Harpers

194 / CHAPTER 23COOHO O Arachidonate2O 2 CYCLOOXYGENASEAspirin– IndomethacinOIbuprofenCOOHCOOHOPGI2OOHPROSTACYCLIN PGG 2*OSYNTHASEPEROXIDASE OOC HCOOH+OC HOH OHOHOOHPGH2Malondialdehyde + HHTCOOHISOMERASETHROMBOXANEImidazoleOSYNTHASE –COOHOCOOHOOH OHOH OHOH TXA 26-Keto PGF 1αPGE2ISOMERASEOHREDUCTASEOH OH*COOHCOOHCOOHCOOHOHOHOOHHOOOHPGF 2 αPGD 2TXB 2Figure 23–6. Conversion of arachidonic acid to prostaglandins and thromboxanes of series 2. (PG,prostaglandin; TX, thromboxane; PGI, prostacyclin; HHT, hydroxyheptadecatrienoate.) (Asterisk: Both of thesestarred activities are attributed to one enzyme: prostaglandin H synthase. Similar conversions occur inprostaglandins and thromboxanes of series 1 and 3.)Cyclooxygenase Is a “Suicide Enzyme”“Switching off” of prostaglandin activity is partly achievedby a remarkable property of cyclooxygenase—that ofself-catalyzed destruction; ie, it is a “suicide enzyme.”Furthermore, the inactivation of prostaglandins by 15-hydroxyprostaglandin dehydrogenase is rapid. Blockingthe action of this enzyme with sulfasalazine or indomethacincan prolong the half-life of prostaglandinsin the body.LEUKOTRIENES & LIPOXINSARE FORMED BY THELIPOXYGENASE PATHWAYThe leukotrienes are a family of conjugated trienesformed from eicosanoic acids in leukocytes, mastocytomacells, platelets, and macrophages by the lipoxygenasepathway in response to both immunologic andnonimmunologic stimuli. Three different lipoxygenases(dioxygenases) insert oxygen into the 5, 12, and 15 positionsof arachidonic acid, giving rise to hydroperoxides(HPETE). Only 5-lipoxygenase forms leukotrienes(details in Figure 23–7). Lipoxins are a family ofconjugated tetraenes also arising in leukocytes. They areformed by the combined action of more than onelipoxygenase (Figure 23–7).CLINICAL ASPECTSSymptoms of Essential Fatty AcidDeficiency in Humans Include SkinLesions & Impairment of Lipid TransportIn adults subsisting on ordinary diets, no signs of essentialfatty acid deficiencies have been reported. How-