28.2 Additional Enzymes Elongate and Desaturate Fatty Acids

The major product of fatty acid synthase is palmitate, a 16-carbon fatty acid. However, all cells require longer-chain fatty acids for a variety of purposes, including the synthesis of signaling molecules. In eukaryotes, enzymes on the cytoplasmic face of the endoplasmic reticulum membrane catalyze the elongation reactions in which longer fatty acids are formed. These reactions use malonyl CoA to add two-carbon units sequentially to the carboxyl ends of both saturated and unsaturated acyl CoA substrates.

Membrane-Bound Enzymes Generate Unsaturated Fatty Acids

Endoplasmic reticulum systems also introduce double bonds into long-chain acyl CoAs, an important step in the synthesis of vital signal molecules such as prostaglandins. For example, in the conversion of stearoyl CoA into oleoyl CoA, a cis-Δ9 double bond is inserted by an oxidase that employs molecular oxygen and NADH (or NADPH):

Unsaturated fatty acids in mammals are derived from either palmitoleate (16:1, 16 carbon atoms, 1 double bond), oleate (18:1), linoleate (18:2), or linolenate (18:3). Mammals lack the enzymes to introduce double bonds at carbon atoms beyond C-9 in the fatty acid chain. Hence, mammals cannot synthesize linoleate (18:2 cis-Δ9, Δ12) and linolenate (18:3 cis-Δ9, Δ12, Δ15). Linoleate and linolenate are the two essential fatty acids, meaning that they must be supplied in the diet because they are required by an organism and cannot be endogenously synthesized. Linoleate (ω-6) and linolenate (ω-3) are the omega (ω) fatty acids that we read so much about. Linoleate and linolenate furnished by the diet are the starting points for the synthesis of a variety of other unsaturated fatty acids, including certain hormones. Safflower and corn oil are particularly rich sources of linoleate, whereas canola and soybean oil provide linolenate.

Eicosanoid Hormones Are Derived from Polyunsaturated Fatty Acids

Arachidonate, a 20:4 fatty acid derived from linoleate, is the major precursor of several classes of signal molecules: prostaglandins, prostacyclins, thromboxanes, and leukotrienes (Figure 28.6). Prostaglandins and related signal molecules are called eicosanoids (from the Greek eikosi, meaning “twenty”) because they contain 20 carbon atoms.

Figure 28.6: Arachidonate is the major precursor of eicosanoid hormones. Prostaglandin synthase catalyzes the first step in a pathway leading to prostaglandins, prostacyclins, and thromboxanes. Lipoxygenases catalyze the initial step in a pathway leading to leukotrienes. Abbreviations: PLA2, phospholipase A2; DG, diacylglycerol.

Prostaglandins and other eicosanoids are local hormones. They are short-lived and alter the activities only of the cells in which they are synthesized and of cells in the immediate vicinity by binding to membrane receptors. These effects may vary from one type of cell to another. Among other effects, prostaglandins stimulate inflammation, regulate blood flow to particular organs, control ion transport across membranes, modulate synaptic transmission, and induce sleep (Figure 28.7).

Figure 28.7: Structures of several eicosanoids.

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!clinic! CLINICAL INSIGHT: Aspirin Exerts Its Effects by Covalently Modifying a Key Enzyme

Aspirin (acetylsalicylate) blocks access to the active site of the enzyme that converts arachidonate into prostaglandin H2. Because arachidonate is the precursor of other prostaglandins, prostacyclins, and thromboxanes, blocking this step affects many signaling pathways. It accounts for the wide-ranging effects that aspirin and related compounds have on inflammation, fever, pain, and blood clotting.

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