthesis) is called ΔG0′, the change in Gibbs free energy at pH 7.0 under standard conditions. Fuel oxidation has a negative ΔG0′; that is, the products have a lower chemical bond energy than the reactants and their formation is energetically favored. ATP synthesis from ADP and inorganic phosphate is endergonic: It requires energy and has a positive ΔG0′. To proceed in our cells, all pathways must have a negative ΔG0′. How is this accomplished for anabolic pathways such as glycogen synthesis? These metabolic pathways incorporate reactions that expend high-energy bonds to compensate for the energy-requiring steps. Because the ΔG0′ values for a sequence of reactions are additive, the overall pathway becomes energetically favorable.
Fuels are oxidized principally by donating electrons to NAD+ and FAD, which then donate electrons to O2 in the electron-transport chain.
The caloric value of a fuel is related to its ΔG0′ for transfer of electrons to O2 and its reduction potential, E0′ (a measure of its willingness to donate or accept electrons). Because fatty acids are more reduced than carbohydrates, they have a higher caloric value. The high affinity of oxygen for electrons (a high positive reduction potential) drives fuel oxidation forward, with release of energy that can be used for ATP synthesis in oxidative phosphorylation. However, smaller amounts of ATP can be generated without the use of O2 in anaerobic glycolysis.
Fuel oxidation can also generate NADPH
which usually donates electrons to biosynthetic pathways and detoxification reactions. For example, in some reactions catalyzed by oxygenases, NADPH is the electron donor and O2 is the electron acceptor.
Energy Available to Do Work
The basic principle of the ATP-ADP cycle is that fuel oxidation generates adenosine triphosphate (ATP), and hydrolysis of ATP to adenosine diphosphate (ADP) provides the energy to perform most of the work required in the cell. ATP has, therefore, been called the energy currency of the cells. Like the $1 bill, it has a defined value, is required to obtain goods and services, and disappears before we know it. To keep up with the demand, we must constantly replenish our ATP supply through the use of O2 for fuel oxidation.
The amount of energy from ATP cleavage available to do useful work is related to the difference in energy levels between the products and substrates of the reaction and is called the change in Gibbs free energy, ΔG (Δ, difference; G, Gibbs free energy). In cells, the ΔG for energy production from fuel oxidation must be greater than the ΔG of energy-requiring processes, such as protein synthesis and muscle contraction, for life to continue.
The High-Energy Phosphate Bonds of ATP
The amount of energy released or required by bond cleavage or formation is determined by the chemical properties of the substrates and products. The bonds between the phosphate groups in ATP are called phosphoanhydride bonds (Fig. 19.2). When these bonds are hydrolyzed, energy is released because the products of the reaction (ADP and phosphate) are more stable, with lower bond energies, than the reactants (ATP and water [H2O]). The instability of the phosphoanhydride bonds arises from their negatively charged phosphate groups, which repel each other and strain the bonds between them. It takes energy to make the phosphate groups stay together. In contrast, there are fewer negative charges in ADP to repel each other. The phosphate group, as a free anion, is more stable than it is in ATP because of an increase in resonance structures (i.e., the electrons of the oxygen double bond are shared by all the oxygen atoms). As a consequence, ATP hydrolysis is energetically favorable and proceeds with release of energy as heat.
Hydrolysis of ATP to ADP and inorganic phosphate (Pi).
Cleavage of the phosphoanhydride bonds between either the β- and γ-phosphates or between the α- and β-phosphates releases the same amount of energy, approximately 7.3 kcal/mol. However, hydrolysis of the phosphate-adenosine bond (a phosphoester bond) releases less energy (≈3.4 kcal/mol), and consequently, this bond is not considered a high-energy phosphate bond. During ATP hydrolysis, the change in disorder during the reaction is small and so ΔG values at physiologic temperature (37°C) are similar to those at standard
In the cell, ATP is not hydrolyzed directly.
Energy released as heat from ATP hydrolysis cannot be transferred efficiently into energy-requiring processes such as biosynthetic reactions or maintaining an ion gradient. Instead, cellular enzymes transfer the phosphate group directly to a metabolic intermediate or protein that is part of the energy-requiring process (a phosphoryl transfer reaction).
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