Arachidonic Acid Metabolism

Arachidonic acid (AA) is a 20-carbon polyunsaturated lipid, with four double bonds, contained in the plasma membrane of virtually all cells. Upon cell activation, AA is released from the phospholipid pool to be metabolized by cyclooxygenase (COX), lipoxygenase (LOX), or cytochrome P450, thus giving rise to families of eicosanoids called the prostaglandins (PGs), leukotrienes (LTs), and epoxyeicosatrienoic acids (EETs), respectively (see Figure 1). PG biosynthesis arises following the metabolism of AA by COX enzymes to PGH2, which may be further metabolized by downstream synthases to both PGs and thromboxane, collectively referred to as the prostanoids. LOXs, on the



Prostaglandins are oxygenated polyunsaturated 20-carbon fatty acids containing a cyclopentane ring. Prostaglandins are designated by the letters A-J depending the nature and position of substituents on the cyclopentane ring and the presence and position of double bonds within the ring, and by a numerical subscript, which indicates the number of double bonds in the alkyl side chains [1]. For instance, metabolism of eicosatrienoic acid (C20 3 n-6) by COX gives rise to prostaglandins of the 1-series; those of the 2 series are from eicosatetraenoic acid (C204 n-6); and the 3 series are from eicosapentaenoic acid (C20:5 n-6). The synthesis of prostanoids and thromboxane occurs wholly within cells following the release of AA from membrane phospholipids by phospholipase A2 (PLA2; of which several isoforms exist) (Figure 1). The hydrolyzed AA is then oxidized to PGG2, which is then rapidly reduced to PGH2 by either COX-1 or COX-2 isoform. These two isoforms are distinctly expressed in different tissues as well as in relation to the activation (inflammation) status. The endoperoxide PGH2 then serves as a substrate for a series of downstream synthases including PGE2 synthase, PGD2 synthase, prostacyclin (or PGI2) synthase, PGF2a synthase, and thromboxane (Tx) A2 synthase, giving rise to PGE2, PGD2, PGI2, PGF2a, and TxA2, respectively (Figure 1). The unique profile of potently bioactive prostanoids released by a particular cell presumably depends upon the expression/enzyme activity and/or functional coupling of these downstream synthases to either COX isoform. PGG2 and PGH2 are relatively short-lived endoperoxide intermediates possessing a dioxygen bridge between C-9 and C-11 on the ring (Figure 1). PGI2 has an oxygen bridge between C-6 and C-9 and is broken down to the stable metabolite, 6-keto-PGF1a. Likewise, as TxA2 has an unstable bicyclic oxane-oxetane ring structure, it is also rapidly converted to a stable oxane derivative, TXB2.




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Essentials of Human Physiology

Essentials of Human Physiology

This ebook provides an introductory explanation of the workings of the human body, with an effort to draw connections between the body systems and explain their interdependencies. A framework for the book is homeostasis and how the body maintains balance within each system. This is intended as a first introduction to physiology for a college-level course.

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