LEUKOTRIENES & LIPOXINS
The control and regulation of leukotrienes is of significant importance due to the fact that these molecules participate, although sometimes by limited means, in critical biological functions. The interest garnered by these recently introduced compounds lies in the actions that they undertake and the manner by which they go about their specific roles.
In order to thoroughly understand the particular characteristics relating to the control and regulation of leukotrienes, a brief basis of relevant background knowledge should be reviewed. They are a subgroup of eicosanoids, which are compounds that function as biological regulators. This unique class of lipids are distinguished by their potent physiological properties, low concentration levels in tissues and rapid metabolic turnover. Leukotrienes are similar to hormones in that they have profound physiological effects at low concentrations. However, they differ from hormones in that they are not produced in a central organ and transported to a specific location but rather they act in the same environment in which they are synthesized. Leukotrienes are involved in several immune-mediated inflammatory reactions of anaphylaxis ( a violent and sometimes fatal allergic reaction) and are recognized as components of slow reacting substances of anaphylaxis (SRS-A). They contract smooth muscle, affect vascular permiability, and are strong attractants of polymorphonuclear leukocytes.The distinctive determinants of the control and regulation of leukotrienes are directly related to the functions they perform and characteristics they contain.
Several factors, both internal and external, possess the ability to affect the control and regulation of leukotrienes at various stages of their short lives. An initial factor is the availibilty of certain fatty acids in the cell's plasma membrane. The short life spans of leukotrienes and the discrete amounts by which they are accessible in the body presents one regulation related affect. Leukotrienes are also influenced by enzymatic control. Without enzymes these compounds cannot be produced, differentiated, and exhibit functional handicaps. A recent yet rapidly advancing field of control and regulation pertaining to leukotrienes is by way of pharmacologic agents. Many of these pharmaceutical drugs being developed concern the artificial inhibiting or activating of leukotriene synthesis, or they focus on regulating their physiological abilities. One or more of these factors are practically always present in order to keep the jurisdiction of leukotrienes limited.
Control & Regulation
The control and regulation of the leukotrienes is dependent on many factors. An important one is the availibility and amount of integral fatty acids, alpha-linolenic acid and linolenic acid, present in the plasma membrane. The significance of this factor is that without these base materials, there is no product. Certain membrane phospholipids, alpha-linolenic acid and linolenic acid, are necessary in the production of leukotrienes because they are the precursors of arachidonic acid . Once these fatty acids are broken down to arachidonic acid, the 5-lipoxygenase pathway can begin and leukotrienes can be formed. The amount and availibility of these phospholipids is a contributing influence on control and regulation because if a shortage exists, the cell is limited in the amount of leukotrienes that can be produced.
The limited amounts of leukotrienes that are available in the body at one time allows for a rather large degree of control. They are metabolized extremely rapidly which allows the body to increase or decrease their amounts very quickly. Their half-life is generally less than five minutes long and most fail to survive one pass through the circulatory system . From a production standpoint, leukotrienes can be efficiently readily manufactured by liberating phospholipids from the cell membrane. This control mechanism is crucial because leukotrienes have profound physiological effects at low concentrations, if they were not restricted, a fatal situation could arise.
