Saturated Fatty Acids

The term saturated in the context of fatty acids refers specifically to fatty acyl chains that are exclusively made up of sp³ hybridized (tetrahedral geometry) carbon atoms arranged as linear −CH₂− chains as shown in Figure 6-1. Such chains are said to be saturated with hydrogen because the chain has no double (or triple) bonds across which hydrogen may be added.

Fatty acids are synthesized predominantly through the successive addition of two-carbon units to a growing acyl chain by the fatty acid synthase enzyme. Chain-elongation ceases at 16 carbons to create palmitic acid in mammals, although small amounts of fatty acids with 14- (myristic acid) and 18- (stearic acid) carbons are also produced. Additional two-carbon units may be added to these fatty acids by elongation enzyme systems to yield longer saturated fatty acids. Table 6-1 presents the chain lengths, systematic names, trivial names, and melting points of the most abundant saturated fatty acids in mammalian tissues.

In mammals, the majority of saturated fatty acids are configured as straight chains, but in rare cases methyl groups extend from the main chain, usually near its terminal methyl. A fatty acid that terminates with two methyl groups (i.e., an isopropyl configuration) at the end of a hydrocarbon chain is referred to as iso. If the chain terminates with a methyl and an ethyl group (i.e., an isobutyl configuration), the fatty acid is said to be anteiso, as shown in Figure 6-2. In humans, branched-chain fatty acids appear in vernix, the protective waxy white substance that coats and protects the fetus during late gestation. They have also been detected as minor components of skin, blood, and hair, as well as in cancer cells. Iso and anteiso C₁₅ and C₁₇ saturated fatty acids are major components of some microorganisms such as gram-positive bacteria.

Unsaturated Fatty Acids

Unsaturated is used to describe fatty acids with at least one double bond, consisting of two adjacent sp² hybridized carbon atoms, with a trigonal, approximately planar geometry. They are unsaturated with respect to hydrogen, because hydrogen can be covalently added across the double bond to yield sp³ carbon atoms. The overwhelming majority of unsaturated sites in mammalian fatty acids are double bonds configured in the cis geometry. When two or more double bonds are present in a molecule, the fatty acid is said to be polyunsaturated. Generally, double bonds in mammalian polyunsaturated fatty acids (PUFAs) are separated by a methylene (−CH₂−) group (“methylene-interrupted”). This structural property of PUFAs confers special chemical properties. One important chemical property is that the double bonds are not conjugated, and thus there is free rotation about the −CH₂− group. As with saturated fatty acids, use of trivial names is very common for unsaturated fatty acids. Table 6-2 is a compilation of the systematic and trivial names for the most common unsaturated fatty acids.

PUFA biosynthesis is discussed in depth in Chapter 18; however, a brief overview is necessary to rationalize PUFA nomenclature. Consider the pathway for synthesis of docosahexaenoic acid (C₂₂, 6 double bonds) from α-linolenic acid (C₁₈, 3 double bonds). This pathway begins with the insertion of a double bond between carbons 6 and 7 of α-linoleic acid by a Δ6-desaturase to make stearidonic acid (C₁₈, 4 double bonds). Two carbons are then added to the carboxyl end of the molecule by an elongase, followed by insertion of a double bond to make eicosatetraenoic acid (C₂₀, 5 double bonds). Additional desaturation, elongation, and oxidation steps finally result in docosahexaenoic acid. Figure 6-3 shows the systematic organic chemistry names and numbering for the first and last structures in this pathway. The systematic name of α-linoleic acid is 9,12,15-octadecadienoic acid, whereas the systematic name of the final product is 4,7,10,13,16,19-docosahexaenoic acid. Counting from the C1 position, as is required in systematic naming, the double bonds that were numbered 9, 12, and 15 in the precursor are now numbered 13, 16, and 19 in the product (9 → 13; 12 →

A solution is to number double bonds from the other end of the molecule, taking advantage of the fact that mammals cannot insert double bonds into the methyl end portion of the PUFA chain. Two conventions that are routinely used, which are effectively identical, are the IUPAC (International Union of Pure and Applied Chemistry) “n minus” convention and the omega convention. Examples of these notations are shown in Figure 6-3 for α-linolenic acid (18:3n−3) and docosahexaenoic acid (22:6n−3).

The IUPAC notation retains a close connection to the systematic organic chemistry notation. The “n” represents the number of carbons in the whole molecule, 18 in the case of α-linolenic acid and 22 in the case of docosahexaenoic acid. The number of double bonds follows the number of carbons, with the two separated by a colon (e.g., C18:3, or simply 18:3 for α-linolenic acid with three double bonds and 22:6 for docosahexaenoic acid with six double bonds). The location of the double bond closest to the methyl end of the fatty acid is indicated by the “n minus” nomenclature; for α-linolenic acid (18:3n−3), the double bond closest to the methyl end is carbon 18−3 or C15 (i.e., between C15 and C16). For docosahexaenoic acid (22:6n−3), the double bond closest to the methyl end is carbon 22−3 or C19 (i.e., between C19 and C20).

