Succinyl CoA

Lsocitrate Dehydrogenase—The First Oxidadon in die Cycle m-Ketoglutarate Dehydrogenase—A Second Decarboxylation Succinyl-CoA Synthetase—A Substrate-Level Phosphoryladon Succinate Dehydrogenase—An Oxidadon Involving FAD... 

Citrate synthase is the first step in this metabolic pathway, and as stated the reaction has a large negative AG°. As might be expected, it is a highly regulated enzyme. NADH, a product of the TCA cycle, is an allosteric inhibitor of citrate synthase, as is succinyl-CoA, the product of the fifth step in the cycle (and an acetyl-CoA analog). 

The mechanism of succinyl-CoA synthetase is postulated to involve displacement of CoA by phosphate, forming succinyl phosphate at the active site, followed by transfer of the phosphoryl group to an active-site histidine (making a phosphohistidine intermediate) and release of succinate. The phosphoryl moiety is then transferred to GDP to form GTP (Figure 20.13). This sequence of steps preserves the energy of the thioester bond of succinyl-CoA in a series of high-energy intermediates that lead to a molecule of ATP ... 

Until now we have viewed the TCA cycle as a catabolic process because it oxidizes acetate units to COg and converts the liberated energy to ATP and reduced coenzymes. The TCA cycle is, after all, the end point for breakdown of food materials, at least in terms of carbon turnover. However, as shown in Figure 20.22, four-, five-, and six-carbon species produced in the TCA cycle also fuel avariety of biosynthetic processes. a-Ketoglutarate, succinyl-CoA, fumarate, and oxaloacetate are all precursors of important cellular species. (In order to par-... 

Oxidation of 2 molecules of glyceraldehyde-3-phosphate yields 2 NADH Pyruvate conversion to acetyl-CoA (mitochondria) 2 NADH Citric acid cycle (mitochondria) 2 molecules of GTP from 2 molecules of succinyl-CoA + 2 + 2... 

Fatty acids with odd numbers of carbon atoms are rare in mammals, but fairly common in plants and marine organisms. Humans and animals whose diets include these food sources metabolize odd-carbon fatty acids via the /3-oxida-tion pathway. The final product of /3-oxidation in this case is the 3-carbon pro-pionyl-CoA instead of acetyl-CoA. Three specialized enzymes then carry out the reactions that convert propionyl-CoA to succinyl-CoA, a TCA cycle intermediate. (Because propionyl-CoA is a degradation product of methionine, valine, and isoleucine, this sequence of reactions is also important in amino acid catabolism, as we shall see in Chapter 26.) The pathway involves an initial carboxylation at the a-carbon of propionyl-CoA to produce D-methylmalonyl-CoA (Figure 24.19). The reaction is catalyzed by a biotin-dependent enzyme, propionyl-CoA carboxylase. The mechanism involves ATP-driven carboxylation of biotin at Nj, followed by nucleophilic attack by the a-carbanion of propi-onyl-CoA in a stereo-specific manner. 

FIGURE 24.19 The conversion of propi-onyl-CoA (formed from /3-oxidation of odd-carbon fatty acids) to succinyl-CoA is carried out by a trio of enzymes as shown. Succinyl-CoA can enter the TCA cycle or be converted to acetyl-CoA. 

A Bi9-Catalyzed Rearrangement Yields Succinyl-CoA from L-Methylmalonyl-CoA... 

Succinyl-CoA derived from propionyl-CoA can enter the TCA cycle. Oxidation of succinate to oxaloacetate provides a substrate for glucose synthesis. Thus, although the acetate units produced in /3-oxidation cannot be utilized in glu-coneogenesis by animals, the occasional propionate produced from oxidation of odd-carbon fatty acids can be used for sugar synthesis. Alternatively, succinate introduced to the TCA cycle from odd-carbon fatty acid oxidation may be oxidized to COg. However, all of the 4-carbon intermediates in the TCA cycle are regenerated in the cycle and thus should be viewed as catalytic species. Net consumption of succinyl-CoA thus does not occur directly in the TCA cycle. Rather, the succinyl-CoA generated from /3-oxidation of odd-carbon fatty acids must be converted to pyruvate and then to acetyl-CoA (which is completely oxidized in the TCA cycle). To follow this latter route, succinyl-CoA entering the TCA cycle must be first converted to malate in the usual way, and then transported from the mitochondrial matrix to the cytosol, where it is oxida-... 

Although /3-oxidation is universally important, there are some instances in which it cannot operate effectively. For example, branched-chain fatty acids with alkyl branches at odd-numbered carbons are not effective substrates for /3-oxidation. For such species, a-oxidation is a useful alternative. Consider phy-tol, a breakdown product of chlorophyll that occurs in the fat of ruminant animals such as sheep and cows and also in dairy products. Ruminants oxidize phytol to phytanic acid, and digestion of phytanic acid in dairy products is thus an important dietary consideration for humans. The methyl group at C-3 will block /3-oxidation, but, as shown in Figure 24.26, phytanic acid a-hydroxylase places an —OFI group at the a-carbon, and phytanic acid a-oxidase decar-boxylates it to yield pristanie add. The CoA ester of this metabolite can undergo /3-oxidation in the normal manner. The terminal product, isobutyryl-CoA, can be sent into the TCA cycle by conversion to succinyl-CoA. 

Step 4 of Figure 29.12 Oxidative Decarboxylation The transformation of cr-ketoglutarate to succinyl CoA in step 4 is a multistep process just like the transformation of pyruvate to acetyl CoA that we saw in Figure 29.11. In both cases, an -keto acid loses C02 and is oxidized to a thioester in a series of steps catalyzed by a multienzynie dehydrogenase complex. As in the conversion of pyruvate to acetyl CoA, the reaction involves an initial nucleophilic addition reaction to a-ketoglutarate by thiamin diphosphate vlide, followed by decarboxylation, reaction with lipoamide, elimination of TPP vlide, and finally a transesterification of the dihydrolipoamide thioester with coenzyme A. 

Write a mechanism for the conversion of a--ketoglutarate to succinyl CoA in step 4 of the citric acid cycle (Figure 29.12). 

Methylmalonyl-CoA mutase 5 -deoxyadenosylco-balamin is part of dimethylbenzimidazolecobamide coenzyme, a constituent of methylmalonyl-CoA mutase. This mutase catalyses the isomerization of methylmalonyl-CoA to succinyl-CoA (anaplerotic reaction of the citric acid cycle). 

In peripheral tissues acetoacetate exported by the liver reacts with succinyl-CoA formed in the citrate cycle to give acetoacetyl-CoA and succinate catalyzed by a specific CoA transferase. 

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