Arachidonic acid biosynthesis, formation

Additional hypotheses concerning prostaglandin biosynthesis in P. homomalla resulted from isolation of 11R-HETE (76) from the polar lipid fraction [95]. Apparently, 11R-HETE (76) is also a minor product of incubations of arachidonic acid with acetone powder preparations of P. homomalla [95], In this alternate hypothesis (Scheme 8), an 11-hydroxy or 11-hydroperoxy-8,9-allene oxide intermediate is formed from a sequence of oxidations at C8 and Cll. Opening of the allene oxide to a transient C8 earboeation induces eycli-zation with a consequent addition of water to C15. This proposed pathway leads initially to formation of PGE2 (16 or 38), which following acetylation, elimination of acetic acid from Cl 1-12, and esterification, forms the observed major natural product in the coral, 15-acetoxy methyl PGA2 (36 or 54). Notably, if... 

Evidence indicates that steroids affect other cells and substances that modulate inflammation. Exposure of human basophils to steroid in culture inhibits histamine release induced by an IgE-dependent stimulus. Steroids inhibit phospholipase A2, which prevents biosynthesis of arachidonic acid and subsequent formation of prostacyclin, thromboxane A, prostaglandins, and leukotrienes. Steroids also decrease capillary permeability and fibroblast proliferation and the quantity of collagen deposition, thereby influencing tissue regeneration and repair. 

Gamma-linolenic acid (18 3n-6) is an important unsaturated fatty acid. It is the precursor for biosynthesis of arachidonic acid that is a precursor for prostaglandin formation. Recently, y-linolenic acid has been recognized for its potential health benefits in prevention and treatment of cardiovascular disorders, premenstrual syndrome, atopic eczema, rheumatic arthritis, and alcoholism (13, 14). Seed oils of blackcurrant and other Ribes species, as well as evening primrose seed oils, are rich sources of natural y-linolenic acid. 

Steps in prostaglandin (PG) biosynthesis PG synthesis involves four steps 1) Release of the substrate, arachidonic acid (20 4), firom membrane phospholipids by a phospholipase. 2) Formation of the common intermediate, PGHj, from arachi-donate by PGH synthase throu sequential cyclo-oxygenase and peroxidase activities, both ofwWch are present within the same enzyme. 3) Fonnation of cell-specific PG products, either "stable" (Dj, E, Fj,) or "imstable" (thromboxane, prostacyclin), by distinct enzymes formd in different cells and tissues. 4) Breakdown of active compoimds to inactive metabolites, using TxAj -> TxB, and PGI -> 6keto PGF as examples. 

Burstein and Hunter (1995) observed that THC stimulated the biosynthesis of anandamide in neuroblastoma cells employing either ethanolamine or arachidonic acid as the label. Anandamide bios5mthesis has also been shown to occur in primary cultures of rat brain neurons labelled with [H]-ethanolamine when stimulated with ionomycin, a Ca ionophore (Di Marzo et al. 1994). These authors proposed an alternate model for the biosynthesis of anandamide in which N-arachidonoyl phosphatidyl ethanolamine is cleaved by a phospholipase D activity to yield phosphatidic acid and ararchidonoylethanolamide. This model is based upon extensive studies undertaken by Schmid and collaborators (1990), who have shown that fatty acid ethanolamide formation results from the N-acylation of phosphatidyl ethanolamine by a transacylase to form N-acyl phosphatidylethanolamine. Possibly resulting from postmortem changes, this compound is subsequently hydrolyzed to the fatty acid ethanolamide and the corresponding phosphatide by a phosphodiesterase, phospholipase D. 

Original evidence for the formation of NADA from arachidonic acid and dopamine or tyrosine (Huang et al. 2002) suggested a biosynthetic pathway common to that of the recently discovered arachidonoyl amino acids (Huang et al. 2001), i.e. from the direct condensation between arachidonic acid and dopamine, or, alternatively, from the condensation between arachidonic acid and tyrosine followed by the transformation of N-arachidonoyl-tyrosine into NADA by the enzymes catalysing dopamine biosynthesis from tyrosine. Preliminary data have shown, however, that NADA cannot be produced from either N-arachidonoyl-tyrosine or N-arachidonoyl-L-DOPA either in vitro, in brain homogenates, or in vivo, and that the lipid formed from tyrosine and arachidonic acid is not NADA (M.J. Walker and V. Di Marzo, unpublished observations). Clearly, further studies are needed to understand the biosynthetic mechanism for this putative endocannabinoid. 

Fig. 6.15 Formation and function of diacylglycerol. The figure schematically shows two main pathways for formation of diacylglycerol (DAG). DAG can be formed from PtdlnsP2 by the action of phospholipase C (PL-C). Another pathway starts from phosphatidyl choline. Phospholipase D (PL-D) converts phosphatidyl choline to phosphatidic acid (Ptd), and the action of phosphatases results in DAG. Arachidonic acid, the starting point of biosynthesis of prostaglandins and other intracellular and extracellular messenger substances, can be cleaved from DAG. PKC protein kinase C Ptdlns phosphatidyl inositol.

The biosynthesis required NADPH and was inhibited by carbon monoxide. Experiments using strongly indicated that the 1,2-diols were formed by hydrolysis of the w6- and arachidonic acid, respectively [396], and these epoxides could later be isolated [397]. Other identified metabolites were formed by wl- and 2-oxidation [395]. Formation of several monohydroxy-eicosatetraenoic acids has also been reported [398]. 

The biosynthesis of TXA from its precursor fatty acid, arachidonic acid, proceeds via the intermediate prostaglandin endoperoxides [19]. Studies on the kinetics of this reaction sequence indicated that the formation of the prostaglandin endoperoxides is the rate limiting step [99]. Variations in the pH of the incubation medium between pH 5 and pH 8 did not influence the reaction rate appreciably [95,100,101]. 

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