Malonyl-coenzyme fatty acid metabolism

Many aroma compounds in fruits and plant materials are derived from lipid metabolism. Fatty acid biosynthesis and degradation and their connections with glycolysis, gluconeogenesis, TCA cycle, glyoxylate cycle and terpene metabolism have been described by Lynen (2) and Stumpf ( ). During fatty acid biosynthesis in the cytoplasm acetyl-CoA is transformed into malonyl-CoA. The de novo synthesis of palmitic acid by palmitoyl-ACP synthetase involves the sequential addition of C2-units by a series of reactions which have been well characterized. Palmitoyl-ACP is transformed into stearoyl-ACP and oleoyl-CoA in chloroplasts and plastides. During B-oxi-dation in mitochondria and microsomes the fatty acids are bound to CoASH. The B-oxidation pathway shows a similar reaction sequence compared to that of de novo synthesis. B-Oxidation and de novo synthesis possess differences in activation, coenzymes, enzymes and the intermediates (SM+)-3-hydroxyacyl-S-CoA (B-oxidation) and (R)-(-)-3-hydroxyacyl-ACP (de novo synthesis). The key enzyme for de novo synthesis (acetyl-CoA carboxylase) is inhibited by palmitoyl-S-CoA and plays an important role in fatty acid metabolism. 

Biotin is the coenzyme required by enzymes that catalyze carboxylation of a carbon adjacent to a carbonyl group. For example, pymvate carboxylase converts pyruvate—the end product of carbohydrate metabolism—to oxaloacetate, a citric acid cycle intermediate (Figure 25.2). Acetyl-CoA carboxylase converts acetyl-CoA into malonyl-CoA, one of the reactions in the anabolic pathway that converts acetyl-CoA into fatty acids (Section 19.21). Biotin-requiring enzymes use bicarbonate (HCOs ) for the source of the carboxyl group that becomes attached to the substrate. 

BCFAs make up the major proportion of fatty acids in the lipid extract from certain bacteria, such as bacilli [2]. Biosynthesis of BCFAs occurs with the branched-chain amino acids as primary precursors and malonyl-CoA (coenzyme A) as the chain extender (Figure 18.1). These BCFAs biosynthesized by bacteria and included in fermented food may contribute to the food s regulation of cell biology or metabolism [3-5]. A saturated BCFA, 13-methyltetradecanoic acid (13-MTD), was purified from a fermented soy product as an antitumor compound [6]. A BCFA was also found to induce apoptotic cell death in human cancer cells [6]. In this review, we describe the biological activities of BCFAs, with special reference to 13-MTD. 

Acetyl-CoA has already been mentioned as a key precursor for many industrially relevant compounds. For example, it is a direct precursor for the mevalonate pathway to obtain isoprenoids. It is also a key precursor for malonyl-CoA, yielding the production of fatty acids (biodiesel) and polyketides [19]. The challenge of engineering the acetyl-CoA availability in yeast lies in its compartmentalization. While acetyl-CoA is readily available in the mitochondrium, the cytosolic pool is low. The cytosolic pool of acetyl-CoA is fed from acetate, which is activated by a bond to coenzyme A at the expense of 1 ATP. It becomes therefore obvious that any metabolic pathway using cytosolic acetyl-CoA aiming at mass production is energetically detrimental and inefficient - if not recombinantly redesigned [20]. 

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. 

Mammals cannot synthesize biotin and depend on a regular dietary supply of this water-soluble vitamin (Zempleni et al., 2009). The Adequate Intake for biotin in adults is 30 pg/d (National Research Council, 1998). The classical role of biotin in mammalian intermediary metabolism is to serve as a covalently bound coenzyme in five carboxylases (Zanpleni et al., 2D09). Both the cytoplasmic acetyl-CoA carboxylase 1 (ACCl) and the mitochondrial acetyl-CoA carboxylase 2 (ACC2) catalyze the binding of bicarbonate to acetyl-CoA to generate malonyl-CoA, but the two isoforms have distinct functions in intermediary metabolism (Kim et al., 1997). ACCl produces malonyl-CoA for the synthesis of fatty acid synthesis in the cytoplasm ACC2... 

Coenzyme A is the active component of transacylases transporting the residues of carboxylic acids. The most common substance is acetyl-CoA, which carries acet)4 groups. In acetyl CoA, acetic acid is bound as a thioester to the thiol group of cysteamine. Other acyl coenzymes A include malonyl-CoA, succinyl-CoA, and other coenzymes that play a role in the metabolism of proteins, fats and sugars. ACP plays a fundamental role in biosynthesis of fatty acids and polyketides. 

Acetyl-coenzyme A carboxylase (ACCase) carboxylates acetyl-coenzyme A to malonyl-coenzyme A which serves as an intermediate metabolite for several diverse pathways in plant metabolism including synthesis of fatty acids, flavonoids, pigments and waxes. Plants likely have more than one ACCase isoform -- one in the plastid for fatty acid synthesis and at least one non-plastidic form to provide malonyl-coenzyme A for the other pathways. In maize, the plastid-localized ACCase required for fatty acid synthesis has been identified as a target site for several herbicide families [1] and herbicide-tolerant maize mutants have been selected [2,3]. 

As a result of the reduced activity of the mutase in vitamin B12 deficiency, there is an accumulation of methyhnalonyl CoA, some of which is hydrolyzed to yield methylmalonic acid, which is excreted in the urine. As discussed in Section 10.10.3, this can be exploited as a means of assessing vitamin B12 nutritional status. There may also be some general metabolic acidosis, which has been attributed to depletion of CoA because of the accumulation of methyl-malonyl CoA. However, vitamin B12 deficiency seems to result in increased synthesis of CoA to maintain normal pools of metabolically useable coenzyme. Unlike coenzyme A and acetyl CoA, neither methylmalonyl CoA nor propionyl CoA (which also accumulates in vitamin B12 deficiency) inhibits pantothenate kinase (Section 12.2.1). Thus, as CoA is sequestered in these metabolic intermediates, there is relief of feedback inhibition of its de novo synthesis. At the same time, CoA may be spared by the formation of short-chain fatty acyl carnitine derivatives (Section 14.1.1), which are excreted in increased amounts in vitamin B12 deficiency. In vitamin Bi2-deficient rats, the urinary excretion of acyl carnitine increases from 10 to 11 nmol per day to 120nmolper day (Brass etal., 1990). 

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