Enzymatic control is another factor that exhibits regulatory characteristics. Enzymes are integral in the process of leukotriene biosynthesis.The amount and presence of specific enzymes not only controls the initial production of leukotrienes but the differentiation reactions as well. Since the production of leukotrienes depends critically on the availibility of free arachidonic acid, the initially important enzyme is a phospholipase. The specific one responsible is phospholipase A2. This enzyme acts directly on phospholipids contained in the membrane and the result is a release of arachidonic acid . The next couple of enzymes are all catalysts along the leukotriene pathway. They are accountable for the production of the principal leukotriene as well as the transformations into its derivatives. The first enzyme of the pathway is 5-lipoxygenase. Due to the fact that it participates in the beginning steps of the reaction process, the route of leukotriene synthesis is usually referred to as the 5-lipoxygenase pathway. This enzyme's main role is to catalyze the insertion of molecular oxygen into the five carbon of arachidonic acid, thus turning arachidonic acid into 5-HPETE (5S-hydroperoxy-6,8-trans-11,14-cis-eicosatetraenoic acid) and eventually producing the unstable epoxide Leukotriene A4 . The next activated enzyme is LTA4 hydrolase. It's job is to catalyze the hydrolysis of Leukotriene A4 to Leukotriene B4. A reaction that can happen simultaneously is the production of Leukotriene C4 by means of Leukotriene A4 and reduced glutathione being catalyzed by LTC4 synthase enzyme, which is a member of the family of glutathione-S-transferases. The enzyme, g-glutamyl transferase, catalyzes the reaction from Leukotriene C4 to Leukotriene D4 and dipeptidase pushes Leukotriene D4 to Leukotriene E4. A visual picture of the enzymes and their place in the 5-lipoxygenase pathway is available.The role of these enzymes in the control and regulation of leukotrienes can basically be summarized by noting that the formation of the various leukotrienes are dependent on the amount of the enzyme and which particular one is present. By inhibiting lipoxygenase enzymes, a reduction of leukocyte accumulation will occur.
A popular and growing external factor of the regulation and control of leukotrienes involves pharmacologic agents. Few problems in the fields of medicinal chemistry or pharmacology provide as much interest as developing selective antagonists for recently discovered agonists. Antagonistic compounds are useful in that they have the ability to lend insight on the physiological and pathological happenings involving the agonist, which for our purposes, of course, will be leukotrienes. The primary target area for pharmacologic control is the production process, namely the 5-lipoxygenase pathway . Compounds that tend to either activate or inhibit certain functions of leukotrienes are also popular interests of research. One group of inhibitors focuses on attempting to suppress phospholipase A2 from executing its function of producing arachidonic acid and therefore terminating the initial step of leukotriene synthesis. Anti-inflammatory compounds are predominantly noticed to be antagonists of receptor sites. These compounds usually cause interference between the interactions of enzymes and activating proteins. The potential areas for possible inhibition besides the lipoxygenase pathway are the accesory protein (FLAP), LTA4 hydrolase for the nonpeptidyl leukotrienes or LTC4 synthase for the peptidyl leukotrienes . Although only initial studies and tests have been performed on the developments of pharmacologic agents related to leukotrienes and we have yet to derive a stable compound that functions efficiently and consistently, the foundation for future exploration has been formed. Some examples of possible antagonists are acetophenone derivatives, fused nitrogen heterocycles, and imidodisulfamides.
In conclusion, although the physiological functions of leukotrienes are known and insights concerning the regulation and control have accumulated, the information stage relating to this subject is relatively immature. There is very little known about the molecular actions of leukotrienes pertaining to their functions and regulation and control. Clinical trials are continuing to produce novel information regularly. Many pharmacologic studies of various compounds remain in the experimental stages without any present conclusive data. Due to their participation in various biological actions, leukotrienes have become a popular and interesting topic of research but only in time will we be able to conclusively view their full functions and characteristics.
Lipoxins, are a class of metabolites of arachidonic acid. They are a very recent addition to the eicosanoid family, having only been discovered in 1984. Their primary significance is that they represent the first natural products containing a fully conjugated tetraene derived from arachidonic acid . Although they are derived from arachidonic acid, like the leukotrienes, they have a different initial enzyme. While leukotrienes are dependent on the availibilty of 5-lipoxygenase, lipoxins rely on 15-lipoxygenase . As you can see in figure, leukocytes produce two types of lipoxins A and B.