An alternative system called the omega notation, proposed by Holman, recognizes that the systematic organic chemistry numbering designates the carbon next to the carboxyl as “α,” and labels the last carbon in the acyl chain “ω.” The first double bond counting from the methyl end of α-linolenic or of docosahexaenoic acid appears at the third carbon and hence is designated ω3 (i.e., “omega three”). Although the IUPAC and omega numbering systems technically refer to different carbon atoms (e.g., C15 in 18:3n−3 versus C16 in 18:3ω3; or C19 in 22:6n−3 versus C20 in 22:6ω3), the n− and omega nomenclature effectively designate the equivalent fatty acids when the numeral following the n− or omega is the same. For example, 18:3n−3 and 18:3ω3 designate the same fatty acid (α-linolenic acid) and 20:4n−6 and 20:4ω6 both designate arachidonic acid.

Because all common PUFAs have cis double bonds arranged in methylene-interrupted positions, both notations are taken to imply cis geometry and methylene interruption of the double bonds. Thus a designation of n−6 (ω6) or n−3 (ω3), along with the number of carbons and number of double bonds, fully defines the structure of the PUFAs. For instance, “18:3n−6” or “18:3ω6” completely defines the structure of γ-linolenic acid as the fatty acid with the systematic name all-cis-6,9,12-octadecatrienoic acid.

Fatty acids with trans or conjugated double bonds do not ordinarily appear at other than trace levels in mammalian tissues (other than in the skin surface lipids), although they may be consumed as part of the diet. Example structures of trans and conjugated unsaturated fatty acids are shown in Figure 6-4. These fatty acids should not be designated with the n− or ω notation, unless further specification is provided. Unlike the situation with common fatty acids, there is no universal specialized notation for these more unusual fatty acids. Either systematic notation or some convenient adaptation of systematic numbering may be used. An example of acceptable notation would be “trans-18:1n−9” to specify the monounsaturated C₁₈ fatty acid with a trans double bond between C9 and C10. For fatty acids with more than one double bond, a “Δ” notation system is frequently used. The superscript Δ precedes the designation of the sites of unsaturation counting from the carboxyl carbon. For instance, 18:3Δ^6,9,12 designates γ-linolenic acid.

γ-Linolenic acid is also similarly designated as 9,12,15-18:3. Notations in which the individual double bonds are denoted, by counting from the carboxyl end, lend themselves to designation of isomers of γ-linolenic acid, often by adding leading “c” or “t” to specify double bond cis or trans geometry (e.g., c9,t11-octadecadienoic acid, or 18:2^{Δ c9,t11}, for rumenic acid.

Prochiral Glycerol

Stereochemistry is an important property of glycerolipids. The glycerol molecule possesses a plane of symmetry such that the central carbon atom can be considered prochiral, a chemical term referring to a carbon atom with four substituents, three of which are different. A prochiral carbon is not chiral, but substitution of one of the equivalent substituent groups with a fourth, nonequivalent group renders the central carbon chiral. This is the case for the central carbon of glycerol: when non–chemically equivalent moieties are added to the −CH₂OH groups, the central carbon becomes chiral. Chirality is very important to biochemical properties and thus must be described unambiguously. Here, the systematic notation of organic chemistry, with rules for designating chiral centers as R or S, leads to even more confusing designations than in the case of fatty acid double bond position. However, a single notation that closely parallels metabolism was introduced in the 1960s and is widely used. As shown in Figure 6-5, glycerol can be positioned so that the top and bottom −CH₂OH are oriented with their −OH groups extending to the right and the middle −OH extending to the left. By convention, the positions are referred to as sn-1, sn-2, and sn-3 (top to bottom), with sn being an abbreviation for “stereospecific numbering.” In some contexts, the sn-1 and sn-3 positions are metabolically equivalent and are designated the α positions, with the center sn-2 position then being designated the β position. When non–chemically equivalent groups are added to the sn-1 and sn-3 positions, glycerol becomes chiral.

