Thioester formation, with coenzyme

Fatty acyl-CoA ligases (specific for short, medium, or long chain fatty acids) catalyze formation of fatty acyl thioester conjugate with coenzyme A (Diagram)... 

There are two major stages in the metabolism of fatty acids (1) Activation of free fatty acids in the cytoplasm through the formation of thioesters with coenzyme A and transport of the activated fatty acids across the inner mitochondrial membrane followed by... 

Acyl CoAs, such as acetyl CoA, are the most common thioesters in nature. Coenzyme A, abbreviated CoA, is a thiol formed by a phosphoric anhydride linkage (0=P-0-P=0) between phosphopantetheine and adenosine 3, 5 -bisphosphate. (The prefix bis- means two and indicates that adenosine 3, 5 -bisphosphate has two phosphate groups, one on C3 and one on C5. ) Reaction of coenzyme A with an acyl phosphate or acyl adenylate gives the acyl CoA (Figure 16.10). As we saw in Section 16.5 (Figure 16.6), formation of the acyl adenylate occurs by reaction of a carboxylic acid with ATP and is itself a nucleophilic acyl substitution reaction that takes place on phosphorus. 

The noteworthy features of these two enzymes may be summarized as follows (1) The oxidation leads to a product which is linked in thioester linkage with CoA—thus conserving part of the oxidative energy in the form of the thioester linkage (2) the process of oxidative decarboxylation proceeds in two steps, first a decarboxylation and then oxidation of the lipoic acid linked product of decarboxylation (3) the oxidation of the coenzyme-linked aldehyde intermediate by ferricyanide leads to the formation of the corresponding acid, whereas the oxidation by DPN+ in presence of CoA leads to the formation of the acyl CoA derivative. -"... 

Subsequent metabolism of m,cw-muconic acid by Pseudomonas results in the formation of j3-ketoadipic acid, which is further degraded as its coenzyme A-thioester to acetyl coenzyme A and succinyl coenzyme A (Katagiri and Hayaishi, 1957). Sistrom and Stanier (1954) have identified the two enzymes that together produce ]8-ketoadipic acid. The first, lactonizing, enzyme equilibrates w,w-muconic acid with (-f)-y-carbo-xymethyl-zl -butenolide this product is irreversibly converted to jS-keto-adipic acid by the second, delactonizing, enzyme. 

Figure 21.9 Formation of the thioester acetyl CoA by nucleophilic acyl substitution reaction of coenzyme A (CoA with acetyl adenylate.

Figure 8-2. Pathway for synthesis of palmitate by the fatty acid synthase (FAS) complex. Schematic representation of a single cycle adding two carbons to the growing acyl chain. Formation of the initial acetyl thioester with a cysteine residue of the enzyme preceded the first step shown. Acyl carrier protein (ACP) is a component of the FAS complex that carries the malonate covalently attached to a sulfhydryl group on its phosphopantatheine coenzyme (-SH in the scheme).

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... 

An unique example of stereoisomer selective tissue uptake of stereoisomers is noted with NSAIDs. The R enantiomer of ibuprofen shows preferential uptake into fat following the administration of the racemate and individual isomersJ However, this apparent difference in fat distribution is probably a consequence of the selective metabolic uptake and formation of the coenzyme A thioester of the R isomer, which does not occur with the S isomer. 

It is known that there are several long-chain acyl-Coenzyme A synthetases (ACS). ACSl shares some similar catalytic and antigenic properties to pahnitoyl-CoA synthetase [29]. Nevertheless, there is evidence of multiple forms of microsomal coenzyme A ligase catalyzing the formation of 2-APA CoA thioesters with several binding sites as well as a catalytic site. For instance, R-ketoprofen CoA appears to be catalyzed by an alternative isoform of a microsomal CoA ligase that is not shared by fenoprofen and ibuprofen [30,31]. 

The process of /3-oxidation begins in the cytoplasm with the formation of a thioester between the carboxyl group of a fatty acid and the sulfhydryl group of coenzyme A. The... 

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