Biosynthesis of fatty acid

Most fatty acids have an even number of carbon atoms, so none are left over after 8-oxidation. Those fatty acids with an odd number of carbon atoms yield the three-carbon propionyl CoA in the final 8-oxidation. Propionyl CoA is then converted to succinate by a multistep radical pathway, and succinate enters the citric acid cycle (Section 22.4). Note that the three-carbon propionyl group should properly be called propanoyl, hut biochemists generally use the nonsystematic name. 

How many molecules of acetyl CoA are produced by catabolism of the following fatty acids, and how many passages of the j8-oxidation pathway are needed  

One of the most striking features of the common fatty acids is that they have an even number of carbon atoms (Table 23.1). This even number results because all fatty acids are derived biosynthetically from acetyl CoA by sequential addition of two-carbon units to a growing chain. The acetyl CoA, in turn, arises primarily from the metabolic breakdown of carbohydrates in the glycolysis pathway (Section 22.2). Thus, dietary carbohydrates consumed in excess of immediate energy needs are turned into fats for storage. 

As noted previously in Section 22.5 when discussing carbohydrate biosynthesis, the anabolic pathway by which a substance is made is not the reverse of the catabolic pathway by which it is degraded. Thus, the )8-oxidation pathway that converts fatty acids into acetyl CoA and the biosynthesis pathway that prepares fatty acids/rom acetyl CoA are related hut are not exact opposites. Differences include the identity of the acyl-group carrier, the stereochemistry of the j8-hydroxyacyl reaction intermediate, and the identity of the redox coenzyme. FAD is used to introduce a double bond in )8-oxidation, while NADPH is used to reduce the double bond in fatty-acid biosynthesis. 

STEPS 1-2 OF FIGURE 23.6 ACYL TRANSFERS The starting material for fatty-acid biosynthesis is the thioester acetyl CoA, the final product of carbohydrate breakdown in the glycolysis pathway (Section 22.2). The pathway begins with several priming reactions, which transport acetyl CoA and convert it into more reactive species. The first priming reaction is a nucleophilic acyl substitution 

In the organism tissues, fatty acids are continually renewed in order to provide not only for the energy requirements, but also for the synthesis of multicomponent lipids (triacylglycerides, phospholipids, etc.). In the organism cells, fatty acids are resynthetized from simpler compounds through the aid of a supramolecular multienzyme complex referred to as fatty acid synthetase. At the Lynen laboratory, this synthetase was first isolated from yeast and then from the liver of birds and mammals. Since in mammals palmitic acid in this process is a major product, this multienzyme complex is also called palmitate synthetase. 

Biosynthesis of fatty acids exhibits a number of specific features  

Production of Malonyl-CoA for the Fatty Acid Biosynthesis. Acetyl-CoA serves as a substrate in the production of malonyl-CoA. There are several routes by which acetyl-CoA is supplied to die cytoplasm. One route is the transfer of acetyl residues from the mitochondrial matrix across the mitochondrial membrane into the cyto-plasm. This process resembles a fatty acid transport and is likewise effected with the participation of carnitine and the enzyme acetyl-CoA-camitine transferase. Another route is the production of acetyl-CoA from citrate. Citrate is delivered from the mitochondria and undergoes cleavage in the cytoplasm by the action of the enzyme ATP-citrate lyase  

The acetyl-CoA supplied to the cytoplasm via the above routes is used for the synthesis of malonyl-CoA  

The reaction is catalyzed by the biotin,enzyme acetyl-CoA carboxylase (E-biotin) assisted by Mg2+ ions. This enzyme is a tetramer with a molecular mass of 400 000-500000. 

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Section 26 3 The biosynthesis of fatty acids follows the pathway outlined in Figure 26 3 Malonyl coenzyme A is a key intermediate... 

Fatty acid synthetase (Section 26 3) Complex of enzymes that catalyzes the biosynthesis of fatty acids from acetate Field effect (Section 19 6) An electronic effect in a molecule that IS transmitted from a substituent to a reaction site via the medium (e g solvent)... 

Fatty acid synthetase (Section 26.3) Complex of enzymes that catalyzes the biosynthesis of fatty acids from acetate. 

