The Cyclooxygenase Pathway Is Responsible For Prostanoid Synthesis

Prostanoid synthesis (Figure 23-6) involves the consumption of two molecules of O2 catalyzed by prostaglandin H synthase (PGHS), which consists of two enzymes, cyclooxygenase and peroxidase. PGHS is present as two isoenzymes, PGHS-1 and PGHS-2. The product, an endoperoxide (PGH), is converted to prostaglandins D, E, and F as well as to a thromboxane

Dihomo-Y-linolenoyl-CoA (A^ -eicosatrienoyl-CoA)

Diet

Membrane phospholipid

Linoleate

Y-Linolenate |+2C

-COOH

8,11,14-Eicosatrienoate (dihomo Y-linolenate)

Angiotensin II Bradykinin Epinephrine Thrombin

Membrane phospholipid

Angiotensin II Bradykinin Epinephrine Thrombin

-COOH

8,11,14-Eicosatrienoate (dihomo Y-linolenate)

GROUP 3

Prostanoids PGD3 PGE3 PGF3

pgi3

TXA3 Leukotrienes LTA5 LTB5 LTC5

Eicosatetraenoate ■ +2C

Octadecatetraenoate -2H

Diet

GROUP 3

Prostanoids PGD3 PGE3 PGF3

pgi3

TXA3 Leukotrienes LTA5 LTB5 LTC5

Diet a-Linolenate

Diet

Figure 23-5. The three groups of eicosanoids and their biosynthetic origins. (PG, prostaglandin; PGI, prostacyclin; TX, thromboxane; LT, leukotriene; LX, lipoxin; ©, cyclooxygenase pathway; ©, lipoxygenase pathway.) The subscript denotes the total number of double bonds in the molecule and the series to which the compound belongs.

(TXA2) and prostacyclin (PGI2). Each cell type produces only one type of prostanoid. Aspirin, a nonsteroidal anti-inflammatory drug (NSAID), inhibits cyclooxygenase of both PGHS-1 and PGHS-2 by acetylation. Most other NSAIDs, such as indomethacin and ibuprofen, inhibit cyclo oxygenases by competing with arachidonate. Transcription of PGHS-2—but not of PGHS-1—is completely inhibited by anti-inflammatory corticosteroids.

Essential Fatty Acids Do Not Exert All Their Physiologic Effects Via Prostaglandin Synthesis

The role of essential fatty acids in membrane formation is unrelated to prostaglandin formation. Prostaglandins do not relieve symptoms of essential fatty acid deficiency, and an essential fatty acid deficiency is not caused by inhibition of prostaglandin synthesis.

Arachidonate

Arachidonate

Cyclooxygenase Pathway

OH PGF2 a

OH PGD2

txb2

Figure 23-6. Conversion of arachidonic acid to prostaglandins and thromboxanes of series 2. (PG, prostaglandin; TX, thromboxane; PGI, prostacyclin; HHT, hydroxyheptadecatrienoate.) (Asterisk: Both of these starred activities are attributed to one enzyme: prostaglandin H synthase. Similar conversions occur in prostaglandins and thromboxanes of series 1 and 3.)

OH PGF2 a

OH PGD2

txb2

Figure 23-6. Conversion of arachidonic acid to prostaglandins and thromboxanes of series 2. (PG, prostaglandin; TX, thromboxane; PGI, prostacyclin; HHT, hydroxyheptadecatrienoate.) (Asterisk: Both of these starred activities are attributed to one enzyme: prostaglandin H synthase. Similar conversions occur in prostaglandins and thromboxanes of series 1 and 3.)

Cyclooxygenase Is a "Suicide Enzyme"

"Switching off' of prostaglandin activity is partly achieved by a remarkable property of cyclooxygenase—that of self-catalyzed destruction; ie, it is a "suicide enzyme." Furthermore, the inactivation of prostaglandins by 15-hydroxyprostaglandin dehydrogenase is rapid. Blocking the action of this enzyme with sulfasalazine or in-domethacin can prolong the half-life of prostaglandins in the body.

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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