Phosphopantetheine and

Acyl CoA s, 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—O—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... 

CoA undergoes dephosphorylation, catalyzed by lysosomal acid phosphatase, to dephospho-CoA, followed by pyrophosphatase action to release 4 -phosphopantetheine and 5 -AMP - the reverse of the final stages of CoA synthesis shown in Figure 12.2. CoA is also a substrate for direct pyrophosphatase action, at about 10% of the rate of action on dephospho-CoA. The pyrophosphatase seems to be a general nucleotide pyrophosphatase of plasma membrane rather than an enzyme specific for the degradation of CoA. 

Pantothenic acid is taken in as dietary CoA compounds and dCphosphopantetheine and hydrolyzed by pyrophosphatase and phosphatase in the intestinal lumen to dephospho-CoA, phosphopantetheine, and pantetheine. This is further hydrolyzed to pantethenic acid. The vitamin is primarily absorbed as pantothenic acid by a saturable process at low concentrations and by simple diffusion at higher ones. The saturable process is facilitated by a sodium-dependent multivitamin transporter, for which biotin and lipoate compete. After absorption, pantothenic acid enters the circulation and is taken up by cells in a manner similar to its intestinal adsorption. The synthesis of CoA from pantothenate is regulated by pantothenate kinase, which itself is subject to negative feedback from the products CoA and acyi-CoA. The steps involved were outlined above. Pantothenic acid is excreted in the urine after hydrolysis of CoA compounds by enzymes that cleave phosphate and the cys-teamine moieties. Only a small fraction of pantothenate is secreted into milk and even less into colostrum. 

The phosphopantetheine prosthetic group of ACP, fatty acid synthetase complexes, and presumably other enzyme systems, turn over rapidly, possibly as part of a cellular control mechanism. A specific phosphodiesterase cleaves holo-ACP to 4 -phosphopantetheine and the apoprotein ... 

Treatment of the enzyme with acyl phosphate in the complete absence of reduced cofactor has allowed the thiol enzyme derivative to be prepared and separated from its reaction mixture. This in turn has permitted considerable characterization of the enzyme thiol. No special cofactor is involved. The thiol of a cysteine residue from the main peptide chain of the enzyme provides the reactive centre. This enzyme demonstrates that the acyl transfer role of thioesters in biological systems is not restricted to phosphopantetheine and dihydrolipoate derivatives. The reactions of the... 

From the pH dependence of the reaction, the formation of a thiolate anion can be concluded (80, Figure 1). Both types of synthetases can be expected to have birrding sites for 4 -phosphopantetheine and, presumably, CoA. The possible transfer of acyl or aminoacyl residues to acyl cairier proteins (ACPs) has not been investigated. However, Heaton and Neuhaus (38) have uncovered a tmique mode of D-Ala attachment to tei-choic acids, consisting of a D-Ala adenylate-fcHming enzyme, a D-Ala carrier protein, and a respiective transferase. Both ACP from Eschencfiid colt and cre))tomyces erythreae also accepted the aminoacyl residue. 

Figure 20.1 Structure of pantothenic acid and bound form coenzyme A (CoA), phosphopantetheine and pantetheine.

Fig. 1.29 Structural comparison between acyl-CoA, ACP-phosphopantetheine and an A-acetyl-cysterunine (SNAC) thioester...

Acyl CoA s, 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... 

In conclusion, it is very likely that pantethine stimulated fatty acid oxidation through activation of fatty acyl CoA synthetase after conversion to phosphopantetheine and through stimulation of the mitochondrial membrane transport system of acyl CoA which is the key step of fatty acid oxidation [ 12 ]. Further studies are now in progress along this line. 

CoA and its precursors was isolated by descending paper chromatography, usually with n-butanol-acetic acid-water (5 2 3, v/v), which gave good separation between CoA/dephosphoCoA, 4-phosphopantetheine and pantothenic acid (c f. 2). ... 

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