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CASE FILES: BIOCHEMISTRY
PGH synthase: Prostaglandin H synthase; the enzyme that catalyzes the
formation of prostaglandin H from C20 polyunsaturated acids. PGH syn-
thase has two activities; the cyclooxygenase activity introduces the five-
membered ring into the polyunsaturated fatty acid while also introducing
an endoperoxide between carbons 9 and 10 and a hydroperoxide at carbon
15. The peroxidase activity reduces the hydroperoxide to a hydroxyl group
using glutathione as the source of reducing equivalents. PGH synthase
exists in two isoforms, PGHS-1 and PGHS-2. PGHS-1 is the “basal” iso-
form and is expressed constitutively, whereas PGHS-2 is the inducible iso-
form and has been implicated in cell proliferation and inflammation.
NSAIDs: Nonsteroidal antiinflammatory drugs; NSAIDs inhibit the
cyclooxygenase activity of PGH synthase, thus inhibiting the production
of prostaglandins and thromboxanes.
Coxibs: A class of NSAIDs that is selective for inhibition of the cyclooxy-
genase activity of PGHS-2, with weaker action against the PGHS-1
cyclooxygenase.
D ISC U SSIO N
Prostanoids are oxygenated lipid-signaling molecules derived from polyun-
saturated fatty acids. The major prostanoids synthesized from the prototypi-
cal polyunsaturated fatty acid, arachidonic acid, are prostaglandin (PG) D2,
PGE2, PGF2a, PGH2, PGI2 (also known as prostacyclin), and thromboxane
(TX) A2. The prostanoid signaling cascade begins with an external stimulus,
most often the binding of a ligand to a cell surface receptor that activates one
or more phospholipases A2. The latter are enzymes that release arachidonic
acid from its esterified form in membrane phospholipids such as phos-
phatidylethanolamine and phosphatidylinositol. Arachidonate is converted to
PGH2 by one of the isoforms of PGH synthase (PGHS-1 or -2), enzymes local-
ized to the endoplasmic reticulum membrane and the nuclear envelope.
PGH2 is in turn metabolized to the prostanoid lipid signals (PGD2, PGE2,
PGF2a, PGH2, PGI2, or TXA2) by one of the secondary enzymes that are named
for the individual prostanoid produced (Figure 32-1). The type of prostanoid
produced is determined by which downstream enzyme is present; usually one
downstream enzyme predominates in a given cell. For example, the prominent
secondary enzyme in platelets is thromboxane synthase, whereas vascular
endothelial cells feature prostacyclin (PGI) synthase. Prostanoid signaling
molecules usually exit the cell that produces them to act on G-protein coupled
receptors on the surface of the same cell or cells nearby (termed autocrine or
paracrine actions). Some prostanoids may be further metabolized to ligands
for a subset of nuclear receptors, the peroxisome proliferator-activated recep-
tors (PPARs). The active prostanoids are rapidly converted to inactive metabo-
lites by enzymes present in a variety of cells. As a result, prostanoid signaling
molecules have very short half-lives in the circulation and are not hormones in
the conventional sense.
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