Cyclic pathway:
Prostaglandin H2 Synthase (PGH2 Synthase) catalyzes the committed step in the "cyclic pathway" that leads to production of prostaglandins, prostacyclins, and thromboxanes. Different cell types convert PGH2 to different compounds.
Prostaglandin H2 Synthase is a heme-containing dioxygenase, bound to endoplasmic reticulum membranes. (A dioxygenase incorporates O2 into a substrate.) PGH2 Synthase exhibits two catalytic activities, Cyclooxygenase and Peroxidase. The enzyme expressing both activities is sometimes referred to as Cyclooxygenase, abbreviated COX.
The interacting cyclooxygenase and peroxidase reaction pathways are complex. A peroxide (such as that generated later in the reaction sequence) oxidizes the heme iron. The oxidized heme accepts an electron from a nearby tyrosine residue (Tyr385). The resulting tyrosine radical is proposed to extract a hydrogen atom from arachidonate, generating a radical species that reacts with O2.
The signal molecule ·NO (nitric oxide) may initiate prostaglandin synthesis by reacting with superoxide anion (O2·-) to produce peroxynitrite, which oxidizes the heme iron enabling electron transfer from the active site tyrosine. Prostaglandin synthesis in response to some inflammatory stimuli is diminished by inhibitors of Nitric Oxide Synthase.
The membrane-binding domain of PGH2 Synthase consists of 4 short amphipathic a-helices that insert into one leaflet of the lipid bilayer, facing the lumen of the endoplasmic reticulum.
Arachidonate, derived from membrane lipids, approaches the heme via a hydrophobic channel extending from the membrane-binding domain of the enzyme.
Some evidence suggests the existence of a third isoform of PGH2 Synthase, designated COX-3, with roles in mediating pain and fever, and subject to inhibition by acetaminophen (Tylenol). Acetaminophen has little effect on COX-1 or COX-2, and thus lacks anti-inflammatory activity.
Linear Pathway:
The first step of the linear pathway for synthesis of leukotrienes is catalyzed by Lipoxygenase. Mammalian organisms have a family of Lipoxygenase enzymes that catalyze oxygenation of various polyunsaturated fatty acids at different sites. Many of the products have signal roles.
For example, 5-Lipoxygenase, found in leukocytes, catalyzes conversion of arachidonate to 5-HPETE (5-hydroperoxyeicosatetraenoic acid). 5-HPETE is converted to leukotriene-A4, which in turn may be converted to various other leukotrienes.
A non-heme iron is the prosthetic group of Lipoxygenase enzymes. Ligands to the iron include 4 histidine nitrogen atoms and the C-terminal carboxylate oxygen. The arachidonate substrate binds in a hydrophobic pocket, adjacent to the catalytic iron atom. O2 is thought to approach from the opposite side of the substrate than the side facing the iron, for a stereospecific reaction.
The reaction starts with extraction of a hydrogen from arachidonate, with transfer of the electron to the iron, reducing it from Fe3+ to Fe2+. The fatty acid radical reacts with O2 to form a hydroperoxy fatty acid. Which hydrogen is extracted, & the position of the resulting hydroperoxy group, varies with different lipoxygenases (e.g., 5-Lipoxgenase shown at right, 15-Lipoxygenase, etc.) Additional reactions then yield the various leukotrienes.
medlibrary.org/medwiki/Prostacyclin
