Fatty acids, biosynthesis metabolism

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. 

Coenzyme A is used as the alcohol part of thioesters, which are more reactive than oxygen esters (see Section 7.9.3) and are thus exploited in biochemistry in a wide range of reactions, e.g. fatty acid biosynthesis and metabolism (see Section 15.5). 

Two of the three attractant pheromones identified to date are very close structurally to those used in primary metabolism. The biosynthesis of the estolide 5 probably starts from 3-hydroxybutyric acid (4), an intermediate in fatty acid biosynthesis (Fig. 4.3). Condensation of two units furnishes the pheromone 5. The formation of cupilure (3 Fig. 4.2) can be easily explained by two methylations from ubiquitous citric acid. Both compounds are unlike any known insect pheromones, whereas the third known attractant pheromone (ketone 1 Fig. 4.1), bears some resemblance to some insect pheromones. A proper comparison of the differences and similarities between insect and arachnid pheromones will require the identification of representative compounds from most of the families of both groups of organisms. 

The NADPH level is clearly important for phase 1 reactions, yet many biochemical processes, such as fatty acid biosynthesis, use this coenzyme. It is derived from either the pentose phosphate shunt or isocitrate dehydrogenase. Consequently, the overall metabolic... 

A natural question is "Why has this complex pathway evolved to do something that could have been done much more directly " One possibility is that the presence of too much malonyl-CoA, the product of the P oxidation pathway of propionate metabolism (Fig. 17-3, pathways a and c), would interfere with lipid metabolism. Malonyl-CoA is formed in the cytosol during fatty acid biosynthesis and retards mitochondrial P oxidation by inhibiting carnitine palmitoyltransferase i.46 70a 75 However, a relationship to mitochondrial propionate catabolism is not clear. 

The fatty acid biosynthesis pathway communicates with at least three other metabolic pathways either by sharing common intermediates or by regulatory mechanisms. Fill in the table below. 

Many of the unusual compounds that indicate the exciting chemistry to be discovered in marine natural products are polyketides. Polyketides are a family of structurally complex natural products that include a number of important pharmaceuticals. They are produced primarily by microorganisms through a specialized metabolism that is a variation of fatty acid biosynthesis [430]. Polyketides fall into two structural classes aromatic and complex. Polyketides are formed by enzyme complexes... 

Ethanoic acid is activated for biosynthesis by combination with the thiol, coenzyme A (CoASH, Figure 18-7) to give the thioester, ethanoyl (acetyl) coenzyme A (CH3COSC0A). You may recall that the metabolic degradation of fats also involves this coenzyme (Section 18-8F) and it is tempting to assume that fatty acid biosynthesis is simply the reverse of fatty acid metabolism to CH3COSCoA. However, this is not quite the case. In fact, it is a general observation in biochemistry that primary metabolites are synthesized by different routes from those by which they are metabolized (for example, compare the pathways of carbon in photosynthesis and metabolism of carbohydrates, Sections 20-9,10). 

Eight enzyme-catalyzed reactions are involved in the conversion of acetyl-CoA into fatty acids. The first reaction is catalyzed by acetyl-CoA carboxylase and requires ATP. This is the reaction that supplies the energy that drives the biosynthesis of fatty acids. The properties of acetyl-CoA carboxylase are similar to those of pyruvate carboxylase, which is important in the gluconeogenesis pathway (see chapter 12). Both enzymes contain the coenzyme biotin covalently linked to a lysine residue of the protein via its e-amino group. In the last section of this chapter we show that the activity of acetyl-CoA carboxylase plays an important role in the control of fatty acid biosynthesis in animals. Regulation of the first enzyme in a biosynthetic pathway is a strategy widely used in metabolism. 

What are the metabolic sources of NADPH used in fatty acid biosynthesis How many moles of NADPH are required for the synthesis of 1 mole of palmitic acid from acetyl-CoA ... 

In chapter 18, Metabolism of Fatty Acids, we discuss the synthesis and breakdown of fatty acids. The chapter starts with a discussion of fatty acid breakdown. A second section covers the pathway for fatty acid biosynthesis. Finally, we consider the regulatory mechanisms that determine the conditions under which each of these processes occurs. As in the case of glucose metabolism, it is convenient to discuss the synthesis and breakdown in the same chapter so that the closely related topic of regulation can be considered alongside. 

The formation of the poly-P-keto chain could be envisaged as a series of Claisen reactions, the reverse of which are involved in the 3-oxidation sequence for the metabolism of fatty acids (see page 18). Thus, two molecules of acetyl-CoA could participate in a Claisen condensation giving acetoacetyl-CoA, and this reaction could be repeated to generate a poly-P-keto ester of appropriate chain length (Figure 3.1). However, a study of the enzymes involved in fatty acid biosynthesis showed this simple rationalization could not be correct, and a more complex series of... 

These results confirmed that branched-chain amino acid catabolism via the BCDH reaction provides the fatty acid precursors for natural avermectin biosynthesis in S. avermitilis. In contrast, B. subtilis appears to possess two mechanisms for branched-chain precursor supply. The dual substrate pyruvate/branched-chain a-keto acid dehydrogenase (aceA) and an a-keto acid dehydrogenase (bfmB), which also has some ability to metabolize pyruvate, appears to be primarily involved in supplying the branched-chain initiators of long, branched-chain fatty acid biosynthesis [32,42], Two mutations are therefore required to generate the bkd phenotype in B. subtilis [31,42],... 

Mutations in desatl affect HC, resulting in a very large decrease in 7-HC in males, and in 7- and 7,11-HC in females, with a parallel increase in saturated HC synthesis (Labeur el al., 2002 Ueyama el al., 2005 Marcillac et al., 2005a,b). Lipid metabolism is impaired too, with both quantitatively and qualitatively altered fatty acid biosynthesis the overall quantity of fatty acids was shown to be reduced by half and that of vaccenic acid, the common precursor to 7-HC in both sexes, reduced by a factor of six in a desatl mutant (Ueyama et al., 2005). 

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. 

An additional problem is that polyketide formation requires acetyl-CoA, malonyl-CoA, and NADPH generated by primary metabolic pathways. These precursors and the cofactor are also used for fatty acid biosynthesis. An inverse relationship between the synthesis of fatty acids and polyketide compounds has been found in the mevinolin (lovastatin)-producing species ot Aspergillus (Dutton, 1988 Greenspan and Yudkovitz, 1985). Thus, any regulatory factor that substantially alters the rate or extent of formation of these precursors and cofactor may affect polyketide formation. 

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