Fatty acid metabolism acyl carrier proteins

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. 

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. 

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

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... 

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. 

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). 

We already mentioned that the enzymes involved in the P-oxidation of fatty acids are located in the mitochondria. The source of two-carbon fragments for the biosynthesis of both fatty acids and isoprenoids like cholesterol is acetyl CoA, which is generated by oxidative metabolism in the mitochondria. Acetyl CoA cannot escape from the mitochondria, but it can be exported to the cyosol as citrate, where it is reconverted to oxaloacete and acetyl CoA. Fatty acid (and cholesterol) biosynthesis takes place in the cyosol, and requires bicarbonate, which is incorporated into acetyl CoA to form malonyl CoA by acetyl CoA carboxylase. The biosynthesis of fatty acids, mostly the Cie palmitate (Chapter 4), requires one molecule of acetyl CoA and seven molecules of malonyl CoA. In animals, the seven enzymatic reactions which are required for fatty acid synthesis are present in a single multifunctional protein complex, known as fatty acid synthase. The synthase also contains an acyl-carrier protein... 

During fatty acid metabolism in humans, coenzyme A (CoA) is different from acyl carrier protein (ACP) in which one of the following ways ... 

Name the common component of acyl carrier protein (ACP) and CoA, give its functions, and describe the overall functions of ACP and CoA in fatty acid metabolism. 

Rehm BHA, Kruger N, Stembtichel A (1998) A new metabolic link between fatty acid de novo synthesis and polyhydroxyalkanoic acid synthesis the phaG gene from Pseudomonas putida KT2440 encodes a 3-hydroxyacyl-acyl carrier protein-coenzyme a transferase. J Biol Chem... 

Biochemical function in human metabolism. Activation of metabolites by coenzyme A while a thioester as a high-energy compound is generated. Examples acetyl CoA, succinyl-CoA, acyl-CoA-derivates. The acyl-carrier protein is a component of the fatty acid-synthetase complex. Both coenzymes transfer acyl groups. 

U.9 Phospholipid biosynthesis (general).- A few only of the very many papers published in this area that appear to have particular mechanistic importance can be described here. Stable carbon isotope ratios ( C/ C) at natural abundance levels were determined for each of the major fatty acid components of the phospholipids of E. coli. The results were consistent with a model of lipid metabolism in which fatty acids were released from the fatty acid synthase in free form, and required re-activation to the acyl-acyl carrier protein prior to esterification. A close coupling of fatty acid and phospholipid synthesis was implied. The characteristics of fatty acid transfer from acyl-acyl carrier protein to sn-glyoerol- -phosphate in E. coli have been inves-... 

Pantothenic acid is a constituent of coenzyme A, which is the important coenzyme in fatty acid oxidation, acetate metabolism, and cholesterol and steroid synthesis. It forms the prosthetic group of acyl carrier protein in fatty acid synthesis. Chemically,... 

J AcetyUCoA carboxylase. Incorporation of metabolically derived acetyl-CoA into fatty acid synthesis is believed generally to involve three major enzyme systems, namely acetyl-CoA carboxylase (EC 6.4.1.2), [acyl-carrier protein] (ACP) acetyltransferase (EC 2.3.1.38)... 

Fatty acid desaturases are responsible for catalysis of the O2- and NADH-dependent desaturation reactions, the insertion of a cis double bond in saturated fatty acids (Table 1) [144]. Such reactions are important in fatty acid metabolism and processes that facilitate the delivery of lipid precursors to prostaglandins and cell membranes [347]. Both soluble and membrane-bound desaturases exist, which exhibit different substrate specificities and reactivities [144,348]. The soluble stearoyl-acyl carrier protein desaturase from Ricinus communis (castor seeds) is the best characterized desaturase and catalyzes the insertion of a cis double bond between the C-9 and C-10 carbon atoms of stearoyl ACP to yield an important in... 

Activity of acyl carrier protein isoforms in reactions of plant fatty acid metabolism. Plant Physiol. 82 448-453. 

Guerra D.J., Ohlrogge J.B., and Frentzen M., 1986. Activity of acyl carrier protein isoforms in reactions of plant fatty acid metabolism. Plant Physiol. 82, 448-453. 

Acyl carrier protein (ACP) Is the best characterized protein In plant lipid metabolism. The stability and relative ease of purification of ACP have resulted In It being the first protein of plant fatty acid synthesis (FAS) to be purified to homogeneity (1), to have specific antiserum raised against It (2), and to have amino acid sequence data available (3-5). To date, ACP has been purified from spinach, avocado, castor bean, barley, rapeseed and soybean (6, and J. Ohlrogge, unpublished data.)... 

