Pantetheine, pantothenate

Pantothenic acid is an essential component of coenzyme A (CoA) (Fig. 2) and - as pantetheine - of fatty acid synthase. The HS-group of cysteamine is... 

Pantothenic acid has a central role in acyl group metabolism when acting as the pantetheine functional moiety of coenzyme A or acyl carrier protein (ACP) (Figure 45-18). The pantetheine moiety is formed after combination of pantothenate with cysteine, which provides... 

Acyl residues are usually activated by transfer to coenzyme A (2). In coenzyme A (see p. 12), pantetheine is linked to 3 -phos-pho-ADP by a phosphoric acid anhydride bond. Pantetheine consists of three components connected by amide bonds—pantoic acid, alanine, and cysteamine. The latter two components are biogenic amines formed by the decarboxylation of aspartate and cysteine, respectively. The compound formed from pantoic acid and p-alanine (pantothenic acid) has vitamin-like characteristics for humans (see p. 368). Reactions between the thiol group of the cysteamine residue and carboxylic acids give rise to thioesters, such as acetyl CoA. This reaction is strongly endergonic, and it is therefore coupled to exergonic processes. Thioesters represent the activated form of carboxylic adds, because acyl residues of this type have a high chemical potential and are easily transferred to other molecules. This property is often exploited in metabolism. 

An additional series of reactions,350 which are shown in Eq. 24-38, leads to pantoic acid, pantetheine, coenzyme A, and related cofactors.350a i The initial reactions of the sequence do not occur in the animal body, explaining our need for pantothenic acid as a vitamin. 

About 85% of dietary pantothenic acid is as CoA or phosphopantetheine. In the intestinal lumen, these undergo hydrolysis to phosphopantetheine, then pantetheine (see Figure 12.2). Intestinal mucosal cells have a high panteth-einase activity and rapidly hydrolyze pantetheine to yield free pantothenic acid. 

Red blood cells contain pantothenic acid, 4 -phosphopantothenic acid, and pantetheine. These seem to enter by diffusion, and their function is not known unsurprisingly, because they contain no mitochondria, erythrocytes do not contain CoA (Annous and Song, 1995). The permeability of erythrocytes to pantothenate is normally relatively low, but in red cells infected with malaria parasites, the permeability is increased considerably the vitamin is taken up and utilized by the parasites, which require CoA (Saliba et al., 1998). 

Alternatively, phosphopantetheine is dephosphorylated, again by a relatively unspecific phosphatase. The resultant pantetheine is cleaved by pante-theinase, a specific amidase, to pantothenic acid and cysteamine. The resultant cysteamine may be an important precursor of taurine (Section 14.5.1). Pan-tetheinase is found in both the liver and kidneys. The kidney isoenzyme acts on both pantetheine and (at a lower rate) on phosphopantetheine, whereas the liver enzyme acts only on pantetheine (Dupreetal., 1973 Wittweretal., 1983). 

Coenzyme A (abbreviated CoA or CoASH, 6) was discovered by Lipmann in the 1940s, and its structure was first reported in 1953 (2, 3). The structure of CoA consists of 3 -phosphoadenosine and pantetheine, linked by a pyrophosphate group (Fig. 1). The pantetheine moiety is derived from pantothenic acid 1, also known as vitamin B5. CoA and its... 

Coenzyme A, Pantetheine Porphyrins Pantothenate, ATP Succinyl-CoA, Glycine ... 

Figure 7 Biosynthesis of pantothenate. 54, aspartate 58, spermine 59, uracil 60, pantothenate 65, pantetheine 4-phosphate 66, coenzyme A.

The concentration of free pantothenic acid in the liver is about 15 xM that in the heart is about tenfold greater (Robishaw and Neely, 1985). The concentration of the cofactor form of the vitamin, coenzyme A, is higher in the mitochondrion than in the cytosol. In the Ever, cytosolic coenzyme A is about 0.06 mM, and mitochondrial coenzjmie A, about 2.6 mM. In the liver, about 70% of coenzyme A is mitochondrial, whereas in the heart about 95% is mitochondrial (Tahiliani and Neely, 1987). These values might be compared with that for carnitine, another molecule used in the handling of fatty acids. Please consult the Carnitine section in Chapter Four. About half of the coenzjrme A in liver occurs as the long-chain fatty acyl-coenzyme A derivative. The concentration of fatty acid s)mthase in the cytoplasm is quite low, about 0.01 pM. Hence, the concentration of the 4 -phospho-pantetheine cofactor is much lower than that of coenzyme A. The pantothenic acid boimd to this enzyme does not make a significant contribution to our dietary vitamin. 

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. 

Characterization of the activities of the horse and pig enzymes has shown that pantetheinase is specific for the pantothenate moiety of its substrate and will not react with CoA, 4 -phosphopantetheine, or /i-alanylcys-teamine. However, it accepts the modification of the cysteamine moiety and hydrolyzes a variety of pantetheine thioesters. The enzyme does not require any cofactors, although it is inhibited by pantetheine (pantetheine disulfide), oxidized glutathione, and thiol inhibitors (such as Hg ), suggesting the involvement of an active site cysteine in catalysis. The pig enzyme has a molecular weight of 72 kDa and exhibits a A n, of 20pmoll for pantetheine. All these studies have been performed on purified or partially purified native enzymes no pantetheinase enzyme has been cloned to date. 

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