Pantothenic acid acyl carrier protein

Amide bonds are found in many proteins. One is the acyl carrier protein of Escherichia coli (see 90), which contains the peptide backbone, and a 4 -phosphopantetheine unit (in violet in the illustration) is attached to a serine residue. Note the amine bonds in the pantothenic acid unit and also the 0-P=0 unit, which is a phosphate ester (an ester of phosphoric acid). An acyl carrier protein is involved in fatty acid synthesis, linking acetyl and malonyl groups from acetyl coenzyme A and malonyl coenzyme A to form P-keto acid acyl carrier protein (abbreviated as ACP). The widely utilized acetyl CoA is an ester (91) attached to coenzyme A. Acetyl CoA is a key intermediate in aerobic intermediary metabolism of carbohydrates, lipids, and some amino acids. 

Biosynthesis of coen2yme A (CoA) ia mammalian cells incorporates pantothenic acid. Coen2yme A, an acyl group carrier, is a cofactor for various en2ymatic reactions and serves as either a hydrogen donor or an acceptor. Pantothenic acid is also a stmctural component of acyl carrier protein (AGP). AGP is an essential component of the fatty acid synthetase complex, and is therefore requited for fatty acid synthesis. Free pantothenic acid is isolated from hver, and is a pale yeUow, viscous, and hygroscopic oil. 

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. 

The 4-phosphopantetheine group of CoA is also utilized (for essentially the same purposes) in acyl carrier proteins (ACPs) involved in fatty acid biosynthesis (see Chapter 25). In acyl carrier proteins, the 4-phosphopantetheine is covalently linked to a serine hydroxyl group. Pantothenic acid is an essential factor for the metabolism of fat, protein, and carbohydrates in the tricarboxylic acid cycle and other pathways. In view of its universal importance in metabolism, it is surprising that pantothenic acid deficiencies are not a more serious problem in humans, but this vitamin is abundant in almost all foods, so that deficiencies are rarely observed. 

In bacteria and plants, the individual enzymes of the fatty acid synthase system are separate, and the acyl radicals are found in combination with a protein called the acyl carrier protein (ACP). However, in yeast, mammals, and birds, the synthase system is a multienzyme polypeptide complex that incorporates ACP, which takes over the role of CoA. It contains the vitamin pantothenic acid in the form of 4 -phosphopan-tetheine (Figure 45-18). The use of one multienzyme functional unit has the advantages of achieving the effect of compartmentalization of the process within the cell without the erection of permeability barriers, and synthesis of all enzymes in the complex is coordinated since it is encoded by a single gene. 

Pantothenic acid Functional part of CoA and acyl carrier protein fatty acid synthesis and metabolism ... 

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... 

Pantothenic acid is present in coenzyme A and acyl carrier protein, which act as carriers for acyl groups in metabolic reactions. Pyridoxine, as pyridoxal phosphate, is the coenzyme for several enzymes of amino acid metabolism, including the aminotransferases, and of glycogen phosphorylase. Biotin is the coenzyme for several carboxylase enzymes. 

Fatty add synthase is a large multienzyme complex in the cytoplasm that is rapidly induced in the liver after a meal by high carbohydrate and the concomitant rise in insulin levels. It contains an acyl carrier protein (AGP) that requires the vitamin pantothenic add. Althoi malonyl CoA is the substrate used by fetty acid synthase, only the carbons from the acetyl CoA portion are actually incorporated into the fatty acid produced. Therefore, the fetty add is derived entirely from acetyl CoA. 

Pantothenic acid is an acid amide consisting of p-alanine and 2,4-dihydroxy-3,3 -di-methylbutyrate (pantoic acid). It is a precursor of coenzyme A, which is required for activation of acyl residues in the lipid metabolism (see pp. 12,106). Acyl carrier protein (ACP see p.l68) also contains pantothenic acid as part of its prosthetic group. Due to the widespread availability of pantothenic acid in food (Greek pantothen = from everywhere ), deficiency diseases are rare. 

Pantothenic acid occurs in foods both in the free form and bonded to coenzyme (CoA) or acyl carrier protein (ACP) therefore hydrolysis is needed to extract it totally. Since it is degraded by acid and alkaline hydrolysis, only an enzymatic digestion can be applied. Enzyme hydrolysis with papain, diastase, clarase, takadiastase, intestinal phosphatase, pigeon liver pantetheinase, or combination of them has been used. 

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. 

Pantothenic acid (8.48), a hydroxyamide, occurs mainly in liver, yeast, vegetables, and milk, but also in just about every other food source, as its name implies [pantos (Greek) = everywhere]. It is part of coenzyme A, the acyl-transporting enzyme of the Krebs cycle and lipid syntheses, as well as a constituent of the acyl carrier protein in the fatty-acid synthase enzyme complex. 

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. 

The remaining series of reactions of fatty acid synthesis in eukary-l otes is catalyzed by the multifunctional, dimeric enzyme, fatty acid synthase. Each fatty acid synthase monomer is a multicatalytic polypeptide with seven different enzymic activities plus a domain that covalently binds a molecule of 4 -phosphopantetheine. [Note 4-Phosphopantetheine, a derivative of the vitamin pantothenic add (see p. 379), carries acetyl and acyl units on its terminal thiol (-SH)j group during fatty acid synthesis. It also is a component of 00-enzyme A.] In prokaryotes, fatty acid synthase is a multienzyme complex, and the 4 -phosphopantetheine domain is a separate protein, referred to as the acyl carrier protein (ACP). ACP is used below to refer to the phosphopantetheine-binding domain of the eukaryotic fatty acid synthase molecule. The reaction numbers in1 brackets below refer to Figure 16.9. [Note The enzyme activities listed are actually separate catalytic domains present in each mulf-1 catalytic fatty acid synthase monomer.]... 

