The biosynthesis of fatty acids

The starting materials are acetyl CoA and malonyl CoA. Successive molecules of malonyl CoA are added to a primer molecule of acetyl CoA with accompanying decarboxylation. Malonate consists of three C atoms. After decarboxylation a 2 C body remains. Thus, in effect, the biosynthesis of the fatty acids consists in arranging 2 C units in series, as we had already deduced from the constitution of the fatty acids. In discussing the biosynthesis in detail the following constituent processes have to be recognized  

This can occur in two ways, one of which is by the fixation of CO2 in acetyl CoA. The coenzyme which is effective here is biotin charged with 

active CO2. This seems to be the main pathway adopted by those parts of the higher plants which are above ground. In the roots, on the other hand, another pathway is widely used a peroxidase oxidizes ox-alacetate to CO2 and malonate. Malonate is then converted to its CoA ester, malonyl CoA. 

---

The repertoire of chemicals that can be used for communication is limited by the biosynthetic ability of the insect. Compared to other insect orders, pheromone biosynthesis in Hymenoptera has received little study [191]. However, the biosynthetic origins of chemically diverse hymenopteran semiochemicals likely include aromatic, fatty acid, and terpenoid pathways as well as simple modifications of host-derived precursors. Notable recent studies include the biosynthesis of the fatty acid components (2 )-9-oxodec-2-enoic acid 52 and (2 )-9-hydroxydec-2-enoic acid of the honeybee queen mandibular pheromone from octadecanoic acid [192,193], and the aliphatic alcohol and ester... 

Full details of the biosynthesis of the fatty acids and their metabolites are in the online chapter Natural products. ... 

Wax esters from jojoba (Simmondsia chinensis, Simmonds-iaceae) consist of molecules with mostly C20 acid (monoene) esterified with about an equal mixture of C20 and C22 alcohols (monoene) (Yermanos, 1978 1981 Miwa, 1971). In studies of the biosynthesis of the fatty acids and alcohols in slices of fresh jojoba cotyledons, a radioactive label from glucose was incorporated into all carbons of both the C20 and C22 acids and alcohols. In contrast, exogenous acetate was used almost entirely for chain elongation from endoge-... 

The A6 desaturation of unsaturated acyl-CoA is the first reaction involved in the normal biosynthesis of all polyunsaturated fatty acids families in animal microsomes. Due to this key position it can regulate the biosynthesis of the fatty acids of the series. The reaction is modified by competition with substrates and products, ATP, and acyl-CoA acceptors. 

Acetyl CoA is the starting material for the biosynthesis of the fatty acids. It is used for the synthesis of the fatty acids by the acetate-malonate pathway. With the terpenoids we become acquainted with a second, large group of natural products whose biosynthesis starts from acetyl CoA. The terpenoids are furnished via the acetate-mevalonate pathway. 

Biosynthesis of coen2yme A (CoA) ia mammalian cells incorporates pantothenic acid. Coen2yme A, an acyl group carrier, is a cofactor for various en2ymatic reactions and serves as either a hydrogen donor or an acceptor. Pantothenic acid is also a stmctural component of acyl carrier protein (AGP). AGP is an essential component of the fatty acid synthetase complex, and is therefore requited for fatty acid synthesis. Free pantothenic acid is isolated from hver, and is a pale yeUow, viscous, and hygroscopic oil. 

The individual steps in the elongation of the fatty acid chain are quite similar in bacteria, fungi, plants, and animals. The ease of purification of the separate enzymes from bacteria and plants made it possible in the beginning to sort out each step in the pathway, and then by extension to see the pattern of biosynthesis in animals. The reactions are summarized in Figure 25.7. The elongation reactions begin with the formation of acetyl-ACP and malonyl-ACP, which... 

Biosynthesis of Unsaturated Fatty Acids. In the mammalian tissues, the forma-tion of monoene fatty acids is only possible. Oleic acid is derived from stearic acid, and palmitooleic acid, from palmitic acid. This synthesis is carried out in the endoplasmic reticulum of the liver cells via the monooxigenase oxidation chain. Any other unsaturated fatty acids are not produced in the human organism and must be supplied in vegetable food (plants are capable of generating polyene fatty acids). Polyene fatty acids are essential food factors for mammals. 

Many Pseudomonas strains accumulate MCL-PHAs from alkane, alkene, al-kanoate, alkenoate, or alkanol [5,6,14,96]. The composition of the PHAs formed by the pseudomonads of the rRNA homology group I is directly related to the structure of the carbon substrate used [6]. These results suggested that MCL-PHAs are synthesized from the intermediates of the fatty acid oxidation pathway. In almost all pseudomonads belonging to the rRNA homology group I except Pseudomonas oleovorans, MCL-PHA can also be synthesized from acetyl-CoA through de novo fatty acid synthetic pathway [97]. The -oxidation pathway and de novo fatty acid synthetic pathway function independently in PHA biosynthesis. 

Once an enzyme-catalysed reaction has occurred the product is released and its engagement with the next enzyme in the sequence is a somewhat random event. Only rarely is the product from one reaction passed directly onto the next enzyme in the sequence. In such cases, enzymes which catalyse consecutive reactions, are physically associated or aggregated with each other to form what is called a multi enzyme complex (MEC). An example of this arrangement is evident in the biosynthesis of saturated fatty acids (described in Section 6.30). Another example of an organized arrangement is one in which the individual enzyme proteins are bound to membrane, as for example with the ATP-generating mitochondrial electron transfer chain (ETC) mechanism. Intermediate substrates (or electrons in the case of the ETC) are passed directly from one immobilized protein to the next in sequence. 