All forms of plant ACP that have been studied are common In their small size (9000 to 11,000 daltons) and In their acidic nature (pH 4.0 -4.2). Acyl carrier proteins have highly conserved structures based both on amino acid sequence homology and antibody cross-reactivity. In addition plant and bacterial acyl carrier proteins can be Interchanged In several reactions of fatty acid synthesis and metabolism (1,7). 

Acyl carrier protein (ACP) plays a central rOle In lipid metabolism, serving as both a component of plant fatty acid synthetase (1) and as a substrate/cofactor for complex lipid biosynthesis (2). The protein has been purified from a number of plant sources and Its amino acid sequence determined for the protein from both barley leaf (3) and spinach leaf (4) material. Both of these two previously mentioned sources of ACP have two detectable forms of the protein (5-6) whilst in seed material only one form has been detected (5). ACP has been shown, using immunological techniques, to be a developmentslly regulated protein In maturing soy bean seeds. The activity of the protein appearing just prior to lipid accumulation (7). Despite the Importance of this protein in lipid metabolism and the fact that seeds are a major site of lipid synthesis there Is no reported literature on the characterization of ACP from seed material. The present study was aimed at a detailed characterization of ACP from rape (Brassica napus ) seed ... 

Figure 2 A proposed model for the acyl carrier protein directed apportionment of oleic acid between the eucaryotlc and prokaryotic pathways of fatty acid metabolism.

The primary role of pantothenic acid is in acyl group activation for lipid metabolism, involving thiol acylation of CoA or of ACP, both of which contain 4-phosphopantotheine, the active group of which is /3-mercaptoethylamine. CoA is essential for oxidation of fatty acids, pyruvate and a-oxogutarate, for metabolism of sterols, and for acetylation of other molecules, so as to modulate their transport characteristics or functions. Acyl carrier protein, which is synthesized... 

For most of the metabolic reactions in which fatty acids take part, whether they be anabolic (synthetic) or catabolic (degradative), thermodynamic considerations dictate that the acids be activated . For these reactions thiol esters are generally utilized. The active form is usually the thiol ester of the fatty acid with the complex nucleotide, coenzyme A (CoA) or the small protein known as acyl carrier protein (ACP) (Figure 3.5). These molecules contain a thiol ester and, at the same time, render the acyl chains water soluble. 

Figure 3.7 Model of intermolecular fatty acid synthetase mechanism in the a2 2 protomer of yeast. A, acetyl transferase E, enoyl reductase D, dehydratase P, palmitoyl transferase M, malonyl transferase C, 5-ketoacyl synthase R. )5-ketoacyl reductase ACP, acyl carrier protein. Dotted lines and arrows delineate the route taken by intermediates when sequentially processed on different FAS domains. Numbers indicate the reaction sequence. Catalytically active dohnains, at a specific moment, are marked by bold lines. Shaded areas on E and P domains potentially interact by hydrophobic attraction in the presence of palmitate (b). On the protomer depicted in (a) fatty acyl chain elongation occurs in one half of the a2 2 protomer. In (b) chain termination is induced by hydrophobic interaction between E> bound palmitate and P. Subsequently, palmitate Is transferred to Its O-ester binding site on P. Inactivation of the left half of simultaneously activates its right half (b). Redrawn from Schweizer (1984) with permission of the author and Elsevier Science Publishers, BV. From Fatty Acid Metabolism and its Regulation (1984) (ed. S. Numa), p. 73, Figure 7.

The coenzyme form of pantothenic acid is coenzyme A and is represented as CoASH. The thiol group acts as a carrier of acyl group. It is an important coenzyme involved in fatty acid oxidation, pyruvate oxidation and is also biosynthesis of terpenes. The epsilon amino group of lysine in carboxylase enzymes combines with the carboxyl carrier protein (BCCP or biocytin) and serve as an intermediate carrier of C02. Acetyl CoA pyruvate and propionyl carboxylayse require the participation of BCCP. The coenzyme form of folic acid is tetrahydro folic acid. It is associated with one carbon metabolism. The oxidised and reduced forms of lipoic acid function as coenzyme in pyruvate and a-ketoglutarate dehydrogenase complexes. The 5-deoxy adenosyl and methyl cobalamins function as coenzyme forms of vitamin B12. Methyl cobalamin is involved in the conversion of homocysteine to methionine. 

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