Acetyl-CoA condensation

Stage Synthesis of Mevalonate from Acetate The first stage in cholesterol biosynthesis leads to the intermediate mevalonate (Fig. 21-34). Two molecules of acetyl-CoA condense to form acetoacetyl-CoA, which condenses with a third molecule of acetyl-CoA to yield the six-carbon compound /3-hydroxy-/3-methylglu-taryl-CoA (HMG-CoA). These first two reactions are catalyzed by thiolase and HMG-CoA synthase, respectively. The cytosolic HMG-CoA synthase in this pathway is distinct from the mitochondrial isozyme that catalyzes HMG-CoA synthesis in ketone body formation (see Fig. 17-18). 

The acetyl-CoA used as substrate for fatty acid synthases in the cytosol originates from the mitochondrion. This acetyl-CoA condenses with C02 to form malonyl-CoA, which eliminates (XL after an initial condensation reaction. After three more steps a two-carbon unit is added to a growing fatty acid chain. This cycle repeats itself many... 

Acetoacetate is formed from acetyl CoA in three steps (Figure 22.19). Two molecules of acetyl CoA condense to form acetoacetyl CoA. This reaction, which is catalyzed hy thiolase, is the reverse of the thiolysis step in the oxidation of fatty acids. Acetoacetyl CoA then reacts with acetyl CoA and water to give 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) and CoA. This condensation resembles the one catalyzed by citrate synthase (Section 17.13). This reaction, which has a favorable equilibrium owing to the hydrolysis of a thioester linkage, compensates for the unfavorable equilibrium in the formation of acetoacetyl CoA. 3-Hydroxy-3-methylglutaryl CoA is then cleaved to acetyl CoA and acetoacetate. The sum of these reactions is... 

Acetyl CoA condenses with oxaloacetate, forming citrate. 

Two molecules of acetyl CoA condense to produce acetoacetyl CoA. This reaction is catalyzed by thiolase or an isoenzyme of thiolase. 

Three molecules of acetyl-CoA condense to form mevalonate. 

A FIGURE 8-9 The citric acid cycle, in which acetyl groups transferred from acetyl CoA are oxidized to CO2. In reaction 1, a two-carbon acetyl residue from acetyl CoA condenses with the four-carbon molecule oxaloacetate to form the six-carbon molecule citrate. In the remaining reactions (2-9) each molecule of citrate is eventually converted back to oxaloacetate, losing two CO2 molecules in the process. In each turn of the cycle, four pairs of electrons are removed from carbon atoms, forming... 

The sequence of events known as the Krebs cycle is indeed a cycle ox-aloacetate is both the first reactant and the final product of the metabolic pathway (creating a loop). Because the Krebs cycle is responsible for the ultimate oxidation of metabolic intermediates produced during the metabolism of fats, proteins, and carbohydrates, it is the central mechanism for metabolism in the cell. In the first reaction of the cycle, acetyl CoA condenses with oxaloacetate to form citric acid. Acetyl CoA utilized in this way by the cycle has been produced either via the oxidation of fatty acids, the breakdown of certain amino acids, or the oxidative decarboxylation of pyruvate (a product of glycolysis). The citric acid produced by the condensation of acetyl CoA and oxaloacetate is a tricarboxylic acid containing three car-boxylate groups. (Hence, the Krebs cycle is also referred to as the citric acid cycle or tricarboxyfic acid cycle.)... 

The glyoxylate cycle (Figure 17.21), like the citric acid cycle, begins with the condensation of acetyl CoA and oxaloacetate to form citrate, which is then isomerized to isocitrate. Instead of being decarboxylated, isocitrate is cleaved by isocitrate lyase into succinate and glyoxylate. The subsequent steps regenerate oxaloacetate from glyoxylate. Acetyl CoA condenses with... 

Citrate synthase binds acetyl CoA, condenses it with oxaloacetate to form citryl CoA, and then hydrolyzes the thioester bond of this intermediate. Why doesn t citrate synthase hydrolyze acetyl CoA ... 

When correspondingly the biosynthetic pathway to terpenes is tracked, three carbons in dimethylaUyl diphosphate carry the label. First, two molecules of acetyl-CoA condense to give acetoacetyl-CoA. Then an enzyme-bound acetyl residue is transferred in the manner of an aldol addition, and reduction with NADPH finally produces (R)-mevalonic acid. Phosphorylation by ATP, dehy-drative decarboxylation and isomerisation of the isopentenyl diphosphate lead to dimethylaUyl diphosphate. 

Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA reductase) converts 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate, a precursor of cholesterol. Human 3-hydroxy-3-methylglutaryl coenzyme A, also abbreviated as HMGR consists of a polypeptide chain of 888 amino acids [9]. Acetyl-CoA condenses with acetoacetyl-CoA to form HMG-CoA reductase. 

Synthesis of PHB from acetyl-CoA condensation (see below) during cell reproduction is never completely non-existent - and can be substantial in A. latus -reflecting the availability of acetyl-CoA to be used for purposes other than oxidation even in these conditions. 

The details of carbon metabolism in the citric acid cycle are beyond the scope of this article. In brief, pyruvate is first oxidatively decarboxylated to yield CO2, NADH, and an acetyl group attached in an ester linkage to a thiol on a large molecule, known as coenzyme A, or CoA. (See Fig. 2.) Acetyl CoA condenses with a four-carbon dicar-boxy lie acid to form the tricarboxylic acid citrate. Free CoA is also a product (Fig. 6). A total of four oxidation-reduction reactions, two of which are oxidative decarboxylations, take place, which results in the generation of the three remaining NADH molecules and one molecule of FADH2. The citric acid cycle is a true cycle. For each two-carbon acetyl moiety oxidized in the cycle, two CO2 molecules are produced and the four-carbon dicarboxylic acid with which acetyl CoA condenses is regenerated. 

A second important anabolic pathway of acetyl-CoA produces the isoprenoid lipids, especially the steroids. Three molecules of acetyl-CoA condense at first to form a branched-chain compound, hydroxymethylglutaryl-CoA. With a superabundance of acetyl-CoA, such as occurs in some pathologic metabolic conditions (like diabetes, cf. Chapt. XX-10), acetoacetate can be formed from hydroxymethyl-glutaryl-CoA (ketogenesis). But normally, the reduction of the thioester group of that compound yields mevalonate which is then converted to isopentenyl pyrophosphate with an expenditure of 3 moles of ATP. The subsequent synthesis of squalene and cholesterol does not require any further energy supply. 

Figure 3 Synthesis of ketone bodies. In the mitochondria of hepatocytes, acetyl-CoA derived from /3-oxidation is converted to ketone bodies, primarily acetoacetate and /3-hydroxybutyrate, rather than entering the tricarboxylic acid cycle. Two molecules of acetyl-CoA condense in a reversal of the last /3-oxidation reaction (3-oxoacyl-CoA thiolase). The product, acetoacetyl-Ck)A, condenses with another molecule of acetyl-CoA, yielding /3-hydroxy, /3-methyl-glutaryl-CoA (HMG-CoA), a reaction catalysed by HMG-CoA synthase. Cleavage of HMG-CoA by HMG-CoA lyase yields acetoacetate, regenerating one molecule of acetyl-CoA. Acetoacetate is reversibly reduced to /3-hydroxybutyrate via the NAD-dependent enzyme /3-hydroxybutyrate dehydrogenase. These ketone bodies can traverse the inner mitochondrial membrane, eventually reaching the bloodstream for ultimate use by the brain and other tissues.

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