Lipoxins biosynthesis

Serhan CN Lipoxin biosynthesis and its impact in inflammatory and vascular events. Biochim Biophys Acta 1994 1212 1. 

Levy BD, Bonnans C, Silverman ES, Palmer LJ, Marigowda G, Israel E (2005) Diminished lipoxin biosynthesis in severe asthma. Am J Respir Crit Care Med 172 824—830... 

Serhan C. N. 2002. Lipoxins and aspirin-triggered 15-epi-lipoxin biosynthesis An update and role in anti-inflammation and pro-resolution. 

Figure 1. Pathways and chemical structures for leukotriene and lipoxin biosynthesis. Enzymes responsible for known catalytic steps are noted in italics. AA, arachidonicacid.5-, 15-LOX, 5-, 15-lipoxygenase. 5-, 15-HETE, 5(5 )-, 15(5)-hydroxyeicosatetraenoicacid.5-, 15-HPETE, 5(5 )-, 15(5 )-hydroperoxyeicosatetraenoic acid. 5(6)-Epoxytetraene, 15(5)-hydroxy-5(6)-epoxy-7,9,13- ra. -ll-c/5-eicosatetraenoic acid. LTA, leukotriene A 5(6)-epoxy-7,9- rafZ5-ll,14-cw-eicosatetraenoic acid. LTB, leukotriene 5(5 ),12(/ )-dihydroxy-6,14-cw-8,10- rfl .y-eicosatetraenoic acid. LTC, peptido-leukotriene C 5(5)-hydroxy-6(/ )-5 -glutathione-7,9-fra 5-ll,14-cw-eicosatetraenoic acid. LTD, peptido-leukotriene D 5(5)-hydroxy-6(/ )-( S-cysteinylglycinyl)-7,9-rra 5-11,14-cA-eicosatetraenoic acid. LTE, peptido-leukotriene E 5(5)-hydroxy-6(/ )-( S-cysteinyl)-7,9-rra 5-ll,14-cw-eicosatetraenoic acid. LXA, lipoxin A 5(5 ),6(/ ), 15(5)-trihydroxy-7,9, 3-trans-11 -cA-eicosatetraenoic acid.

Detailed accounts of the biosynthesis of the prostanoids have been pubUshed (14—17). Under normal circumstances arachidonic acid (AA) is the most abundant C-20 fatty acid m vivo (18—21) which accounts for the predominance of the prostanoids containing two double bonds eg, PGE2 (see Fig. 1). Prostanoids of the one and three series are biosynthesized from dihomo-S-linolenic and eicosapentaenoic acids, respectively. Concentrations ia human tissue of the one-series precursor, dihomo-S-linolenic acid, are about one-fourth those of AA (22) and the presence of PGE has been noted ia a variety of tissues (23). The biosynthesis of the two-series prostaglandins from AA is shown ia Eigure 1. These reactions make up a portion of what is known as the arachidonic acid cascade. Other Hpid products of the cascade iaclude the leukotrienes, lipoxins, and the hydroxyeicosatetraenoic acids (HETEs). Collectively, these substances are termed eicosanoids. 

Samuelsson B, Dahlen SE, Lindgren JA, Rouzer CA, Serhan CN. Leuko-trienes and lipoxins structures, biosynthesis, and biological effects. Science 1987 237 1171-1176. 

Figure 21-8 The 5-lipoxygenase pathway for biosynthesis of the hydroperoxy- and hydroxy-eicosanoic acids, leukotrienes, and lipoxins.

Eicosanoids (prostaglandins, thromboxanes, leuko-trienes, lipoxins) is the name given to a group of 20-carbon unsaturated fatty acids derived principally from arachidorric acid in cell walls. They are shortlived, extremely potent and formed in almost every tissue in the body. Eicosanoids are involved in most types of inflammation and it is on manipulation of their biosynthesis that most present anti-inflammatory therapy is based. Their biosynthetic paths appear in Figure 15.1 and are amplified by the following account. 

Bannenberg GL, Aliberti J, Hong S, Sher A, Serhan C (2004) Exogenous pathogen and plant 15-lipoxygenase initiate endogenous lipoxin A4 biosynthesis. J Exp Med 199 515—523... 

Lindgren JA, Edenius C Transcellular biosynthesis of leukotrienes and lipoxins via leukotriene A4 transfer. Trends Pharmacol Sci 1993 14 351-354. 

Papayianni A, Serhan CN, Phillips ML, Rennke HG, Brady HR Transcellular biosynthesis of lipoxin A4 during adhesion of platelets and neutrophils in experimental immime complex glomerulonephritis. Kidney Int 1995 47 1295-1302. 

Claria J, Titos E, Jimenez W, Ros J, Gines P, Arroyo V, Rivera F, Rodes J Altered biosynthesis of leukotrienes and lipoxins and host defense disorders in patients with cirrhosis and ascites. Gastroenterology 1998 15 147—156. 

Biosynthesis The endoperoxides PGG2 and PGH2 are formed in the so-called arachidonic acid cascade from eicosatetraenoic acid (arachidonic acid) liberated from membrane phospholipids by phospholipase A2 (EC 3.1.1.4) (see figure under thromboxanes) under the action of cyclooxygenase. All other PG are then formed by further enzymatic reactions. In contrast to other hormones, PG are not stored in the cell but are always newly synthesized when required. The close relatives of the PG, the thromboxanes, prostacyclins, leuko-trienes, and lipoxins are also generated from eicosa-polyenoic acids in the lipoxygenase pathway. For synthesis, see Ut.. ... 

This chapter is focused on the biosynthesis and actions of lipoxins, resolvins, protectins, and maresins. Each group of PUFA-derived lipid mediators has its own distinct biosynthetic pathways and features a specialized biological activity profile. 

Similarly to the biosynthesis of lipoxins and E-resolvins, the postulated formation of D-resolvins [15] takes place from DHA and involves similar dual lipoxy-genations (Figure 9.5). The action of 15-LO on DHA forms 17S-HpDHA followed... 

Lipoxins constitute an additional family of bioactive LOX products which are characterized by a conjugated tetraene structure and three asymmetric carbons to which hydroxy groups are attached [25]. Lipoxins are abbreviated to LX followed by a capital letter (A or B) that indicates the position of the OH-groups, and by a subscript which gives the number of the double bonds. The biosynthesis of lipoxins [26,27] involves a concerted action of 5- and 15-LOXs or of 5- and 12-LOXs as well as an enzymic hydrolysis of an epoxide intermediate (Scheme 6). However, in vitro experiments with purified rabbit 15-LOX suggested that lipoxin B4 can be formed... 

Synthesis of lipoxins can occur by activation of various biosynthetic pathways (Serhan, 1994). Besides derivation from LTA as mentioned above, catalysis by 15-LOX, or by a combination of 5-LOX and 12-LOX, can give rise to various lipoxin isomers. The first pathway to be described was that involving the formation by 15-LOX of 15(5 )-hydroperoxyeicosatetraenoic acid [15(5)-HPETE see Figure 1] followed by the formation of a 5(6)-epoxytetraene intermediate [15(5)-hydroxy-5(6)-epoxy-7,9,13-frans-ll-cw-eicosatetraenoic acid] in a two-step 15-LOX catalytic cycle analogous to that observed with 5-LOX in the biosynthesis of LTA (Serhan, 1994,2002). In addition to these LOX-initiated pathways, more recently a COX-2 dependent synthesis of LXA epimers at the carbon 5 position has been demonstrated. This pathway is... 

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