Structure/Overview: Leukotrienes and Lipoxins




Structure.html


Leukotrienes are a family of macromolecules that are derived from arachidonic acid by the lipoxygenase pathway. Its main function is similar to hormones but work on localized places. There main functions are to promote inflammation and allergic reactions such as the bronchial constriction of asthma and any swelling that might occure. These acids are responsible for all swelling that occurs in the body. Lipoxins are linked to leukotrienes in the form that lipoxins are a derivative from the same mechanism as leukotrienes. The following is a picture of a scheme of how leukotrienes are synthesised.




The image that follows is where arachidonic acid is synthesises. Which which all leukotrienes and lipoxins are derived from.





The structure of leukotrienes and lipoxins are conjugated chemicals that have double bonds that are saturated. What separates each one is the functional group at the end of there chain. All leukotrienes are derived from arachidonic acid and other polyunsaturated fatty acids. The first leukotriene was Leukotriene C which was discovered in the class of white blood cells called polymorphonuclear leukocytes. It was named this way because of the Leuko cytes and the triene structure which consist of three double bonds.[1] The picture that follows is how arachidonic acid is synthesised to some leukotrienes.





This is a yet another picture on how Arachidonic acid is formed into other leukotrienes.





Lipoxins are very similar to Leukotrienes. They are synthesized by the 5-lipoxygenase pathway. They are slow reacting substance of anaphylaxis (a.k.a. asthma) and other inflammatory diseases. Lipoxins are also derived by arachidonic acid(see fig. below). They produce cyclooxygenase and the lipoxygenases enzymes that catalyze the stereospecific insertion of the molecular oxygen into different positions in the arachidonic acid. They are named according to the position of the carbon atom into which the oxygen's inserted. It is usually called "energy currency" of the molecule that distinguishes each acid from each other.[2]


Lipoxins are metabolised a little differently from leukotrienes. Lipoxins are tetraene-containing eicosanoids. They are metabolized to form triene products. The result of dehydrogenation and reduction of the conjugated tetraene systems yeilds the lipoxins. A major lipoxin is Lipoxin A4 (LXA4) it is formed from 15-oxo-LXl4, 13, 14-dihydro-15-oXo and 13, 14-dihydro-LXA4 lipoxin. It is metabalized in human neutrophils, pronuclocytic leukemia (HL-60) cells and adherent monocytes. The important thing to get from this study was that lipoxins as well as leukotrienes are derived from various mechanisms.[4] The follwing picture is how a single scheme on how to senthesis lipoxin.





In a recent study some resurches found that the 5-lipoxygenase contains one atom of iron per molecule of enzyme. The nature of the iorn-binding ligands is also being studyed. They are doing this by site directed mutagenesis. This was found by the Department of Medical Biochemistry and Biophysics Div. of Phsiological Chemistry Karolinska institutet in Stockholm, Sweden.


[2]




Leukotrienes and Lipoxins and there affects:




Leukotriene affects collagen-induced arthritis. Some experiments that were done on leukotriene B4(LTB4) receptor sites worked to eleviate swelling for some patents that who were suffering from rheumatoid arthritis induced by collagen. The receptor antagonist of LTB4 stoped the linkage between neutrophil membranes and LTB4 in the cells affected. The thing is that it does not inhibit this proccess through suppression of the humoral immuno response to collagen, but the stopage of the formation of the chemical that coused the swelling which is LTB4. The following figure shows the sentheses of LTB4.[3]





Another apperence made by leukotrienes is in the stomach. Mast cells regulate the gastric mucosal integrity of the stomic by relesing IL-1 and nitric oxide. What this means is that leukotriene one swells up the belly if too much acid is produced. This study found that the increase in the number of mast cells does not increase mucosal susceptibility to injury coused by the large amount of acid. It is coused by the activatio of the irritant which is mediated by a peptidoleukotriene dependent mechanism. There are other studies on this topic that are underway to find inhibitors to this mehcanism.[5]


Human immunodeficiency virus (HIV) infection of brain macrophages and the deteriation of parts of the brain are central features of HIV-induced central nervous system (CNS) disorders coused by AIDS. Leukotriene B4, leukotriene D4, lipoxin A4, and platelet-activating factors were found in large amounts in the patients studied. High performance luquid chromatography separation and correlated with cytokine activity found these substances. What this means is that specific inhibitors of the arachidonic cascade might deminishe the cytokine response. this suggests that there is a regulatory relationship between these factors.[6]


STRUCTURE/FUNCTION/REGULAION/CONTROL