We turn now to the biosynthesis of lipid structures. We begin with a discussion of the biosynthesis of fatty acids, stressing the basic pathways, additional means of elongation, mechanisms for the introduction of double bonds, and regulation of fatty acid synthesis. Sections then follow on the biosynthesis of glyc-erophospholipids, sphingolipids, eicosanoids, and cholesterol. The transport of lipids through the body in lipoprotein complexes is described, and the chapter closes with discussions of the biosynthesis of bile salts and steroid hormones. 

On the other hand, a carboxyl group is effective to increase the acidity of the proton on the a-carbon. Thus, carboxylation of a methylene group is an important step for the following C—C bond-forming reactions as seen in the biosynthesis of fatty acids (Fig. 4). 

AGP, acyl carrier protein Figure 4 Biosynthesis of fatty acids. 

Nature, however, has performed more than simple stepwise transformations using a combination of enzymes in so-called multienzyme complexes, it performs multistep synthetic processes. A well-known example in this context is the biosynthesis of fatty acids. Thus, Nature can be quoted as the inventor of domino reactions. Usually, as has been described earlier in this book, domino processes are initiated by the application of an organic or inorganic reagent, or by thermal or photochemical treatment. The use of enzymes in a flask for initiating a domino reaction is a rather new development. One of the first examples for this type of reaction dates back to 1981 [3], although it should be noted that in 1976 a bio-triggered domino reaction was observed as an undesired side reaction by serendipity [4]. 

Schweizer E (1989) Biosynthesis of fatty acids and related compounds. In Ratledge C, Wilkinson SG (eds), Microbial lipids, vol. 2. Academic Press, London, p 3 -50... 

W3. Wakil, S. J., and Gibson, D. M., Studies on the mechanism of fatty acid synthesis. VIII. The participation of protein bound biotin in the biosynthesis of fatty acids. Biochim. et Biophys. Acta 41, 122-129 (1960). 

Phosphopantetheine tethering is a posttranslational modification that takes place on the active site serine of carrier proteins - acyl carrier proteins (ACPs) and peptidyl carrier proteins (PCPs), also termed thiolation (T) domains - during the biosynthesis of fatty acids (FAs) (use ACPs) (Scheme 23), polyketides (PKs) (use ACPs) (Scheme 24), and nonribosomal peptides (NRPs) (use T domain) (Scheme 25). It is only after the covalent attachment of the 20-A Ppant arm, required for facile transfer of the various building block constituents of the molecules to be formed, that the carrier proteins can interact with the other components of the different multi-modular assembly lines (fatty acid synthases (FASs), polyketide synthases (PKSs), and nonribosomal peptide synthetases (NRPSs)) on which the compounds of interest are assembled. The structural organizations of FASs, PKSs, and NRPSs are analogous and can be divided into three broad classes the types I, II, and III systems. Even though the role of the carrier proteins is the same in all systems, their mode of action differs from one system to another. In the type I systems the carrier proteins usually only interact in cis with domains to which they are physically attached, with the exception of the PPTases and external type II thioesterase (TEII) domains that act in trans. In the type II systems the carrier proteins selectively interact... 

Malonyl-CoA is used as the nucleophilic species in the biosynthesis of fatty acids (see Section 15.5) and a whole host of other natural products, including the aromatic compounds seen in Box 10.14. 

The tricarboxylic acid cycle not only takes up acetyl CoA from fatty acid degradation, but also supplies the material for the biosynthesis of fatty acids and isoprenoids. Acetyl CoA, which is formed in the matrix space of mitochondria by pyruvate dehydrogenase (see p. 134), is not capable of passing through the inner mitochondrial membrane. The acetyl residue is therefore condensed with oxaloacetate by mitochondrial citrate synthase to form citrate. This then leaves the mitochondria by antiport with malate (right see p. 212). In the cytoplasm, it is cleaved again by ATP-dependent citrate lyase [4] into acetyl-CoA and oxaloacetate. The oxaloacetate formed is reduced by a cytoplasmic malate dehydrogenase to malate [2], which then returns to the mitochondrion via the antiport already mentioned. Alternatively, the malate can be oxidized by malic enzyme" [5], with decarboxylation, to pyruvate. The NADPH+H formed in this process is also used for fatty acid biosynthesis. 

