Biosynthesis of eicosanoids Prostaglandins are found in most tissues and organs. They are
produced by almost all nucleated cells. They are
autocrine and
paracrine lipid mediators that act upon
platelets,
endothelium,
uterine and
mast cells. They are synthesized in the cell from the
fatty acid arachidonic acid. Alternatively, the lipoxygenase enzyme pathway is active in
leukocytes and in
macrophages and synthesizes
leukotrienes.
Release of prostaglandins from the cell Prostaglandins were originally believed to leave the cells via passive diffusion because of their high lipophilicity. The discovery of the
prostaglandin transporter (PGT, SLCO2A1), which mediates the cellular uptake of prostaglandin, demonstrated that diffusion alone cannot explain the penetration of prostaglandin through the cellular membrane. The release of prostaglandin has now also been shown to be mediated by a specific transporter, namely the
multidrug resistance protein 4 (MRP4, ABCC4), a member of the
ATP-binding cassette transporter superfamily. Whether MRP4 is the only transporter releasing prostaglandins from the cells is still unclear.
Cyclooxygenases Prostaglandins are produced following the sequential oxygenation of arachidonic acid, DGLA or EPA by
cyclooxygenases (COX-1 and COX-2) and terminal prostaglandin syntheses. The classic dogma is as follows: •
COX-1 is responsible for the baseline levels of prostaglandins. •
COX-2 produces prostaglandins through stimulation. However, while COX-1 and COX-2 are both located in the
blood vessels,
stomach and the
kidneys, prostaglandin levels are increased by COX-2 in scenarios of
inflammation and
growth.
Prostaglandin E synthase Prostaglandin E2 (PGE2) — the most abundant prostaglandin — is generated from the action of
prostaglandin E synthases on prostaglandin H2 (
prostaglandin H2, PGH2). Several prostaglandin E syntheses have been identified. To date, microsomal (named as
misoprostol) prostaglandin E synthase-1 emerges as a key enzyme in the formation of PGE2.
Other terminal prostaglandin synthases Terminal prostaglandin syntheses have been identified that are responsible for the formation of other prostaglandins. For example, two types of
prostaglandin-D synthase,
hematopoietic-type PGDS and
lipocalin-type PGDS, are responsible for the formation of
PGD2 from PGH2. Similarly, prostacyclin (PGI2) synthase (PGIS) converts PGH2 into PGI2. A thromboxane synthase (
TxAS) has also been identified.
Prostaglandin-F synthase (PGFS) catalyzes the formation of 9α,11β-PGF2α,β from PGD2 and PGF2α from PGH2 in the presence of NADPH. This enzyme has recently been crystallized in complex with PGD2 and bimatoprost (a synthetic analogue of PGF2α). == Functions ==