Biosynthesis of leukotriene

The (Z)-8-eicosen-5-ynoic acid F, another rationally devised irreversible inhibitor of the biosynthesis of leukotrienes and SRS-A s was synthesized as shown below (Ref. 3) ... 

The other major arachidonic acid (AA) converting enzyme is an integral binding protein, 5-lipoxygenase, which is responsible for the initial transformation in a cascade of events towards the biosynthesis of leukotrienes. Leukotrienes are major mediators of numerous biological processes, including chemotaxis, and are implicated in hypersensitivity disorders like asthma. It was discovered in the early 1990s that another protein is necessary for the cellular synthesis of... 

Samuelsson B, Funk CD. (1989) Enzymes involved in the biosynthesis of leukotriene B4. J Biol Chem. 264, 19469-19472. 

Oxime derivatives of heterocyclic compounds, such as pyrrole and quinoline, were proposed as anti-inflammatory agents, probably due to their ability to inhibit the biosynthesis of leukotrienes . Inhibition of 5-lipogenase by oximes of biphenyl sulfides , and by 0-aIkylcarboxylate oximes of indole " , were suggested as key leads for the development of efficient anti-inflammatory drugs. 

Other details of the biosynthesis of leukotrienes and prostaglandins were given in Sections 9.16 and 19.6, respectively. 

Inhibitor of the S-lipoxygenase enzyme necessary for the biosynthesis of leukotrienes including LTD,. 

Ziboh VA, Fletcher MP. Dose-response effects of dietary gamma-linolenic acid-enriched oils on human polymorphonuclear-neutrophil biosynthesis of leukotriene B4. Am J ClinNutr 1992 55 39-45. 

Although most studies have focused on the role of GSH S-transferases in xenobiotic metabolism, these enzymes also have multiple endogenous metabolic functions. For example, the biosynthesis of leukotriene C4, the GSH conjugate of the epoxide leukotriene A, was shown to be catalyzed by the GSH S-transferase from Dirofilaria immitis (54). In addition to the selenium-dependent GSH peroxidase, eukaryotic cells have selenium-independent GSH peroxidase activity that is attributable to GSH... 

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

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. 

In this section, papers concerning the structures and biosynthesis of leukotrienes are reviewed. Initially leukotrienes of the A and B types (oxygen substituents only) are described, while the latter part deals with the leukotrienes of C, D and E types (i.e. amino acid containing compounds with SRS properties). 

The first enzymatic transformation in the biosynthesis of leukotrienes is an oxygenation of the fatty acid substrate, by a lipoxygenase, giving a hydroperoxide. Thus, arachidonic acid can be converted to 5-hydroperoxyeicosatetraenoic acid (5-HPETE)... 

In addition to fatty acid cyclooxygenase (11,15-bis-lipoxygenase) there are several other lipoxygenases in mammalian tissues (Fig. 12). Leukocytes and mast cells contain a 5-lipoxygenase which leads to the biosynthesis of leukotrienes from arachidonic acid [176,177]. 12-Lipoxygenase, rich in platelets, initiates a bio.synthetic... 

Lipoxygenases (originally termed lipoxidases) were discovered in higher plants before the first reports on their presence in mammalian cells [1-4]. Nevertheless, the first clear biological function of a lipoxygenase was established for a mammalian enzyme (the arachidonate 5-lipoxygenase) when the biosynthesis of leukotrienes was elucidated [5]. More recently, research into plant lipoxygenases has intensified. 

Caffeic acid, one of the most prominent naturally occurring cinnamic acids, is known to selectively block the biosynthesis of leukotrienes, components involved in immunoregulation diseases, asthma, and allergic reactions [35]. 

Recently, total absence of cysteinyl leukotrienes in the CSF of patients with a severe neurodevelopmental syndrome led to the discovery of LTC4-synthase deficiency [6, 7]. In the meantime there is evidence of two further defects in the biosynthesis of leukotrienes representing a new group of neurometabolic disorders [8]. 

Figure 1 Biosynthesis of leukotriene B4. 5-HPETE, 5-hydroperoxy-eicosatetrae-noic acid FLAP, 5-lipoxygenase-activat-ing protein.

---