Control & Regulation
Due to the fact that they are a recent discovery, only limited studies related to their function have been performed. This is turn has restricted the amount of knowledge available concerning their regulation and control because the operations and actions of a compound must be known before an attempt at controlling it can progress. Preliminary studies have shown that lipoxins exhibit some qualities that oppose those of the leukotrienes. Examples of these characteristics would be that lipoxins generally inhibit neutrophil and eiosinphil migration while leukotrienes promote it and they regulateand limit inflammation while leukotrienes activate this action. This anti-inflammatory quality is very unique and could, in time, develop into a useful means of regulating certain biological actions. Another means of possible control stems from the possible use of pharmacologic agents to activate or inhibit certain processes along the 15-lipoxygnase pathway. Since the functions of lipoxins seem to have antagonistic attributes relative to the actions of the leukotrienes, it would only seem correct in hypothesizing that factors that inhibit leukotrienes could possibly activate lipoxins and factors detrimental to lipoxins would be promote leukotrienes. As research on this unexplored realm continues to advance, many potentially advantageous functions are bound to surface.
Diets Rich in Marine Lipids May Decrease Leukotriene Levels
The major unsaturated component of marine lipids is 5,8,11,14,17-eicosapentaenoic acid (EPA) which is an w-3 fatty acid, rather than the arachidonic acid precursor linoleic acid, an w-6 fatty acid . Particularly rich sources of EPA are salmon, mackerel, blue fish, herring, and menhaden, fishes that live in deep cold waters. These fishes have fat in their muscles and skin.
Below is an image of the molecule of EPA. The available products of Prostaglandins (PG), Prostacyclins (PGI), Thromboxanes (TX), and Leukotrienes (LT) are shown at right.
Evidence for this can be traced to fishing villages in Japan, the people of Okinawa, and the Greenland Eskimos, whom despite their high dietary intake of cholesterol and fat, have a very low incidence of coronary heart disease and thrombosis. Their consumption of marine animals provides them with a higher proportion of unsaturated fats than the typical American diet. EPA inhibits the formation of Thromboxane A2. Instead, it is more likely to form Thromboxane A3. This is beneficial because Thromboxane A3 is a much weaker aggregator of platelets than is Thromboxane A2. The overall net effect is an antiplatelet effect, which is beneficial in helping to avoid thrombotic symptoms . EPA is also a precursor of the series-5 leukotrienes. The series-5 leukotrienes are compounds with substantially lower physiological activities than their arachidonic acid derived (series-4) counterparts . This suggests that a diet containing marine lipids should decrease the extent of leukotriene-mediated inflammatory responses. In fact, this is exactly the case. Dietary enrichment with EPA inhibits the in vitro chemotactic and aggregating activities of neutrophils. Another benefit is that unsaturated fat ingestion is correlated with low plasma cholesterol levels. An EPA rich diet decreases the cholesterol and tricylglycerol levels in the plasma. This is another area of interest that will evolve as arachidonate metabolism and its physiological effects become better known and understood.
References - Leukotrienes - Regulation and Control
1. Bhagavan, N.V. Medical Biochemistry. Boston: Jones and Bartlett Publishers, 1992. ppg. 408, 411, 418- 419, 813.
2. Chakrin, Lawrence W., and Denis M. Bailey. The Leukotrienes. New York: Academic Press, Inc., 1984. ppg. 163- 175.
3. Hood, Leroy E., Irving L. Weissman, William B. Wood, and John H. Wilson. Immunology. Second Ed. Menlo Park: The Benjamin/Cummings Publishing Co., 1984. ppg. 349, 351-352, 461-462.
4. Levi, Roberto, and Robert D. Krell. Biology of the Leukotrienes. New York: The New York Academy of Sciences, 1988. ppg. 122-123, 201-205, 218-219, 252-255.
5. Piper, Priscilla J. The Leukotrienes: Their Biological Significance. New York: Raven Press, 1988. ppg. 1-11, 41-55, 91-97, 100-105, 109- 121, 127- 131.
6. Tortora, Gerard J., Berdall R. Funke and Christine L. Case. Microbiology: An Introduction. Fifth Ed. Menlo Park: The Benjamin/Cummings Publishing Co., 1995. ppg.414, 467-468.
7. Voet, Donald, and Judith G. Voet. Biochemistry. New York: John Wiley and Sons, 1990. ppg. 618- 619, 658- 665, 710, 1159.
STRUCTURE FUNCTION REGULATION/CONTROL