The pentose phosphate pathway (PPP, also known as the hexose monophosphate pathway) is an oxidative metabolic pathway located in the cytoplasm, which, like glycolysis, starts from glucose 6-phosphate. It supplies two important precursors for anabolic pathways NADPH+H+, which is required for the biosynthesis of fatty acids and isopren-oids, for example (see p. 168), and ribose 5-phosphate, a precursor in nucleotide biosynthesis (see p. 188). 

In the vertebrates, biosynthesis of fatty acids is catalyzed by fatty add synthase, a multifunctional enzyme. Located in the cytoplasm, the enzyme requires acetyl CoA as a starter molecule. In a cyclic reaction, the acetyl residue is elongated by one C2 unit at a time for seven cycles. NADPH+H is used as a reducing agent in the process. The end product of the reaction is the saturated Cie acid, palmitic acid. 

The biosynthesis of fatty acids produced during alcoholic fermentation is initiated in the yeast cell by the formation of acetylcoenzyme A, which reacts with malonylcoenzyme A to form mainly saturated straight-chained fatty acids with an even number of four to 18 carbon atoms the appearance of relatively low levels of fatty acids with odd numbers of carbon atoms as well as unsaturated fatty acids depends on the fermentation conditions [6]. The volatile fatty acids contribute to the flavour of fermented beverages like wine or beer and their concentration usually lies between 100 and 250 mg 0.1 L p.e. In distilled spirits the concentration of free fatty acids is significantly lower owing to the esterification... 

NADPH provides reducing power for biosynthetic reactions, and ribose 5-phosphate is a precursor for nucleotide and nucleic acid synthesis. Rapidly growing tissues and tissues carrying out active biosynthesis of fatty acids, cholesterol, or steroid hormones send more glucose 6-phosphate through the pentose phosphate pathway than do tissues with less demand for pentose phosphates and reducing power. 

This three-step process for transferring fatty acids into the mitochondrion—esterification to CoA, transesterification to carnitine followed by transport, and transesterification back to CoA—links two separate pools of coenzyme A and of fatty acyl-CoA, one in the cytosol, the other in mitochondria These pools have different functions. Coenzyme A in the mitochondrial matrix is largely used in oxidative degradation of pyruvate, fatty acids, and some amino acids, whereas cytosolic coenzyme A is used in the biosynthesis of fatty acids (see Fig. 21-10). Fatty acyl-CoA in the cytosolic pool can be used for membrane lipid synthesis or can be moved into the mitochondrial matrix for oxidation and ATP production. Conversion to the carnitine ester commits the fatty acyl moiety to the oxidative fate. 

We first describe the biosynthesis of fatty acids, the primary components of both triacylglycerols and phospholipids, then examine the assembly of fatty acids into triacylglycerols and the simpler membrane phospholipids. Finally, we consider the synthesis of cholesterol, a component of some membranes and the precursor of steroids such as the bile acids, sex hormones, and adrenocortical hormones. 

After the discovery that fatty acid oxidation takes place by the oxidative removal of successive two-carbon (acetyl-CoA) units (see Fig. 17-8), biochemists thought the biosynthesis of fatty acids might proceed by a simple reversal of the same enzymatic steps. However, as they were to find out, fatty acid biosynthesis and breakdown occur by different pathways, are catalyzed by different sets of enzymes, and take place in different parts of the cell. Moreover, biosynthesis requires the participation of a three-carbon intermediate, malonyl-CoA, that is not involved in fatty acid breakdown. 

The biosynthesis of fatty acids such as palmitate thus requires acetyl-CoA and the input of chemical energy7 in two forms the group transfer potential of ATP and the reducing power of NADPH. The ATP is required to attach C02 to acetyl-CoA to make malonyl-CoA the NADPH is required to reduce the double bonds. We return to the sources of acetyl-CoA and NADPH soon, but first let s consider the structure of the remarkable enzyme complex that catalyzes the synthesis of fatty acids. 

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