Condensation of acetyl-CoA with

Thermodynamics of Citrate Synthase Reaction in Cells Citrate is formed by the condensation of acetyl-CoA with oxaloacetate, catalyzed by citrate synthase ... 

Polycarboxylic acid synthases. Several enzymes, including citrate synthase, the key enzyme which catalyzes the first step of the citric acid cycle, promote condensations of acetyl-CoA with ketones (Eq. 13-38). An a-oxo acid is most often the second substrate, and a thioester intermediate (Eq. 13-38) undergoes hydrolysis to release coenzyme A.199 Because the substrate acetyl-CoA is a thioester, the reaction is often described as a Claisen condensation. The same enzyme that catalyzes the condensation of acetyl-CoA with a ketone also catalyzes the second step, the hydrolysis of the CoA thioester. These polycarboxylic acid synthases are important in biosynthesis. They carry out the initial steps in a general chain elongation process (Fig. 17-18). While one function of the thioester group in acetyl-CoA is to activate the methyl hydrogens toward the aldol condensation, the subsequent hydrolysis of the thioester linkage provides for overall irreversibility and "drives" the synthetic reaction. 

Stereochemical relationships in the synthesis and metabolism of citrate. When oxaloacetate labeled with l3C in the carbonyl group /3 to the keto group ( ) was used as substrate, the researchers expected that half of the label would be found in succinate and half in C02. That prediction was based on the assumption that the two —CH2—COO- arms of citrate must be equivalent in every way. In fact, all of the label was found in C02. Thus, only the intermediates shown on the left were produced. This result shows that both the condensation of acetyl-CoA with oxaloacetate and the isomerization of citrate are stereospecific reactions. The carbon atoms supplied by acetyl-CoA are shown in red. Neither of those atoms is lost in the first turn of the cycle after their entry. 

In the first control point, citrate synthase catalyzes the condensation of acetyl-CoA with oxaloacetate to produce citrate (AG° = -32.2 kJ mol ). Although the reaction is reversible, the equilibrium lies very much in favor of citrate formation because of the hydrolysis of a bond in the intermediate compound, citroyl-CoA (Fig. 12-4). Citroyl-CoA is bound to citrate synthase, and the hydrolysis of the thioester bond, to produce citrate and coenzyme A, is an exergonic process. Citrate synthase is inhibited by its substrates (acetyl-CoA and oxaloacetate), and its activity is affected by... 

The synthesis of palmitate requires the input of 8 molecules of acetyl CoA, 14 molecules of NADPH, and 7 molecules of ATP. Fatty acids are synthesized in the cytosol, whereas acetyl CoA is formed from pyruvate in mitochondria. Hence, acetyl CoA must be transferred from mitochondria to the cytosol. Mitochondria, however, are not readily permeable to acetyl CoA. Recall that carnitine carries only long-chain fatty acids. The barrier to acetyl CoA is bypassed by citrate, which carries acetyl groups across the inner mitochondrial membrane. Citrate is formed in the mitochondrial matrix by the condensation of acetyl CoA with oxaloacetate (Figyu-e 22.25). When present at high levels, citrate is transported to the cytosol, where it is cleaved hy ATP-citrate lyase. 

The enzyme that catalyzes the condensation of acetyl-CoA with... 

Stabilization of the 2-carbanion by enolization is thought to be a critical step in the reactions catalyzed by citrate synthase and acetyl-CoA carboxylase. >ftth the former enz5rme, the carbanion attacks an incoming molecule of OAA. As shown in Figure 4.78, condensation of acetyl-CoA with OAA forms citryl-CoA. Hydrolysis of citryl-CoA then produces citric acid and acetyl-CoA. In the case of acetyl-CoA carboxylase, the carbanion attacks an incoming molecule of CO2, resulting in formation of malonyl-CoA (Figure 4.79). 

Condensation of Acetyl-CoA with Oxaloacetate to Form Citrate... 

Acetyl-CoA has many metabolic fates, but there are two that begin with the condensation of acetyl-CoA with oxaloacetate to give citrate. 