Protein biotinylation is catalyzed by biotin protein ligase (BPL). In the active site of the enzyme, biotin is activated at the expense of ATP to form AMP-biotin the activated biotin can then react with a nucleophile on the targeted protein. BPL transfers the biotin to a special lysine on biotin carboxyl carrier protein (BCCP), a subunit of AcCoA carboxylase (Scheme 21). Biotinylation of BCCP is very important in fatty acid biosynthesis, starting the growth of the fatty acid with AcCoA carboxylase to generate malonyl-CoA. Recently the crystal structures of mutated BPL and BCCP have been solved together with biotin and ATP to get a better idea of how the transfer fiinctions. ... 

On the other hand, as we have already seen, cholesterol tends to reduce the mobility of molecules in membranes and causes phospholipid molecules to occupy a smaller area than they would otherwise. Myelin is especially rich in long-chain sphingolipids and cholesterol, both of which tend to stabilize artificial bilayers. Within our bodies, the bilayers of myelin tend to be almost solid. Bilayers of some gram-positive bacteria growing at elevated temperatures are stiffened by biosynthesis of bifunctional fatty acids with covalently joined "tails" that link the opposite sides of a bilayer.149... 

Figure 17-12 The reactions of cytoplasmic biosynthesis of saturated fatty acids. Compare with pathway of (3 oxidation (Fig. 17-1).

Cells regulate the lipid compositions of their plasma membrane so that a reasonable membrane fluidity is main-tained. They do this by controlling fatty acid biosynthesis so as to vary the lengths of the fatty acid chains and the ratio of unsaturated to saturated fatty acids (see chapter 19). If cells are grown at low temperatures, their phospholipids contain more unsaturated fatty acids or fatty acids with shorter chains or both. These adjustments shift the Tm to lower temperatures, with the result that (to the extent that the melting transition is sharp enough to be measureable) the Tm re-... 

Fatty Acid Oxidation Yields Large Amounts of ATP Additional Enzymes Are Required for Oxidation of Unsaturated Fatty Acids in Mitochondria Ketone Bodies Formed in the Liver Are Used for Energy in Other Tissues Summary of Fatty Acid Degradation Biosynthesis of Saturated Fatty Acids... 

The Organization of the Fatty Acid Synthase Is Different in E. coli and Animals Biosynthesis of Monounsaturated Fatty Acids Follows Distinct Routes in E. coli and Animal Cells... 

As mentioned in chapter 17, unsaturated fatty acids are abundant in all living organisms. Alternative mechanisms for the biosynthesis of unsaturated fatty acids have evolved. Two chemically distinct pathways exist for the introduction of a cis double bond into saturated fatty acids The anaero-bic pathway as typified in E. coli, and the aerobic pathway found in eukaryotes. 

Anaerobic pathway for biosynthesis of monounsaturated fatty acids in E. coli. Synthesis of monounsaturated fatty acids follows the pathway described previously for saturated fatty acids until the intermediate j8-hydroxydecanoyl-ACP is reached. At this point an apparent competition arises between the enzymes involved in saturated and unsaturated fatty acid synthesis. 

As the name anaerobic implies, the double bond of the fatty acid is inserted in the absence of oxygen. Biosynthesis of monounsaturated fatty acids follows the pathway described previously for saturated fatty acids until the intermediate /3-hydroxydecanoyl-ACP is reached (fig. 18.15). At this point, a new enzyme, /3-hydroxydecanoyl-ACP dehydrase, becomes involved. This dehydrase can form the a-j8 trans double bond, and saturated fatty acid synthesis can occur as previously discussed. In addition, this dehydrase is capable of isomerization of the double bond to a cis /3-y double bond as shown in figure 18.15. The /3-y unsaturated fatty acyl-ACP is subsequently elongated by the normal enzymes of fatty acid synthesis to yield pal-mitoleoyl-ACP (16 1A9). The conversion of this compound to the major unsaturated fatty acid of E. coli, cA-vacccnic acid (18 1A11), requires a condensing enzyme that we have not previously discussed, /3-ketoacyl-ACP synthase II, which shows a preference for palmitoleoyl-ACP as a substrate. The subsequent conversion to vaccenyl-ACP is cata-... 

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. 

Harwood JL (1996) Recent advances in the biosynthesis of plant fatty acids. Biochim Biophys Acta 1301, 7-56. 

Jeffcoat R. (1979) The biosynthesis of unsaturated fatty acids and its control in mammalian liver. Essays Biochem. 15, 1-36. 

In prokaryotes, each of the reactions of fatty acid synthesis is catalyzed by a separate enzyme. However, in eukaryotes, the enzymes of the fatty acid synthesis elongation cycle are present in a single polypeptide chain, multifunctional enzyme complex, called fatty acid synthase. The fatty acid synthase complex exists as a dimer, with the ACP moiety shuttling the fatty acyl chain between successive catalytic sites, and from one subunit of the dimer to the other. It is, in effect, a highly efficient production line for fatty acid biosynthesis. 

---