Acyl-carrier protein phosphopantetheine group

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. 

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

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. 

FIGURE 21-5 Sequence of events during synthesis of a fatty acid. The fatty acid synthase complex is shown schematically. Each segment of the disk represents one of the six enzymatic activities of the complex. At the center is acyl carrier protein (ACP), with its phosphopantetheine arm ending in an —SH. The enzyme shown in blue is the one that will act in the next step. As in Figure 21-3, the initial acetyl group is shaded yellow, C-1 and C-2 of malonate are shaded pink, and the carbon released as C02 is shaded green. Steps (T) to (7) are described in the text. 

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.]... 

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. 

Fatty acid synthesis takes place in eight steps. All except the first step take place on a multienzyme complex. The intermediates on this complex are carried by attachment of the acid group in thioester linkage to phosphopantetheine of the acyl carrier protein (ACP). The multienzyme complex greatly increases the efficiency of fatty acid synthesis, because for each step in the pathway the next enzyme is always near at hand, and the dilution of intermediates is minimized. 

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 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... 

Phosphopantetheine group of CoA FIGURE 5.16 The phosphopantetheine group in acyl-carrier protein (ACP) and in CoA. 

The answer is c. (Murray, pp 627-661. Scriver, pp 3897-3964. Sack, pp 121—138. Wilson, pp 287-320.1 The almost universal carrier of acyl groups is coenzyme A (CoA). However, acyl carrier protein (ACP) also functions as a carrier ol acyl groups. In fatty acid synthesis, ACP carries the acyl intermediates. The reactive prosthetic group of both ACP and CoA is a phosphopantetheine sulfhiydryl. In ACP, the phosphopantetheine group is attached to the 77-residue polypeptide chain via a serine hydroxyl. In CoA, the phosphopantetheine is linked to the 5 -phosphate of adenosine that is phosphorylated in its 3 -hydroxyl. 

Comparison of the Phosphopantetheine Group in Acyl Carrier Protein (ACP) and in Coenzyme A (CoASH). 

The structure of the phosphopantetheine group, the reactive group common to coenzyme A and acyl carrier protein, is highlighted in yellow. 

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.

Synthesis of long-chain fatty acids from acetyl-CoA and malonyl-CoA involves a number of sequential reactions (Fig. 11.1). Acyl groups are attached to the 4 -phosphopantetheine prosthetic group of acyl carrier protein (ACP) during modification by fatty acid synthetase. 

Acyl carrier protein, ACP a small, acidic, heat-stable globular protein which is part of the fatty acid synthesizing complex in . coli and other bacteria, yeast and plants. It carries the fatty acid chain during biosynthesis of the latter. The ACP from E. coii contains 77 amino acids (M, 8,847), and the primary structure is known. Sulfiir-containing amino adds are absent, but a molecule of phosphopantetheine (which possesses -SH) is linked to the protein via a phosphate ester to the hydroxyl of serine 36. All ac l residues formed during fatty acid biosynthesis are bound as thioesters to the SH of this prosthetic group. The M, of isolated ACP lie between 8,600 (Clostridium butyrkum) and 16,000 (yeast). 

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. 

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