Biosynthesis of platelet-activating factor

Benveniste J, Chignard M, Le Couedic JP, and Vargaftig BB. (1982). Biosynthesis of platelet-activating factor (PAF-ACETHER). II. Involvement of pho fiiolipase A2 in the formation of PAF-ACETHER and lyso-PAF-ACETHER fiom rabbit platelets. Thromb. Res. 25,375-385. 

Fig. 9. Biosynthesis of platelet-activating factor (PAF) via the remodeling pathway. Lyso-PAF, the immediate precursor of PAF, can be formed from l-alkyl-2-acyl-sn-glycero-3-phosphocholine through the direct action of (I) PLAj or (II) CoA-independent transacylase. The lysoplasmenylethanolamine (or other potential ethanolamine- and choline-containing lysoglycerophospholipids) is thought to be generated by (III) a PLAj that exhibits a high degree of selectivity for substrates with an atachidonoyl moiety at the sn-2 position. The transacylase (II) appears to possess both acyl transfer and PLAj hydrolytic activities. Lyso-PAF produced by either the transacylation (II) or direct PLAj (I) action can be acetylated to form PAF by (IV) an acetyl-CoA acetyltransferase.

Fig. 11. Biosynthesis of platelet-activating factor (PAF) via the de novo pathway. The three-step reaction sequence, beginning with l-alkyl-2-lyso-s -glycero-3-phosphate as the precursor, is catalyzed by (I) acetyl-CoAialkyllysoglycerophosphate acetyltransferase, (II) alkylacetylglycero-phosphate phosphohydrolase, and (HI) dithiothreitol-insensitive CDP-choline alkylacetylglycerol cholinephosphotransferase.

Snyder, F., Fitzgerald, V., Blank, M.L. 19%. Biosynthesis of platelet-activating factor and enzyme inhibitors. Adv. Exp. Med. Biol. 416 5-10. 

Figure 24-1. Overview of acylglycerol biosynthesis. (PAF, platelet-activating factor.)...

Figure 24-4. Biosynthesis of ether lipids, including plasmalogens, and platelet-activating factor (PAF). In the de novo pathway for PAF synthesis, acetyl-CoA is incorporated at stage, avoiding the last two steps in the pathway shown here.

Pei, Y. et al., Activation of the epidermal platelet-activating factor receptor results in cytokine and cyclooxygenase-2 biosynthesis, J. Immunol. 161,1954—1961, 1998. 

Very little is known about the biosynthesis of the three most recently proposed endocannabinoids, 2-AGE, virodhamine and NADA. Regarding 2-AGE (noladin ether), this compound was previously identified in pig brain (Hanus et al. 2001) and in some rat tissues and brain areas (Fezza et al. 2002) by using mass-spectrometric (MS) methods coupled to chromatographic separations. However, a recent study cast some doubt on the actual existence of 2-AGE in mammalian brain tissue (Oka et al. 2003). At the time of this study it was already known that (1) the only acyl ethers to have been detected in animals before the discovery of 2-AGE were 2-acyl ethers (e.g. alkenyl ethers such as platelet activating factor and plasmalogens) (2) there was no evidence for the existence of any enzyme catalysing the formation... 

P ADP -I- l-alkyl-sn-glycero-3-phosphate <1> (<1> the product l-alkyl-2-lyso-sn-glycero-3-phosphate is the branch point intermediate in the de novo biosynthesis of ether-linked glycerolipids, plasmanylcholine, i.e. ethanolamine, and corresponding plasmalogenic analogs in membranes or platelet-activating factor PAF [2]) [1, 2]... 

Ramesha, C.S. and Pickett, W.C. (1986). Platelet activating factor and leukotriene biosynthesis is inhibited in polymorphonuclear leukocytes depleted of arachidonic acid. J. Biol Chem., 261, 7592-7595... 

Two clinical studies have demonstrated that aspirin reduces the incidence of myocardial infarction and death by up to 50% in patients with unstable angina, suggesting an important role for thromboxane A2 in their occur-rence . Whether platelet activation and thromboxane A2 also play a role in the episodic ischaemia of unstable angina is unknown. Evidence of platelet activation " in patients with unstable angina based on plasma levels of platelet granule proteins, such as j8-thromboglobulin and platelet factor 4, is difficult to interpret since such measurements are highly sensitive to ex vivo platelet activation . Similarly, studies of thromboxane A2 biosynthesis have been... 

Although some details of the biosynthesis of HA have still to be clarified, epidermal growth factor (EGF), platelet-derived growth factor (PDGF), transforming growth factor P (TGF-P) and other cytokines, e.g. interleukin-1 (IL-1) are known to activate the synthesis of HA in the cells [86]. 

A second, potentially confounding, factor is that, at the doses of aspirin used, prostacyclin biosynthesis is markedly depressed. Whether prostacyclin limits platelet activation in this disease is not known. However, prostacyclin... 

Suzuki, M. Asplund, T. Yamashita, H. Heldin, C.-H. Heldin, P. Stimulation of hyaluronan biosynthesis by platelet-derived growth factor-BB and transforming growth factor-pi involves activation of protein kinase C. Biochem. J. 1995, 307, 817-821. 

---