At the present time the data suggest multiple points of action of the adrenocortical hormones. Of the reactions which Villee et al. (1952) suggested might be influenced by the adrenocortical hormones, the condensation of pyruvate with oxaloacetate is known to require coenzyme A, as was described earlier. However, both Lipsett and Moore s (1952) experiments showing that the production of ketone bodies from pyruvate was not influenced by adrenalectomy and the observation that the acetylation of aromatic amines was not influenced by adrenalectomy (Dumm and Ralli, 1951) appear to exclude the reactions leading to the production of acetyl-CoA from pyruvate as probable points of action of the adrenocortical hormones. Therefore, of the reactions leading to the production of citrate from pyruvate and oxaloacetate, the most likely to be influenced by the adrenocortical hormones would appear to be the final condensation of acetyl-CoA with oxaloacetate. If further work should establish a direct influence of the adrenocortical hormones on the condensation of acetyl-CoA with oxaloacetate, an additional basis for the interrelations between pantothenic acid and the functions of the cortical hormones would be established. 

Isoprene units all originate by the same biochemical route through isopentenyl pyrophosphate. This latter compound is formed from mevalonic acid in a series of enzyme-assisted steps using energy transfer from ATP ADP hydrolysis. Mevalonic acid (mevalonate) is obtained by condensation of acetyl-CoA with acetoacetyl-CoA. 

Oxidation in the TCA-cycle is achieved by the addition of water and subsequent removal of hydrogen there is no direct involvement of oxygen CH3CO - S-CoA -t 3H,0 -> 2CO, -t 8[H] t- HSCoA. The initiating reaction of the TCA-cycle is the condensation of acetyl-CoA with oxaloacetate, catalysed by citrate synthase. One molecule of water Is consumed, and the products are citrate and coenzyme A. Citrate is... 

The metabolic map (see Fig. 1-13) illustrates the reactions involved in the citric acid cycle. After the condensation of acetyl-CoA with oxaloacetate to form citric acid, this carbon compound is transformed into isocitrate, which is itself oxidized and decarboxylated by the same enzyme to yield a-ketoglutarate and CO2. Oxalosuccinate is an intermediate in this reaction. 

Formation of a polyketide involves condensation of acetyl-CoA with the appropriate number of malonyl-CoA units, modification of the completed poly-j3-ketone where required, and release of the product in stable form, as, for example, in 6-methylsalicylic acid biosynthesis (Scheme 3.4). The whole sequence occurs enzyme-bound, without release, or acceptance, of intermediates externally. Thus probing of the biosynthetic sequence by normal feeding experiments with possible intermediates fails. Instead, very properly, information is gained in different ways by working with the actual enzymes involved. The biosynthesis of several polyketides has been explored in this way, and most extensively that of 6-methylsalicyclic acid 3.14) [14-17]. 

Condensation of acetyl-CoA with oxaloacetate to produce citrate is the first reaction of the TCA cycle. This reaction is catalysed by the condensing enzyme (or citrate synthetase) which has been obtained in crystalline finm ... 

RCOCH,COSCoA + CtoASH - RCOSCoA + CH,COSCoA (12) Condensation of acetyl CoA with oxalacetate. ... 

The condensation of acetyl CoA with acetate was attempted using the pigeon Uver enzyme. Such a condensation does not occur in this system, however two molecules of acetyl CoA are required. Acetyl CoA thus exhibits head and tail activation. This double activation may be the result of an equilibrium between two tautomeric forms of acetyl CoA,... 

Fatty acid synthesis in plants is carried out by a type I dissociable fatty acid synthase (FAS). There are three p-ketoacyl-ACP synthases (KAS) associated with FAS in plants. The short-chain condensing enzyme (KAS III) catalyses the initial condensation of acetyl-CoA with malonyl-ACP [1,2] to form acetoacetyl-ACP (4C) and may catalyse further rounds of condensation in vivo [3]. Further rounds of condensation are carried out by KAS I which catalyses the condensation of malonyl-ACP with intermediate length acyl-ACPs from acetoacetyl-ACP to myristoyl-ACP (14C) to give palmitoyl-ACP (16C). KAS II elongates palmItoyl-ACP (16C) to stearoyl-ACP (18C) [4J. 

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