Palmitate and stearate serve as precursors of the two most common monounsaturated fatty acids of animal tissues: palmitoleate, 16:1(Δ9), and oleate, 18:1(Δ9) (Fig. 20-13). Each of these fatty acids has a single cis double bond in the Δ9 position (between C-9 and C-10). The double bond is introduced into the fatty acid chain by an oxidative reaction catalyzed by fatty acyl-CoA desaturase (Fig. 20-14). This enzymeis an example of a mixed-function oxidase (Box 20-1). Two different substrates, the fatty acid and NADPH, simultaneously undergo twoelectron oxidations. The path of electron flow includes a cytochrome (cytochrome b5) and a flavoprotein (cytochrome b5 reductase), both of which, like fatty acyl-CoA desaturase itself, are present in the smooth endoplasmic reticulum.
Mammalian hepatocytes can readily introduce double bonds at the Δ9 position of fatty acids but cannot introduce additional double bonds in the fatty acid chain between C-10 and the methyl-terminal end.
Linoleate, 18:2(Δ9,12), and α-linolenate, 18:3(Δ9,12,15, cannot be synthesized by mammals, but plants can synthesize both. The plant desaturases that introduce double bonds at Δ12 and Δ15 positions are located in the endoplasmic reticulum. These enzymes act not on free fatty acids but on a phospholipid, phosphatidylcholine, containing at least one oleate linked to glycerol (Fig. 20-15, p. 656).
Because they are necessary precursors for the synthesis of other products, linoleate and linolenate are essential fatty acids for mammals; they must be obtained from plant material in the diet. Once ingested, linoleate may be converted into certain other polyunsaturated acids, particularly y-linolenate, eicosatrienoate, and eicosatetraenoate (arachidonate), which can be made only from linoleate (Fig. 20-13). Arachidonate, 20: 4(Δ5,8,11,14), is an essential precursor of regulatory lipids, the eicosanoids.
Eicosanoids Are Formed from Arachidonate
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Arachidonate is parent to the eicosanoids, a family of very potent
biological signaling molecules that act as short-range messengers, affecting
tissues near the cells that produce them. In response to a hormonal or other
stimulus, a specific phospholipase present in most types of mammalian cells
attacks membrane phospholipids, releasing arachidonate. Enzymes of the smooth
endoplasmic reticulum then convert arachidonate into prostaglandins, beginning
with the formation of PGH2, the immediate precursor of
many other prostaglandins and thromboxanes (Fig. 20-16a). The two reactions that
lead to PGH2 involve the addition of molecular oxygen;
both are catalyzed by a bifunctional enzyme, prostaglandin endoperoxide
synthase. Aspirin (acetylsalicylate; Fig. 20-16b) irreversibly inactivates this
enzyme (thus blocking the synthesis of prostaglandins and thromboxanes) by
acetylating a Ser residue essential to catalytic activity. Ibuprofen, a widely
used nonsteroidal antiinflammatory drug (Fig. 20-16c), also acts by inhibiting
this enzyme.
Thromboxanes, like prostaglandins, contain a ring of five or six atoms, and the pathway that leads from arachidonate to these two classes of compounds is sometimes called the "cyclic" pathway, to distinguish it from the "linear" pathway that leads from arachidonate to the leukotrienes, which are linear (Fig. 20-17, p. 658). Leukotriene synthesis begins with the action of several lipoxygenases that catalyze the incorporation of molecular oxygen into arachidonate. These enzymes, found in leukocytes and in heart, brain, lung, and spleen, are mixed-function oxidases that use cytochrome P-450 The various leukotrienes differ in the position of the peroxide that is introduced by these lipoxygenases. This linear pathway from arachidonate, unlike the cyclic pathway, is not inhibited by aspirin or the other nonsteroidal antiinflammatory drugs. |
