Coenzyme A in Activation of Metabolic Pathways

The reaction is spontaneous, as indicated by the AG°. However, remember that even though this reaction is spontaneous, nothing would happen if you simply put these chemicals in a test tube. Biochemical reactions require enzymes to catalyze them. 

In the coupling of biochemical reactions, the energy released by one reaction, such as ATP hydrolysis, provides energy for another. 

A step frequently encountered in metabolism is the process of activation. In a reaction of this sort, a metabolite (a component of a metabolic pathway) is bonded to some other molecule, such as a coenzyme, and the free-enei change for breaking this new bond is negative. In other words, the next reaction in the metabolic pathway is exergonic. For example, if substance A is the metabolite 

Chapter 15 The Importance of Energy Changes and Electron Transfer in Metabolism 

The formation of a more reactive substance in this fashion is called activation. 

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The oxidation of aciy lic acid can be rationalized in terms of the endogenous catabolism of propionic acid, in which acrylyl coenzyme A is an intermediate. This pathway is analogous with fatty acid 3-oxidation, common to all species and, unlike the corresponding pathway in plants, does not involve vitamin 8,2. 3-Hydroxypropionic acid has been found as an intennediate in the metabolism of acrylic acid in vitro in rat liver and mitochondria (Finch Frederick, 1992). The CO2 excreted derives from the carboxyl carbon, while carbon atoms 2 and 3 are converted to acetyl coenzyme A, which participates in a variety of reactions. The oxidation of acrylic acid is catalysed by enzymes in a variety of tissues (Black Finch, 1995). In mice, the greatest activity was found in kidney, which was five times more active than liver and 50 times more active than skin (Black et al., 1993). 

Divalent sulfur compounds are achiral, but trivalent sulfur compounds called sulfonium stilts (R3S+) can be chiral. Like phosphines, sulfonium salts undergo relatively slow inversion, so chiral sulfonium salts are configurationally stable and can be isolated. The best known example is the coenzyme 5-adenosylmethionine, the so-called biological methyl donor, which is involved in many metabolic pathways as a source of CH3 groups. (The S" in the name S-adenosylmethionine stands for sulfur and means that the adeno-syl group is attached to the sulfur atom of methionine.) The molecule has S stereochemistry at sulfur ana is configurationally stable for several days at room temperature. Jts R enantiomer is also known but has no biological activity. 

Finally, the activity of key enzymes can be regulated by ligands (substrates, products, coenzymes, or other effectors), which as allosteric effectors do not bind at the active center itself, but at another site in the enzyme, thereby modulating enzyme activity (6 see p. 116). Key enzymes are often inhibited by immediate reaction products, by end products of the reaction chain concerned feedback inhibition), or by metabolites from completely different metabolic pathways. The precursors for a reaction chain can stimulate their own utilization through enzyme activation. 

The most important process in the degradation of fatty acids is p-oxidation—a metabolic pathway in the mitochondrial matrix (see p. 164). initially, the fatty acids in the cytoplasm are activated by binding to coenzyme A into acyl CoA [3]. Then, with the help of a transport system (the carnitine shuttle [4] see p. 164), the activated fatty acids enter the mitochondrial matrix, where they are broken down into acetyl CoA. The resulting acetyl residues can be oxidized to CO2 in the tricarboxylic acid cycle, producing reduced... 

Any process by which there is direct transfer of noncova-lently bound substrate(s) or coenzyme from the active site of the enzyme producing the metabolite to the active site of an enzyme catalyzing a succeeding step in a metabolic pathway or to another enzyme utilizing the coenzyme product. 

Ethanoic acid is activated for biosynthesis by combination with the thiol, coenzyme A (CoASH, Figure 18-7) to give the thioester, ethanoyl (acetyl) coenzyme A (CH3COSC0A). You may recall that the metabolic degradation of fats also involves this coenzyme (Section 18-8F) and it is tempting to assume that fatty acid biosynthesis is simply the reverse of fatty acid metabolism to CH3COSCoA. However, this is not quite the case. In fact, it is a general observation in biochemistry that primary metabolites are synthesized by different routes from those by which they are metabolized (for example, compare the pathways of carbon in photosynthesis and metabolism of carbohydrates, Sections 20-9,10). 

The biochemical importance of flavin coenzymes ap-pears to be their versatility in mediating a variety of redox processes, including electron transfer and the activation of molecular oxygen for oxygenation reactions. An especially important manifestation of their redox versatility is their ability to serve as the switch point from the two-electron processes, which predominate in cytosolic carbon metabo-lism, to the one-electron transfer processes, which predomi-nate in membrane-associated terminal electron-transfer pathways. In mammalian cells, for example, the end products of the aerobic metabolism of glucose are C02 and NADH (see chapter 13). The terminal electron-transfer pathway is a membrane-bound system of cytochromes, nonheme iron proteins, and copper-heme proteins—all one-electron acceptors that transfer electrons ultimately to 02 to produce H20 and NAD+ with the concomitant production of ATP from ADP and P . The interaction of NADH with this pathway is mediated by NADH dehydrogenase, a flavoprotein that couples the two-electron oxidation of NADH with the one-electron reductive processes of the membrane. 

Eight enzyme-catalyzed reactions are involved in the conversion of acetyl-CoA into fatty acids. The first reaction is catalyzed by acetyl-CoA carboxylase and requires ATP. This is the reaction that supplies the energy that drives the biosynthesis of fatty acids. The properties of acetyl-CoA carboxylase are similar to those of pyruvate carboxylase, which is important in the gluconeogenesis pathway (see chapter 12). Both enzymes contain the coenzyme biotin covalently linked to a lysine residue of the protein via its e-amino group. In the last section of this chapter we show that the activity of acetyl-CoA carboxylase plays an important role in the control of fatty acid biosynthesis in animals. Regulation of the first enzyme in a biosynthetic pathway is a strategy widely used in metabolism. 

The pathway can be divided into two metabolic cycles (Figure 3.4). In the first cycle, acetyl-CoA is carboxylated to malonyl-CoA, which is subsequently reduced and converted into propionyl-CoA via 3-hydroxypropionate as a free intermediate. Propionyl-CoA is carboxylated to methylmalonyl-CoA, which is subsequently converted to succinyl-CoA the latter is then used to activate L-malate by succinyl-CoA L-malate coenzyme A transferase, which forms L-malyl-CoA and succinate. Succinate is oxidized to L-malate via conventional steps. L-Malyl-CoA, the second characteristic intermediate of this cycle, is cleaved by L-malyl-CoA/P-methylmalyl-CoA lyase, thus regenerating the starting molecule acetyl-CoA and releasing gly-oxylate as a first carbon-fixation product [27]. 

In general, the entry of a fatty acid into a metabolic pathway is preceded by its conversion to its coenzyme A (CoASH) derivative this acyl derivative is called an alkanoyl- or alkenoyl-CoA, and in this form the fatty acid is said to have been activated. 

Fig. 13 Relative changes in metabolic fluxes. Relative changes in the metabolic fluxes of B. megaterium WH323 carrying TFH encoding pYYBm9 after induction of recombinant protein production with either glucose (a) or pyruvate (b) as the sole carbon source are given. AcCoA acetyl-coenzyme A Activ activation F6P fructose 6-phosphate G6P glucose 6-phosphate MAL malate OAA oxaloacetate PEP phosphoenolpyruvate PPP pentose phosphate pathway PYR pyruvate TCA tricarboxylic acid. Data adapted from [88]...

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