CHEMISTRY OF ESSENTIAL FATTY ACIDS

II. CHEMISTRY OF ESSENTIAL FATTY ACIDS

A. Fatty Acid Biochemistry

The most biologically relevant fatty acids are straight chain hydrocarbons (12–22 carbons in length) with a terminal carboxyl group. They are synthesized by a series of enzymatic steps that result in the successive elongation of precursor molecules by two-carbon incre- ments, and can either be fully saturated or dehydrated by the insertion of one to six double bonds at specific locations in the hydrocarbon chain. All fatty acids with multiple double bonds have the double bonds interrupted by a methylene group, and all double bonds are in the cis configuration. The position of the double bond is indicated by the number of carbon atoms from the functional (acid) group (e.g., oleic acid has a single cis double bond at the ∆9 position). The standard biochemical nomenclature used in this chapter describes the fatty acid in terms of its carbon chain length, followed by the number of double bonds, and then the position of those double bonds. Oleic acid is, therefore, referred to as C18:1( ∆9), or a fatty acid with 18 carbons and one double bond at the 9 position ( Fig. 1 ).

Nutritionists also use a form of nomenclature which classifies families of fatty acids in terms of the position of the double bond closest to the methyl end of the molecule. Linoleic acid, for example would be chemically described as C18:2( ∆9,12), but also de- scribed as an omega-6 (or n-6) fatty acid since the double bond closest to the methyl end of the molecule is six carbons away from that terminal methyl group. This nomenclature is functionally useful because different fatty acid families have significantly different phys- iological and biochemical effects in the body. The other essential fatty acid, linolenic acid, is chemically described as C18:3( ∆9,12,15), and is nutritionally a part of the omega-3 (n-3) family of fatty acids. The scientific and common names for the principle fatty acids in biology are provided in Table 1 .

B. Omega-6 and Omega-3 Fatty Acids

The essential fatty acids, LA and ALA, are the parent molecules of the omega-6 and omega-3 pathways, respectively ( Fig. 2 ). Through the use of stable isotope tracer experi- ments, it is clear that humans have the ability to synthesize all the fatty acids of the omega-

3 and omega-6 pathway from the EFA precursors (Greiner et al., 1997; Salem et al.,

Figure 1 Chemical structure of (a) oleic acid in a stick model; (b) in a space filling model; (c) docosahexaenoic acid in a stick model; and (d) in a space filling model.

capability of desaturating fatty acids toward the methyl terminal of the fatty acyl chain. As shown in Fig. 2 the formation of all members of the omega-3 and omega-6 families of fatty acids require only a ∆6 or a ∆5 desaturation in conjunction with successive elonga- tion steps. The final steps in the conversion of eicosapentaenoic acid (EPA) to docosahex- aenoic acid (DHA) was thought to involve the additional elongation of EPA to C22:

Table 1 Scientific and Common Names of the Essential Fatty Acids and Their Common Derivatives

Common name

Chemical notation Omega-6 family

Scientific name

linoleic acid (LA)

C18:2( ∆9,12) gammalinolenic acid (GLA)

octadecadienoic acid

C18:3( ∆6,9,12) dihomogammalinolenic acid

octadecatrienoic acid

C20:3( ∆8,11,14) arachidonic acid

eicosatetraenoic acid

C20:4( ∆5,8,11,14) osbond acid

eicosatetraenoic acid

C22:5( ∆4,7,10,13,16) Omega-3 family linolenic acid

docosapentaenoic acid

C18:3( ∆9,12,15) steriodonic acid

octadecatrienoic acid

C18:4( ∆6,9,12,15) timnodonic acid

octadecatetraenoic acid

C20:5( ∆5,8,11,14,17) cervonic acid

eicosapentaenoic acid

docosahexaenoic acid

C22:6( ∆4,7,10,13,16,19)

Figure 2 Omega-3 and omega-6 fatty acid biosynthetic pathway.

5( ∆7,10,13,16,19), followed by a ∆4-desaturation to produce DHA [C22:6(∆4, 7,10,13,16,19)]. Recent studies by Sprecher and colleagues, however, have established that this is not the case (Voss et al., 1991). Rather, a more elaborate pathway involving

a progressive elongation of EPA to 22:5( ∆7,10,13,16,19) and then to 24:5(∆9,12,15,18,21) is followed by a ∆6-desaturation to form 24:6(∆6,9,12,15,18,21). This fatty acid is then transferred to the peroxisome, where it undergoes one cycle of β-oxidation to form 22: 6( ∆4,7,10,13,16,19), or DHA (Fig. 2). A similar process can occur with the omega-6 pathway to form 22:5( ∆4,7,10,13,16), docosapentaenoic acid (n-6), when an organism is deficient in omega-3 fatty acids.

The twenty carbon fatty acids of the omega-6 and omega-3 families [arachidonic acid (ARA) and EPA, respectively] are the precursors for a family of circulating bioactive molecules called eicosanoids. Both precursors are acted upon by lipoxygenases to form

a series of leukotrienes, and by cyclooxygenases to form prostaglandins, prostacyclins, and thromboxanes (Fig. 3). These circulating eicosanoids can affect immune responses, vascular tone, platelet aggregation, and many other cellular functions. In many cases the eicosanoids derived from the omega-6 fatty acids have an opposite effect from those de-

Figure 3 Formation of various eicosanoids from the LC-PUFA precursors: dihomogamma- linolenic acid (DGLA); arachidonic acid (ARA); eicosapentaenoic acid (EPA), prostaglandins (PGEx); thromboxanes (TXAx); prostacyclins (PGIx); leukotrienes (LTAx, LTBx. LTCx, LTDx); 5-hydroxyeicosatetraenoate. (5-HPETE); and 5-hydroxyeicosapentaenoate (5-HPEPE).

rived from the omega-3 fatty acids, and it is, therefore, important to keep the body in a healthy equilibrium between these two fatty acid families. It is because our modern diet has upset this balance that we now consider adding certain components back to the diet to restore this balance.

Docosahexaenoic acid plays a unique role in the body. It is not an eicosanoid precur- sor and therefore does not feed into the production of prostaglandins, thromboxanes, leuko- trienes, or prostacyclins. It is, however, found in massive abundance in the membranes of certain tissues of the central nervous system (Crawford, 1990). Docosahexaenoic acid is the most abundant omega-3 fatty acid of the membranes that make up the grey matter of the brain, and it is found in exceptionally high levels in the synaptic vesicles (Arbuckle and Innis, 1993; Bazan and Scott, 1990), in the retina of the eye (Bazan and Scott, 1990), in cardiac muscle (Gudbjarnason et al., 1978), and certain reproductive tissues (Connor et al., 1995; Zalata et al., 1998). Docosahexaenoic acid, therefore, likely plays a unique role in the integrity or functionality of these tissues.

C. Complex Lipid Forms

Fatty acids are not generally found in the body in the free fatty acid form. Rather, they are found in more complex lipid forms such as triglycerides, phospholipids, sphingomye- lin, sterol esters, etc. ( Fig. 4 ). Triglycerides are the primary lipid storage form, and are found in greatest abundance in adipose tissues. Other than triglycerides, the vast majority of fatty acid in the body is found as membrane phospholipid. There are four main phospho- lipid forms characterized by their polar head groups. They are phosphatidyl choline (PC), phosphatidyl ethanolamine (PE), phosphatidyl inositol (PI), and phosphatidyl serine (PS). All these phospholipid forms are found to different extents in different tissues, and the fatty acyl moieties on the phospholipids help to define the physical and chemical character- istics of the membranes.