Acetyl CoA hydrolysis

L-metilionine to -adenosylmethionine. In this process a positively charged sulphur is produced and facilitates the nucleophilic reaction. By the activity of diamine oxidase, the A -methyl-A -pyrrolinium cation is formed and after that the first alkaloid, hygrine. From hygrine, by way of acetyl CoA, hydrolysis and intramolecular Mannich reactions, other pyrrolidine and tropane alkaloids are synthesized cuscohygrine, hyoscyamine or tropinone, tropine and cocaine. The Mannich reaction involves the combination of an amine, an aldehyde or a ketone with a nucleophilic carbon. This reaction is typical in alkaloid synthesis, and can be written as follows ... 

The standard Gibbs energy Aj.G° for the acetyl-(CoA) hydrolysis is very negative ... 

The activation of acyl groups for transfer by CoA can be appreciated by comparing the hydrolysis of the thioester bond of acetyl-CoA with hydrolysis of a simple oxygen ester ... 

FIGURE 20.5 Citrate is formed in the citrate synthase reaction from oxaloacetate and acetyl-CoA. The mechanism involves nncieophiiic attack by the carbanion of acetyl-CoA on the carbonyl carbon of oxaloacetate, followed by thioester hydrolysis. 

Aldol-like condensation of acetoacetyl CoA with a third molecule of acetyl CoA, followed by hydrolysis, gives (3S)-3-hydroxy-3-melhylglutaryl CoA. 

The fatty acids released on triacylglycerol hydrolysis are transported to mitochondria and degraded to acetyl CoA, while the glycerol is carried to the liver for further metabolism. In the liver, glycerol is first phosphorylated by reaction with ATP. Oxidation by NAD+ then yields dihydroxyacetone phosphate (DHAP), which enters the carbohydrate metabolic pathway. We ll discuss this carbohydrate pathway in more detail in Section 29.5. 

The amino acid leucine is biosynthesized from n-ketoisocaproate, which is itself prepared from -ketoisovalerate by a multistep route that involves (1) reaction with acetyl CoA, (2) hydrolysis, (3) dehydration, (4) hydration. (5) oxidation, and (6) decarboxylation. Show lhe steps in the transformation, and propose a mechanism for each. 

The activity of carbamoyl phosphate synthase I is determined by A -acetylglutamate, whose steady-state level is dictated by its rate of synthesis from acetyl-CoA and glutamate and its rate of hydrolysis to acetate and glutamate. These reactions are catalyzed by A -acetylglu-tamate synthase and A -acetylglutamate hydrolase, respectively. Major changes in diet can increase the concentrations of individual urea cycle enzymes 10-fold to 20-fold. Starvation, for example, elevates enzyme levels, presumably to cope with the increased production... 

Thiolester hydrolases (EC 3.1.2) play an important role in the biochemistry of lipids. They catalyze the hydrolysis of acyl-coenzyme A thiolesters of various chain lengths to free fatty acids and coenzyme A. The current list of over 20 specific enzymes includes acetyl-CoA hydrolase (EC 3.1.2.1), pal-mi toy 1-Co A hydrolase (EC 3.1.2.2), and an acyl-CoA hydrolase (EC 3.1.2.20) of broad specificity for medium- to long-chain acyl-CoA [128],... 

The physiological pathway for oxidation of fatty acids in organs or tissues starts with the enzyme triacylglycerol lipase within adipose tissue, that is, the hormone-sensitive lipase. This enzyme, plus the other two lipases, results in complete hydrolysis of the triacylglycerol to fatty acids, which are transported to various tissues that take them up and oxidise them by P-oxidation to acetyl-CoA. This provides a further example of a metabolic pathway that spans more than one tissue (Figure 7.13) (Box 7.1). 

The physiological pathway for oxidation of ketone bodies starts with the hydrolysis of triacylglycerol in adipose tissue, which provides fatty acids that are taken up by the liver, oxidised to acetyl-CoAby P-oxidation and the acetyl-CoA is converted to ketone bodies, via the synthetic part of the pathway. Both hydroxybutyrate and acetoacetate are taken up by the tissues, which can oxidise them to generate ATP (Figure 7.19). 

Citrate is transported across the mitochondrial membrane by a specific carrier. In the cytosol, acetyl-CoA is reformed in a reaction catalysed by ATP citrate lyase (Figure 11.3). This reaction involves the hydrolysis of ATP ... 

Sugar The hydrolysis of sucrose in the intestine produces both glucose and fructose, which are transported across the epithelial cells by specific carrier proteins. The fructose is taken up solely by the liver. Fructose is metabolised in the liver to the triose phosphates, dihydroxy-acetone and glycer-aldehyde phosphates. These can be converted either to glucose or to acetyl-CoA for lipid synthesis. In addition, they can be converted to glycerol 3-phosphate which is required for, and stimulates, esterification of fatty acids. The resulting triacylglycerol is incorporated into the VLDL which is then secreted. In this way, fructose increases the blood level of VLDL (Chapter 11). 