Monoacylglycerols, Diacylglycerols, and Triacylglycerols

Acylglycerols are formed by the esterification of one or more of the glycerol –OH groups with a fatty acid carboxyl group by means of an ester linkage. A single acyl substitution to form an ester bond forms a monoacylglycerol, which may be designated as a 1-, 2-, or 3-monoacyl-sn-glycerol, depending on location of the fatty acid on the glycerol moiety. For example, esterification of hexadecanoic acid (palmitic acid) to the 1-position of glycerol produces 1-hexadecanoyl-sn-glycerol (1-palmitoyl-sn-glycerol). When two fatty acids are reacted with glycerol to form ester bonds, a diacylglycerol is formed (e.g., 1,3-diacyl-sn-glycerol or 1,2-diacyl-sn-glycerol). Both monoacylglycerols and diacylglycerols occur in relatively low proportion in mammals but are important as biochemical intermediates in many lipolytic reactions and are critical building blocks in the synthesis of more complex phospholipids and triacylglycerols. Diacylglycerols also act as second messengers for some membrane-triggered reactions.

A triacylglycerol (TAG) is formed when all three hydroxyls of glycerol form ester bonds with fatty acids. TAGs are the most common form of lipids in food and in mammalian tissues. The older abbreviated term triglyceride and its abbreviation TG are also used as synonyms for TAG, primarily in the medical literature. The properties of acylglycerols (e.g., melting point) depend greatly on the fatty acid chains involved. The fatty acids in a TAG may be all the same, all different, or two of a kind with one different one. If all three fatty acids are the same, the TAG is called a simple TAG (e.g., triolein). If one of the fatty acids is different, it becomes a complex TAG. If the fatty acids at the sn-1 and sn-3 positions are different, the TAG is chiral. Chirality in TAG is of less physiological importance than in other glycerolipids because many enzymes catalyzing reactions involving TAGs do not distinguish between the sn-1 and sn-3 (i.e., α) positions. Saturated fatty acyl chains tend to be found in the sn-1 and sn-3 positions, whereas unsaturated fatty acyl chains tend to be found in the sn-2 position of acylglycerols. There are notable exceptions, however, as in lard (pork fat) and human milk, for which 16:0 is predominantly in the sn-2 position and unsaturated fatty acyl chains are in the sn-1 and sn-3 positions.

The three unique positions of the glycerol backbone permit a tremendous number of positional isomers—that is, TAG with the same three fatty acids arranged in many different ways on the three positions of glycerol. For instance, consider the number of isomeric TAGs with the three fatty acids: palmitic (P), oleic (O), and stearic (S) acids. They could be arranged in six different ways listed in sn-1,2,3 order: POS and SOP, PSO and OSP, OPS and SPO, where the pairs are stereoisomers. Moreover, a fat containing these three fatty acids may not contain all fatty acids on all distinct TAG molecules; it may also contain PPP, PPS, OSO, and other combinations. In general, the number of unique TAG isomers is F³, where F is the number of fatty acids present in a sample. Even simple fats have more than 10 different fatty acids, which could be present as 10³, or 1,000, chemically distinct TAG molecules.

TAGs are the major storage lipids of plants and higher animals. Both plant oils (olive, corn, safflower) and animal fats (lard, suet, tallow) are predominantly mixtures of complex TAGs. A few percent of sterols, vitamins, free fatty acids, carotenoids, and other fat-soluble molecules are usually present in oils and fats. In animals, adipose tissue is the main source of fat, but skeletal muscle, heart, liver, skin, and bone marrow often contain appreciable amounts of TAGs in intracellular oil droplets.

Examples of structures and nomenclature for monoacylglycerols, diacylglycerols, and triacylglycerols are shown in Figure 6-6. Use of the IUPAC-IUB sn nomenclature is generally preferred over the use of the trivial names in most cases, although trivial names are commonly used for simple acylglycerols (e.g., the use of triolein for 1,2,3-tri-cis-9-octadecenoyl-sn-glycerol). A benefit of the sn nomenclature is that it clearly reveals the relationship between the precursor TAG and its DAG and MAG hydrolysis products. For example, the hydrolysis of 1-palmitoyl-2-stearoyl-3-myristoyl-sn-glycerol at the 1 position yields 2-stearoyl-3-myristoyl-sn-glycerol (Figure 6-7).

Diacylphospholipids, the Common Phospholipids

The general structure of the diacylphospholipids is presented in Figure 6-8, and the several classes of common phospholipids and their structures are shown in Figure 6-9. In all cases, a phosphate group is esterified to the sn-3 position of glycerol, and fatty acids are esterified to the sn-1 and sn-2 positions. Most commonly, the sn-2 position is occupied by an unsaturated acyl chain, whereas the sn-1 position is occupied by a saturated chain. However, there are notable exceptions to this generality. For instance, the major surfactant lipid of the lung has 16:0 in both positions, and some of the phospholipids of the retinal photoreceptors have very high concentrations of unsaturated fatty acyl chains in both positions.

The simplest phospholipid is phosphatidic acid (diacylglycerol 3-phosphate), in which phosphoric acid is esterified to

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