Special topic: Arachidonate, Eicosanoids, and Endocannabinoids

  
[ Wed 02-27-02 ] CHEM 445: [ home ] [ syllabus ]
Reading: Stryer, Ch.24, pp.624-625     [ Back to Lecture 14 ]
This page was last updated on 27-Feb-2002  
Synopsis: Arachidonate is derived from the essential fatty acid linoleate. Linoleic acid is an w-6 fatty acid, and the dietary requirement for w-6 fatty acids is at least in part due to its conversion to arachidonate, which is itself a precursor of several important classes of signaling molecules. These molecules, collectively referred to as eicosanoids, are involved in a large variety of physiological processes, such as inflammation and other aspects of immune system response, regulation of blood flow and clotting, ion transport, synaptic transmission, and reproductive phenomena. The major classes of eicosanoids are the prostaglandins, prostacyclins, thromboxanes, and leukotrienes. In addition, neutral derivatives of arachidonate, such as anandamide (arachidonylethanolamide) and 2-AG (sn-2-arachidonylglycerol) have been found to serve as natural ligands for cannabinoid (CB) receptors. The pharmacological effects of these endocannabinoids suggest that they participate in regulating mood, memory, appetite, and perception of pain. CB receptor agonists have been reported to have a role in control of neuronal excitability. Thus, consideration of the metabolic provenance and fate of arachidonate leads into a complex, yet fascinating story that weaves together aspects of biochemistry, nutrition, immunology, neurobiology and pharmacology. The unfolding of this story is at a relatively early stage, and investigations relating to arachidonate derivatives are current and active areas of research.
   

Arachidonate is derived from linoleate by elongation and desaturation

  
Given the availability of linoleate from dietary sources, the synthesis of arachidonate can proceed by means of the elongase and desaturase activities associated with the smooth ER. The scheme at left shows one possible pathway.
 
     
   

Arachidonate is stored as an ester in membrane phospholipids

  
Very little free arachidonate exists in cells. Instead, it is typically stored as an ester in membrane phospholipids. The fatty acids in membrane phospholipids are mobilized by phospholipase enzymes. Phospholipases are classified according to which bond of the phospholipid is hydrolyzed, as shown in the figure.
  Analysis of membrane phospholipids has shown that saturated fatty acids predominate at the sn-1 position of 3-phosphoglycerol derivatives, while unsaturated fatty acids predominate at the 2 position. Thus, arachidonate is typically liberated by phospholipase A2 (PLA2). Alternatively, arachidonate may be modified within the membrane itself, and PLA2 action would then liberate the arachidonate derivative. Either way, it provides an example of how membrane phospholipids are themselves integral parts of signaling pathways of cells. Another example is that of phosphoinositol phosphates (X in the figure at left would correspond to a phosphorylated form of inositol). The activity of PLA2 could itself be regulated by some type of signal, perhaps a rise in intracellular [Ca2+], leading to the release of arachidonate, and its subsequent conversion to the signaling molecules derived from it, as explained further below.
   

Cyclooxygenase enzymes convert arachidonate into eicosanoid signaling molecules

  

Much of the arachidonate that is destined to become eicosanoid molecules is converted to the common precursor of prostaglandins, prostacyclins, and thromboxanes by PGH2 synthase - also sometimes referred to as prostaglandin synthase, but quite commonly referred to simply as cyclooxygenase (COX). The synthase has two distinct activities - a cyclooxygenase activity that utilizes molecular oxygen to attach peroxide to arachidonate, while at the same time introducing a cyclopentane ring. This intermediate product is referred to as PGG2. A subsequent reductive step - the peroxidase step - takes place at distinct site within the enzyme, and forms the product PGH2. This is itself quite labile, and is normally converted into one of many eicosanoid derivatives, depending on the context. Isomerases convert PGH2 into the different types of prostaglandins. Prostacyclin synthase converts PGH2 into PGI2, which undergoes further conversions. Thromboxane synthase converts PGH2 into TXA2, which can also undergo further conversion (see figure below).

An interesting pharmacological feature of COX enzymes is that they are inactivated by aspirin (acetylsalicylate). The inactivation is due to aspirin's ability to acetylate a serine residue of COX that is necessary for catalysis. Although aspirin itself was one of the first drugs ever synthesized, and herbal remedies based on plants containing salicylate derivatives have been used for centuries, the mode by which aspirin exerts its effects was not understood until 1971, when John Vane discovered that aspirin blocked the formation of prostaglandins and thromboxanes. The therapeutic utility of aspirin is now thought to be largely due to this effect, as these eicosanoids have an impressive range of physiological effects. Sune Bergström, Bengt Samuelson, and Vane were awarded the 1982 Nobel Prize in Physiology or Medicine for their discoveries concerning "prostaglandins and related biologically active substances".

    

Coming soon:

More of the story....stay tiuned!
 

References

Campbell WB & Halushka PV. (1996) "Ch.26: Lipid-derived autacoids" from Goodman & Gilman's The Pharamacological Basis of Therapeutics (9th ed., McGraw-Hill)
Christie Mc & Vaughn C. (2001) "Cannabinoids act backwards" (News and views). Nature 410: 527-530.
DiMarzo et al. (2001). "Leptin-regulated endocannabinoids are involved in maintaining food intake" Nature 410: 822-825.
Kurumbail RG, Kiefer JR, Marnett LJ. (2001) "Cyclooxygenase enzymes: catalysis and inhibition" Curr Opin Struct Biol 11: 752-760.
Mechoulam R & Fride E. (2001) "A hunger for cannabinoids" (News and views). Nature 410: 763-765.
Wilson RL & Nicoll RA. (2001) "Endogenous cannabinoids mediate retrograde signalling at hippocampal synapses" Nature 410: 588-592.
 
   
 
[ Back to top of page ] [ Back to Lecture 14 ] [ E-mail: cronk@gonzaga.edu ]