Phosphopantetheine, coenzyme

Phosphopantetheine coenzymes are the biochemically active forms of the vitamin pantothenic acid. In figure 10.11, 4 -phosphopantetheine is shown as covalently linked to an adenylyl group in coenzyme A or it can also be linked to a protein such as a serine hydroxyl group in acyl carrier protein (ACP). It is also found bonded to proteins that catalyze the activation and polymerization of amino acids to polypeptide antibiotics. Coenzyme A was discovered, purified, and structurally characterized by Fritz Lipmann and colleagues in work for which Lipmann was awarded the Nobel Prize in 1953. 

Phosphine(s), chirality of, 314 Phosphite, DNA synthesis and, 1115 oxidation of, 1116 Phospholipid, 1066-1067 classification of, 1066 Phosphopantetheine, coenzyme A from. 817 structure of, 1127 Phosphoramidite, DNA synthesis and, 1115 Phosphoranc, 720 Phosphoric acid, pKa of, 51 Phosphoric acid anhydride, 1127 Phosphorus, hybridization of, 20 Phosphorus oxychloride, alcohol dehydration with. 620-622 Phosphorus tribromide, reaction with alcohols. 344. 618 Photochemical reaction, 1181 Photolithography, 505-506 resists for, 505-506 Photon, 419 energy- of. 420 Photosynthesis, 973-974 Phthalic acid, structure of, 753 Phthalimide, Gabriel amine synthesis and, 929... 

Reactions Requiring Acyl Activation Frequently Use Phosphopantetheine Coenzymes a-Lipoic Acid Is the Coenzyme of Choice for... 

Reactions Requiring Acyl Activation Frequently Use Phosphopantetheine Coenzymes... 

Phosphopantetheine coenzymes form thioester linkages with acyl groups, which they activate for group transfer reactions. 

Pantothenic acid, sometimes called vitamin B3, is a vitamin that makes up one part of a complex coenzyme called coenzyme A (CoA) (Figure 18.23). Pantothenic acid is also a constituent of acyl carrier proteins. Coenzyme A consists of 3, 5 -adenosine bisphosphate joined to 4-phosphopantetheine in a phosphoric anhydride linkage. Phosphopantetheine in turn consists of three parts /3-mercaptoethylamine linked to /3-alanine, which makes an amide bond with a branched-chain dihydroxy acid. As was the case for the nicotinamide and flavin coenzymes, the adenine nucleotide moiety of CoA acts as a recognition site, increasing the affinity and specificity of CoA binding to its enzymes. 

FIGURE 25.6 Fatty acids are conjugated both to coenzyme A and to acyl carrier protein through the sulfliydryl of phosphopantetheine prosthetic groups. 

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... 

Earlier in this chapter, it was mentioned that many of the nonprotein amino acids are components of nonribosomal peptides. During such a biosynthesis, the peptide is attached to a carrier protein through a thioester bond, until chain termination occurs and the final product is released. The carrier protein is posttranslationally modified by the attachment of a phosphopantetheinyl group from coenzyme A. This step gives rise to the active carrier protein with a phosphopantetheine arm upon which amino acids are added to during NRPS. As an example, loading of isoleucine onto the carrier protein is depicted below (Scheme 5). Further details about nonribosomal peptide syntheses and enzymatic reactions can be found in Chapter 5.19. 

Some enzymes are nonfunctional until posttranslationally modified. Examples of these enzymes include the acyl- and carboxyltransferases. While lipoate and phosphopantetheine are necessary for acyl transfer chemistry, tethered biotin is used in carboxyl transfer chemistry. Biotin and lipoate tethering occur under a similar mechanism the natural small molecule is activated with ATP to form biotinyl-AMP or lipoyl-AMP (Scheme 20). A lysine from the target protein then attacks the activated acid and transfers the group to the protein. The phosphopantetheine moiety is transferred using its own enzyme, the phosphopantetheinyltrans-ferase (PPTase). The PPTase uses a nucleophilic hydroxy-containing amino acid, serine, to attach the phosphopantetheinyl (Ppant) arm found in coenzyme A to convert the apo (inactive) carrier protein to its holo (active) form. The reaction is Mg -dependent. 

The section of the molecule discussed so far represents a functional unit. In the cell, it is produced from pantothenate. The molecule also occurs in a protein-bound form as 4 -phosphopantetheine in the enzyme fatty acid synthase (see p. 168). In coenzyme A, however, it is bound to 3, 5 -adenosine diphosphate. 

Pantothenic acid (vitamin B5) is both present in many nutrientcients and it is also produced by intestinal bacteria. Deficiency is therefore thought to be unlikely. Its active form, 4-phosphopantetheine, is an element of both coenzyme-A and acyl-carrier protein and thus participates in fatty acid synthesis and in the posttranslational modification of proteins. Acetylcoenzyme-A is important for the synthesis of the neurotransmitter acetylcholine. 

FIGURE 21-4 Acyl carrier protein (ACP). The prosthetic group is 4 -phosphopantetheine, which is covalently attached to the hydroxyl group of a Ser residue in ACP. Phosphopantetheine contains the B vitamin pantothenic acid, also found in the coenzyme A molecule. Its —SH group is the site of entry of malonyl groups during fatty acid synthesis. 

Phosphopantetheine-containing active carriers Acyl carrier protein domain, coenzyme A Coenzyme A... 

Figure 12.2. Biosynthesis of coenzyme A. Pantothenate kinase, EC 2.7.1.33 phosphopantothenylcysteine synthase, EC 6.3.2.5 phosphopantothenylcysteine decarboxylase, EC 4.1.1.36 phosphopantetheine adenyltransferase, EC 2.7.7.S and dephospho-CoA kinase, EC 2.7.1.24. CoASH, free coenzyme A.

Organisms of all biological kingdoms convert 64 into the cys-teamine derivative phosphopantetheine (65) using L-cysteine as substrate. 65 is converted to coenzyme A (66) by attachment of an adenosine moiety via a pyrophosphate linker and phosphorylation of the ribose moiety. Phosphopantetheine can be attached covalently to serine residues of acyl carrier proteins that are parts of fatty acid synthases and polyketide synthases. 

The most important functions of pantothenic acid are its incorporation in coenzyme A and acyl carrier protein (AGP). Both CoA and AGP/4-phosphopantetheine function metabolically as carriers of acyl groups. Coenzyme A forms high-eneigy thioester bonds with carboxylic acids. The most important coenzyme is acetyl CoA. Acetic acid is produced during the metabolism of fatty acids, amino acids, or carbohydrates. The active acetate group of acetyl CoA can enter the Krebs cycle and is used in the synthesis of fatty acids or cholesterol. AGP is a component of the fatty acid synthase multienzyme complex. This complex catalyzes several reactions of fatty acid synthesis (condensation and reduction). The nature of the fatty acid synthase complex varies considerably among different species (91). 

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