Prostaglandin and Thromboxane Synthesis

Arachidonic acid, an ω-6 FA containing 20 carbons and four double bonds (an eicosatetraenoic FA), is the immediate precursor of the predominant type of human PG (series 2 or those with two double bonds, as shown in Fig. 1). It is derived by the elongation and desaturation of the essential FA linoleic acid, also an ω-6 FA. Arachidonic acid is incorporated into membrane phospholipids (typically PI) at carbon 2, from which it is released by phospholipase A2 (Fig. 2) in response to a variety of signals, such as a rise in calcium. [Note: Series 1 PG contain one double bond and are derived from an ω-6 eicosatrienoic FA, dihomo-γ-linolenic acid, whereas series 3 PG contain three double bonds and are derived from eicosapentaenoic acid (EPA), an ω-3 FA.]

Figure 1: Oxidation and cyclization of arachidonic acid by the two catalytic activities (cyclooxygenase and peroxidase) of PGH2 synthase (prostaglandin endoperoxide synthase). G-SH = reduced glutathione; G-S-S-G = oxidized glutathione; PG = prostaglandin.

Figure 2: Overview of the biosynthesis and function of some important prostaglandins (PG), leukotrienes (LT), and a thromboxane (TX) from arachidonic acid. [Note: The arachidonic acid in the membrane phospholipid was derived from the ω-6 essential fatty acid (FA), linoleic, also an ω-6 FA.] PI = phosphatidylinositol; NSAID = nonsteroidal anti-inflammatory drugs; Glu = glutamate; Cys = cysteine; Gly = glycine.

1. Prostaglandin H2 synthase: The first step in PG and TX synthesis is the oxidative cyclization of free arachidonic acid to yield PGH2 by PGH2 synthase (or, prostaglandin endoperoxide synthase). This enzyme is an ER membrane-bound protein that has two catalytic activities: fatty acid cyclooxygenase (COX), which requires two molecules of O2, and peroxidase, which requires reduced glutathione . PGH2 is converted to a variety of PG and TX, as shown in Figure 2, by cellspecific synthases. [Note: PG contain a five-carbon ring, whereas TX contain a heterocyclic six-membered oxane ring .] Two isozymes of PGH2 synthase, usually denoted as COX-1 and COX-2, are known. COX-1 is made constitutively in most tissues and is required for maintenance of healthy gastric tissue, renal homeostasis, and platelet aggregation. COX-2 is inducible in a limited number of tissues in response to products of activated immune and inflammatory cells. [Note: The increase in PG synthesis subsequent to the induction of COX-2 mediates the pain, heat, redness, and swelling of inflammation and the fever of infection.]
2. Synthesis inhibition: The synthesis of PG and TX can be inhibited by unrelated compounds. For example, cortisol (a steroidal antiinflammatory agent) inhibits phospholipase A2 activity (see Fig. 2) and, therefore, arachidonic acid, the substrate for PG and TX synthesis, is not released from membrane phospholipids. Aspirin, indomethacin, and phenylbutazone (all nonsteroidal anti-inflammatory drugs [NSAID]) inhibit both COX-1 and COX-2 and, thus, prevent the synthesis of the parent molecule, PGH2. [Note: Systemic inhibition of COX-1, with subsequent damage to the stomach and the kidneys and impaired clotting of blood, is the basis of aspirin’s toxicity.] Aspirin (but not other NSAID) also induces synthesis of lipoxins (anti-inflammatory mediators made from arachidonic acid) and resolvins and protectins (inflammationresolving mediators made from EPA). Inhibitors specific for COX-2 (the coxibs, for example, celecoxib) were designed to reduce pathologic inflammatory processes mediated by COX-2 while maintaining the physiologic functions of COX-1. However, their use has been associated with increased risk of heart attacks, likely as a result of decreased PGI2 synthesis (see B. below), and some have been withdrawn from the market.

مواضيع ذات صلة

Blood clotting (coagulation)

Platelet Plug Formation: Aggregation

Platelet Plug Formation: Activation

Platelet Plug Formation: Adhesion

Limiting Clotting : Fibrinolysis

Limiting Clotting : Inactivating proteins

Fibrin Meshwork Formation : Pathways

Fibrin Meshwork Formation : Formation of γ-carboxyglutamate residues

Fibrin Meshwork Formation :Role of phosphatidylserine and calcium

Fibrin Meshwork Formation: Proteolytic cascade

Blood Clotting : Overview

Biotechnology and Human Disease