The major product of the fatty acid synthase is palmitate. In eukaryotes, longer fatty acids are formed by elongation reactions catalyzed by enzymes on the cytoplasmic face of the endoplasmic reticulum membrane. These reactions add two-carbon units sequentially to the carboxyl ends of both saturated and unsaturated fatty acyl CoA substrates. Malonyl CoA is the two-carbon donor in the elongation of fatty acyl CoAs. Again, condensation is driven by the decarboxylation of malonyl CoA.

Endoplasmic reticulum systems also introduce double bonds into long-chain acyl CoAs. 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).

This reaction is catalyzed by a complex of three membrane-bound proteins: NADH-cytochrome b₅ reductase, cytochrome b₅, and stearoyl CoA desaturase (Figure 22.31). First, electrons are transferred from NADH to the FAD moiety of NADH-cytochrome b₅ reductase. The heme iron atom of cytochrome b₅ is then reduced to the Fe²⁺ state. The nonheme iron atom of the desaturase is subsequently converted into the Fe²⁺ state, which enables it to interact with O₂ and the saturated fatty acyl CoA substrate. A double bond is formed and two molecules of H₂O are released. Two electrons come from NADH and two from the single bond of the fatty acyl substrate.

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A variety of unsaturated fatty acids can be formed from oleate by a combination of elongation and desaturation reactions. For example, oleate can be elongated to a 20:1 cis-Δ¹¹ fatty acid. Alternatively, a second double bond can be inserted to yield an 18:2 cis-Δ⁶, Δ⁹ fatty acid. Similarly, palmitate (16:0) can be oxidized to palmitoleate (16:1 cis-Δ⁹), which can then be elongated to mcis-vaccenate (18:1 cis-Δ¹¹).

Unsaturated fatty acids in mammals are derived from either palmitoleate (16:1), oleate (18:1), linoleate (18:2), or linolenate (18:3). The number of carbon atoms from the ω end of a derived unsaturated fatty acid to the nearest double bond identifies its precursor.

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. The term essential means that they must be supplied in the diet because they are required by an organism and cannot be synthesized by the organism itself. Linoleate and linolenate furnished by the diet are the starting points for the synthesis of a variety of other unsaturated 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 22.32).

A prostaglandin is a 20-carbon fatty acid containing a 5-carbon ring (Figure 22.33). This basic compound is modified by reductases and isomerases to yield nine major classes of prostaglandins, designated PGA through PGI; a subscript denotes the number of carbon–carbon double bonds outside the ring. Prostaglandins with two double bonds, such as PGE₂, are derived from arachidonate; the other two double bonds of this precursor are lost in forming a 5-membered ring. Prostacyclin and thromboxanes are related compounds that arise from a nascent prostaglandin. They are generated by prostacyclin synthase and thromboxane synthase, respectively. Alternatively, arachidonate can be converted into leukotrienes by the action of lipoxygenase. Leukotrienes, first found in leukocytes, contain three conjugated double bonds—hence the name. Prostaglandins, prostacyclin, thromboxanes, and leukotrienes are called eicosanoids (from the Greek eikosi, “twenty”) because they contain 20 carbon atoms.

Prostaglandins and other eicosanoids are local hormones because they are short-lived. They alter the activities both of the cells in which they are synthesized and of adjoining cells by binding to 7TM receptors. Their effects may vary from one cell type to another, in contrast with the more-uniform actions of global hormones such as insulin and glucagon. Prostaglandins stimulate inflammation, regulate blood flow to particular organs, control ion transport across membranes, modulate synaptic transmission, and induce sleep.

Recall that aspirin blocks access to the active site of the enzyme that converts arachidonate into prostaglandin H₂ (Section 12.3). Because arachidonate is the precursor of other prostaglandins, prostacyclin, and thromboxanes, blocking this step interferes with many signaling pathways. Aspirin’s ability to obstruct these pathways accounts for its wide-ranging effects on inflammation, fever, pain, and blood clotting.

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The mammalian multifunctional fatty acid synthase is a member of a large family of complex enzymes termed megasynthases that participate in step-by-step synthetic pathways. Two important classes of compounds that are synthesized by such enzymes are the polyketides and the nonribosomal peptides. These classes of compounds provide a variety of useful drugs, including antibiotics, immunosuppressants, antifungal agents and anticancer drugs. The antibiotic erythromycin is an example of a polyketide, whereas penicillin (Section 8.5) is a nonribosomal peptide.

Research is underway to learn how to manipulate the pathways and the enzymes of polyketide and nonribosomal peptide synthesis in order to generate new therapeutics.