Endogenous pantothenic acid occurs in food primarily in the bound form as a component of coenzyme A (CoA or CoASH), acyl-coenzyme A, and acyl carrier protein (ACP) (185,186). These are the principal vitamers in foods free pantothenic acid (Fig. 9) is much less common. Only the D( + ) or (R) enantiomer of pantothenic acid occurs naturally. 

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. 

Panthenol is absorbed via passive diffusion after topical or oral application and then enzymatically oxidized to pantothenic acid. This is a component of coenzyme A and acyl carrier protein, and as such of great importance in fatty acid, carbohydrate, and amino acid metabolism. Deficiency leads to uncharacteristic symptoms such as headaches, apathy, gastrointestinal disturbances, palpitations, and paraesthesia typically in the feet, also known as burning feet syndrome. Wound healing is impaired. The recommended daily allowance is 5 to 7 mg.112... 

Fatty acid synthesis starts with acetyl-CoA, and the chain grows from the tail end so that carbon 1 and the alpha-carbon of the complete fatty acid are added last. The first reaction is the transfer of the acetyl group to a pantothenate group of acyl carrier protein (ACP), a region of the large mammalian FAS protein. (The acyl carrier protein is a small, independent peptide in bacterial FAS, hence the name.) The pantothenate group of ACP is the same as is found on Coenzyme A, so the transfer requires no energy input ... 

Pantothenic acid has a central role in energy-yielding metabolism as the functional moiety of coenzyme A (CoA), in the biosynthesis of fatty acids as the prosthetic group of acyl carrier protein, and through its role in CoA in the mitochondrial elongation of fatty acids the biosynthesis of steroids, porphyrins, and acetylcholine and other acyl transfer reactions, including postsynthetic acylation of proteins. Perhaps 4% of all known enzymes utilize CoA derivatives. CoA is also bound by disulfide links to protein cysteine residues in sporulating bacteria, where it may be involved with heat resistance of the spores, and in mitochondrial proteins, where it seems to be involved in the assembly of active cytochrome c oxidase and ATP synthetase complexes. 

Phosphopantetheine, arising from either the catabolism of CoA or the inactivation of holo - acyl carrier protein (ACP), can be reutilized for CoA synthesis. Phosphopantetheine is a potent inhibitor of pantothenic acid kinase, the first step of de novo CoA synthesis. 

Pantothenic acid is part of the CoA molecule (for instance, as acetyl CoA, malonyl CoA, and succinyl CoA), and part of the acyl carrier protein of fatty acid biosynthesis. 

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). 

Pantothenic acid is required for synthesis of coenzyme A, CoA and is a component of the acyl carrier protein (ACP) domain of fatty acid synthase. 

Pantothenic acid is of ubiquitous occurrence in nature, where it is synthesized by most microorganisms and plants fi-om pantoic acid (D-2,4-dihydroxy-3,3-dimethylbutyric acid) derived from L-vafine, and p-alanine derived from L-aspartate. Addition of cysteamine at the C-terminal end and phosphorylation at C4 of pantoic acid forms 4 -phosphopantetheine, which serves as a covalently attached prosthetic group of acyl carrier proteins, and, when attached... 

Acyl group carriers. The activated intermediates of fatty acid biosynthesis are bound to a carrier molecule called the acyl carrier protein (ACP) (Figure 23.12). In p-oxidation the acyl group carrier was coenzyme A. However, there are important similarities between these two carriers. Both contain the phosphopantetheine group, which is made from the vitamin pantothenic acid. In both cases the fatty acyl group is bound by a thioester bond to the phosphopantetheine group. 

Fig. 33.12. Phosphopantetheinyl residue of the fatty acid synthase complex. The portion derived from the vitamin, pantothenic acid, is indicated. Phosphopantetheine is covalently linked to a serine residue of the acyl carrier protein (ACP) segment of the enzyme. The sulfhydryl group reacts with malonyl CoA to form a thioester.

CoA plays an important role in various metabolic reactions. This compound is used widely in biochemistry, and its usefulness in medicine and in analytical fields has been discussed. The recent discovery of an acyl carrier protein containing an intermediate of CoA biosynthesis, P-pantetheine, as a prosthetic group, has emphasized the significance of CoA and its derivatives in biochemistry. The biosynthesis of this coenz3mie from pantothenic acid, cysteine and ATP requires five sequential enz3miatic steps as follows (3)5... 

The activating sulphiu attachment is not to CoA but to a much larger object, a small protein, called the acyl carrier protein (ACP). In both cases, CoA and ACP, the sulphur-containing bit is derived from dietary pantothenic acid (a B-vitamin). 

Nomenclature. The term pantothenic acid is used for the free acid, i.e., pantothenic acid itself as well as for the physiologically active forms coenzyme A and acyl-carrier protein. 

Coenzyme form(s). (1) Coenzyme A, composed of cysteamine, pantothenic acid, phosphate, and adenosine-3, 5 -diphosphate (2) acyl-carrier protein. 

Niacin (nicotinic acid) (11.108a) or nicotinamide (11.108b) form part of NAD+ (coenzyme-I) and NADP (coenzyme-II) (11.23). Pantothenic acid (11.108c) forms part of Coenzyme A (CoA-SH) (11.20) and of acyl carrier protein (ACP) (Figure 11.16). 

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