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19.5: Stage III of Catabolism

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     (or or tricarboxylic acid [TCA] cycle). The cyclical design of this complex series of reactions, which bring about the oxidation of the acetyl group of to carbon dioxide and water, was first proposed by Hans Krebs in 1937. (He was awarded the 1953 Nobel Prize in Physiology or Medicine.) ’s entrance into the is the beginning of stage III of catabolism. The produces adenosine triphosphate (ATP), reduced nicotinamide adenine dinucleotide (NADH), reduced flavin adenine dinucleotide (FADH), and metabolic intermediates for the synthesis of needed compounds. appears rather complex (Figure \(\PageIndex{1}\)). All the reactions, however, are familiar types in : , oxidation, decarboxylation, and . Each reaction of the is numbered, and in Figure \(\PageIndex{1}\), the two acetyl carbon atoms are highlighted in red. Each intermediate in the cycle is a carboxylic acid, existing as an anion at physiological pH. All the reactions occur within the , which are small organelles within the cells of plants and animals. released by the of the high- thioester bond of succinyl-CoA is used to form guanosine triphosphate (GTP) from guanosine diphosphate (GDP) and inorganic phosphate in a reaction catalyzed by . This step is the only reaction in the that directly forms a high- phosphate . GTP can readily transfer its terminal phosphate group to adenosine diphosphate (ADP) to generate ATP in the presence of . . Succinate dehydrogenase is the only enzyme of the located within the inner mitochondrial membrane. We will see soon the importance of this. of water is added to the of fumarate to form L-malate in a reaction catalyzed by . . Oxaloacetate can accept an acetyl group from , allowing the cycle to begin again. can be defined as the process by which cells oxidize organic molecules in the presence of gaseous oxygen to produce carbon dioxide, water, and in the form of ATP. We have seen that two carbon atoms enter the from (step 1), and two different carbon atoms exit the cycle as carbon dioxide (steps 3 and 4). Yet nowhere in our discussion of the have we indicated how oxygen is used. Recall, however, that in the four oxidation-reduction steps occurring in the , the coenzyme NAD or FAD is reduced to NADH or FADH, respectively. . Recall, too, that very little ATP is obtained directly from the . Instead, oxygen participation and significant ATP production occur subsequent to the , in two pathways that are closely linked: transport and . for the , the reoxidation of NADH and FADH and the production of ATP are located in the , which are small, oval organelles with double membranes, often referred to as the “ plants” of the cell (Figure \(\PageIndex{2}\)). A cell may contain 100–5,000 , depending on its function, and the can reproduce themselves if the requirements of the cell increase. : the , which lies between the membranes, and the , which lies inside the inner membrane. The outer membrane is permeable, whereas the inner membrane is impermeable to most molecules and ions, although water, oxygen, and carbon dioxide can freely penetrate both membranes. The matrix contains all the enzymes of the with the exception of succinate dehydrogenase, which is embedded in the inner membrane. The enzymes that are needed for the reoxidation of NADH and FADH and ATP production are also located in the inner membrane. They are arranged in specific positions so that they function in a manner analogous to a bucket brigade. This highly organized sequence of oxidation-reduction enzymes is known as the . transport chain. The components of the chain are organized into four complexes designated I, II, III, and IV. Each complex contains several enzymes, other , and metal ions. The metal ions can be reduced and then oxidized repeatedly as electrons are passed from one component to the next. Recall that a is reduced when it gains electrons or hydrogen atoms and is oxidized when it loses electrons or hydrogen atoms. transport chain through either complex I or II. We will look first at electrons entering at complex I. These electrons come from NADH, which is formed in three reactions of the . Let’s use step 8 as an example, the reaction in which L-malate is oxidized to oxaloacetate and NAD is reduced to NADH. This reaction can be divided into two : accepts both of those electrons and one of the H ions. The other H ion is transported from the matrix, across the inner mitochondrial membrane, and into the intermembrane space. The NADH diffuses through the matrix and is bound by complex I of the transport chain. In the complex, the coenzyme flavin mononucleotide (FMN) accepts both electrons from NADH. By passing the electrons along, NADH is oxidized back to NAD and FMN is reduced to FMNH (reduced form of flavin mononucleotide). Again, the reaction can be illustrated by dividing it into its respective half-reactions. that have iron-sulfur (Fe·S) centers. The electrons that reduced FMN to FMNH are now transferred to these . The iron ions in the Fe·S centers are in the Fe(III) form at first, but by accepting an , each ion is reduced to the Fe(II) form. Because each Fe·S center can transfer only one , two centers are needed to accept the two electrons that will regenerate FMN. , enter the transport chain through complex II. Succinate dehydrogenase, the enzyme in the that catalyzes the formation of FADH from FAD is part of complex II. The electrons from FADH are then transferred to an Fe·S protein. carrier that acts as the shuttle between complexes I or II and complex III. known as . The iron in these enzymes is located in substructures known as iron porphyrins (Figure \(\PageIndex{4}\)). Like the Fe·S centers, the characteristic feature of the is the ability of their iron atoms to exist as either Fe(II) or Fe(III). Thus, each cytochrome in its oxidized form—Fe(III)—can accept one and be reduced to the Fe(II) form. This change in oxidation state is reversible, so the reduced form can donate its to the next cytochrome, and so on. Complex III contains b and c, as well as Fe·S , with cytochrome c acting as the shuttle between complex III and IV. Complex IV contains a and a in an enzyme known as . This enzyme has the ability to transfer electrons to molecular oxygen, the last acceptor in the chain of transport reactions. In this final step, water (HO) is formed. in the transport chain is reduced by the addition of one or two electrons in one reaction and then subsequently restored to its original form by delivering the (s) to the next along the chain. The successive transfers result in production. But how is this used for the synthesis of ATP? The process that links ATP synthesis to the operation of the transport chain is referred to as . transport is tightly coupled to . The NADH and FADH are oxidized by the respiratory chain if ADP is simultaneously phosphorylated to ATP. The currently accepted model explaining how these two processes are linked is known as the , which was proposed by Peter Mitchell, resulting in Mitchell being awarded the 1978 Nobel Prize in Chemistry. transport chain, hydrogen (H) ions are being transported across the inner mitochondrial membrane from the matrix to the intermembrane space. The of H is already higher in the intermembrane space than in the matrix, so is required to transport the additional H there. This comes from the transfer reactions in the transport chain. But how does the extreme difference in H then lead to ATP synthesis? The buildup of H ions in the intermembrane space results in an H ion gradient that is a large source, like water behind a dam (because, given the opportunity, the protons will flow out of the intermembrane space and into the less concentrated matrix). Current research indicates that the flow of H down this gradient through a fifth enzyme complex, known as ATP synthase, leads to a change in the structure of the synthase, causing the synthesis and release of ATP. , the turnover of ATP is very high, so these cells contain high levels of ADP. They must therefore consume large quantities of oxygen continuously, so as to have the necessary to phosphorylate ADP to form ATP. Consider, for example, that resting skeletal muscles use about 30% of a resting adult’s oxygen consumption, but when the same muscles are working strenuously, they account for almost 90% of the total oxygen consumption of the organism. of NADH oxidized in the transport chain, and 1.5–2 ATP molecules are formed for every of FADH oxidized. Table \(\PageIndex{1}\) summarizes the theoretical maximum yield of ATP produced by the complete oxidation of 1 mol of through the sequential action of the , the transport chain, and .

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