Acetyl CoA Derived from Pyruvate Is Oxidized to Yield CO2 and Reduced Coenzymes in Mitochondria

Immediately after pyruvate is transported from the cytosol across the mitochondrial membranes to the matrix, it reacts with coenzyme A, forming CO2 and the intermediate acetyl CoA (Figure 8-8). This reaction, catalyzed by pyruvate dehydrogenase, is highly exergonic (AG°' = —8.0 kcal/mol) and essentially irreversible. Note that during the pyruvate de-hydrogenase reaction, NAD+ is reduced, forming NADH; in contrast, during the reactions catalyzed by lactate dehy-drogenase and alcohol dehydrogenase, NADH is oxidized, forming NAD+ (see Figure 8-5).

As discussed later, acetyl CoA plays a central role in the oxidation of fatty acids and many amino acids. In addition, it is an intermediate in numerous biosynthetic reactions, such as the transfer of an acetyl group to lysine residues in histone proteins and to the N-termini of many mammalian proteins. Acetyl CoA also is a biosynthetic precursor of cholesterol and other steroids and of the farnesyl and related groups that form the lipid anchors used to attach some proteins (e.g., Ras) to membranes (see Figure 5-15). In respiring mitochondria, however, the acetyl group of acetyl CoA is almost always oxidized to CO2.

The final stage in the oxidation of glucose entails a set of nine reactions in which the acetyl group of acetyl CoA is oxidized to CO2. These reactions operate in a cycle that is referred to by several names: the citric acid cycle, the tricar-boxylic acid cycle, and the Krebs cycle. The net result is that for each acetyl group entering the cycle as acetyl CoA, two molecules of CO2 are produced.

As shown in Figure 8-9, the cycle begins with condensation of the two-carbon acetyl group from acetyl CoA with the four-carbon molecule oxaloacetate to yield the six-carbon citric acid. The two-step conversion of citrate to iso-citrate (reactions 2 and 3) is carried out by a single multifunctional enzyme. In both reactions 4 and 5, a CO2 molecule is released. Reaction 5, catalyzed by the enzyme a-ketoglutarate dehydrogenase, also results in reduction of NAD+ to NADH. This reaction is chemically similar to that catalyzed by pyru-vate dehydrogenase, and indeed these two large enzyme complexes are similar in structure and mechanism. Reduction of NAD+ to NADH also occurs during reactions 4 and 9; thus three molecules of NADH are generated per turn of the cycle. In reaction 7, two electrons and two protons are transferred

I III II II

S — (CH2)2— N—C — (CH2)2— N — C — C — C—CH2— O—P — O—P — O— Ribose — Adenine

Coenzyme A (CoA)

▲ FIGURE 8-8 The structure of acetyl CoA. This compound is an important intermediate in the aerobic oxidation of pyruvate, fatty acids, and many amino acids. It also contributes acetyl groups in many biosynthetic pathways.

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