Fatty acid biosynthesis strategy

See also Acetyl-CoA, Fats, Albumin, Fatty Acid Activation, Oxidation of Saturated Fatty Acids, Oxidation of Unsaturated Fatty Acids, Fatty Acid Biosynthesis Strategy, Palmitate Synthesis from Acetyl-CoA, Fatty Acid Desaturation, Essential Fatty Acids, Control of Fatty Acid Synthesis, Molecular Structures and Properties of Lipids (from Chapter 10)... 

See also Palmitate Biosynthesis from Acetyl-CoA, Fatty Acid Biosynthesis Strategy, Synthesis of Long Chain Fatty Acids, Figure 18.29, Figure 18.30, Fatty Acids... 

See also Fatty Acid Biosynthesis Strategy, Figure 18.23, Figure 18.24, Fatty Acid Synthase... 

See also Polyketides, Erythromycin, Oxytetracycline, Fatty Acid Biosynthesis Strategy... 

Not only eukaryotic cells but also bacteria have successfully been targeted by PNA anhsense strategies. Thus it has been shown that PNA complementary to ribosomal RNA or mRNA encoding an essential fatty acid biosynthesis protein, effectively kills E. coli. Furthermore, it has been shown that PNA directed to the start codon of the y -lactamase gene re-sensitized otherwise resistant E. coli to the antibiohc ampiciUin [64—66]. Conjugating a simple transporter peptide to the PNA increased the potency significantly, and an even more potent antibacterial PNA... 

The strategy evolved to generate the diversity of fatty acids and not the detailed biochemical mechanisms involved in fatty acid biosynthesis (why organisms make such a diversity of fatty acids is discussed in Chapter 9) is the important point to grasp. It is... 

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. 

Because they often function as virulence factors, the enzymes involved in siderophore biosynthesis are potential targets for developing antimicrobial strategies. The mechanisms of siderophore biosynthesis follow the same fundamental biosynthetic logic involving similar protein machinery, which we describe in greater detail in Chapter 5 for fatty acid biosynthesis. It is also used in the microbial biosynthesis of many important natural products polyketides and peptides (including many antibiotics). Essentially, as is illustrated in Fig. 4.20, for enterobactin, it involves... 

Fatty acid biosynthesis is similar in all known prokaryotes and eukaryotes. In eukaryotes, the biosynthesis of a fatty acid such as palmitate (Cl6) occurs in the cytoplasm. The basic strategy includes the following three possible steps ... 

The pathway for the synthesis of dipalmitoyl-phos-phatidylcholine is illustrated in figure 19.5. The starting species of phosphatidylcholine is made by the CDP-choline pathway (see fig. 19.4). The fatty acid at the sn-2 position, which is usually unsaturated, is hydrolyzed by phospholi-pase A2, and the lysophosphatidylcholine is reacylated with palmitoyl-CoA. This modification permits alteration of the properties of the phospholipid without resynthesis of the entire molecule, a strategy called remodeling. Deacylation-reacylation of phosphatidylcholine occurs in other tissues and provides an important route for alteration of the fatty acid substituents at both the sn-1 and sn-2 positions. For example, fatty acids at the sn-2 position can be replaced by arachidonic acid, which is stored there until needed for eicosanoid biosynthesis, as we discuss later in this chapter. 

The development of these chronic. Western-type diseases is associated with an excessive formation and function of eicosanoids derived from n-6 fatty acids. As balance can be restored to eicosanoid biosynthesis by dietary n-3 fatty acids, an effective strategy to diminish cardio-cerebrovascular mortality (in addition to several other serious disorders) may be to decrease the intake of n-6 fatty acids and replace them with n-3 fatty acids (116). Such a strategy is supported by studies that show an increased incidence of cardiovascular diseases, specifically ischemic heart disease, in Japanese whose diet has increasingly become more Westernized (113, 117). 

A similar strategy has been developed in the avermectin system, using an S. avermi-tilis strain that lacks a branched-chain a-keto acid dehydrogenase (BCDH) activity. This dehydrogenase activity is required to produce the acyl-CoAs that are required for avermectin biosynthesis, and thus the BCDH mutant is unable to produce avermectin without the addition of exogenous fatty acids to the fermentation media. The addition of isobutyric acid or isovaleric acid allows the production of the natural avermectins, while the addition of non-natural carboxyhc acids results in the production of novel avermectins [92-94]. 

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