The Krebs cycle intermediate that reacts with acetyl-CoA is oxaloacetate, and this reacts via an aldol reaction, giving citryl-CoA. However, the enzyme citrate synthase also carries out hydrolysis of the thioester linkage, so that the product is citrate hence the terminology citric acid cycle . The hydrolysis of the thioester is actually responsible for disturbing the eqnilibrinm and driving the reaction to completion. 

As discussed on p. 16, the group transfer potential can be expressed quantitatively as the change in free enthalpy (AG) during hydrolysis of the compound concerned. This is an arbitrary determination, but it provides important indications of the chemical energy stored in such a group. In the case of acetyl-CoA, the reaction to be considered is ... 

In standard conditions and at pH 7, the change in the chemical potential G (AG°, see p.l8) in this reaction amounts to -32 kj mol and it is therefore as high as the AG° of ATP hydrolysis (see p. 18). In addition to the energy-rich thioester bond, acetyl-CoA also has seven other hydrolyzable bonds with different degrees of stability. These bonds, and the fragments that arise when they are hydrolyzed, will be discussed here in sequence. 

Acetylcholine is synthesized from acetyl-CoA and choline in the cytoplasm of the presynap-tic axon [1] and is stored in synaptic vesicles, each of which contains around 1000-10 000 ACh molecules. After it is released by exocy-tosis (see p. 228), the transmitter travels by diffusion to the receptors on the postsynaptic membrane. Catalyzed by acetylcholinesterase, hydrolysis of ACh to acetate and choline immediately starts in the synaptic cleft [2], and within a few milliseconds, the ACh released has been eliminated again. The cleavage products choline and acetate are taken up again by the presynaptic neuron and reused for acetylcholine synthesis [3j. 

The cholesterol required for biosynthesis of the steroid hormones is obtained from various sources, it is either taken up as a constituent of LDL lipoproteins (see p. 278) into the hormone-synthesizing glandular cells, or synthesized by glandular cells themselves from acetyl-CoA (see p. 172). Excess cholesterol is stored in the form of fatty acid esters in lipid droplets. Hydrolysis allows rapid mobilization of the cholesterol from this reserve again. 

The synthetic pathway starts with the preakuammicine structure (Figure 42) by hydrolysis, decarboxylation and condensation reactions to aldehyde (Wieland-Gumlich), and subsequently reacts with acetyl-CoA to make a hemiacetal form of aldehyde (Wieland-Gumlich) and strychnine (Figure 43). 

Citrate synthase catalyzes the aldol reaction between acetyl-CoA and oxaloace-tate. The acyl-CoA Hnk is then cleaved by hydrolysis, releasing a molecule of citrate and free CoA. 

Thioesters, in which a sulfur atom replaces the usual oxygen in the ester bond, also have large, negative, standard free energies of hydrolysis. Acetyl-coenzyme A, or acetyl-CoA (Fig. 13-6), is one of many thioesters important in metabolism. The acyl group in... 

TABLE 13-6 Standard Free Energies of Hydrolysis of Some Phosphorylated Compounds and Acetyl-CoA (a Thioester)... 

RGURE 13-6 Hydrolysis of acetyl-coenzyme A Acetyl-CoA is a thioester with a large, negative, standard free energy of hydrolysis Thioesters contain a sulfur atom in the position occupied by an oxygen atom in oxygen esters. The complete structure of coenzyme A (CoA, or CoASH) is shown in Rgure 8-41. 

Conversion of Succinyl-CoA to Succinate Succinyl-CoA, like acetyl-CoA, has a thioester bond with a strongly negative standard free energy of hydrolysis (AG ° = -36 kJ/mol). In the next step of the citric acid cycle, energy released in the breakage of this bond is used to drive the synthesis of a phosphoanhydride bond in either GTP or ATP, with a net AG ° of only -2.9 kJ/mol. Succinate is formed in the process ... 

The fourth and last step of the /3-oxidation cycle is catalyzed by acyl-CoA acetyltransferase, more commonly called thiolase, which promotes reaction of /3-ketoacyl-CoA with a molecule of free coenzyme A to split off the carboxyl-terminal two-carbon fragment of the original fatty acid as acetyl-CoA The other product is the coenzyme A thioester of the fatty acid, now shortened by two carbon atoms (Fig. 17-8a). This reaction is called thiolysis, by analogy with the process of hydrolysis, because the /3-ketoacyl-CoA is cleaved by reaction with the thiol group of coenzyme A... 

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