Structural Biochemistry/Lipids/Fatty Acids/Eicosanoids
Arachidonate, a 20:4 fatty acid derived from linoleate, is the dominant precursor of several eicosanoid hormones. There are four families of eicosanoids—the prostaglandins, prostacyclins, the thromboxanes and the leukotrienes. These molecules react with cell receptors to produce signal transduction responses. Also, anti-inflammatory drugs and aspirin are known to reduce effects of these molecules.
Eicosanoids are molecules which affect the synthesis of other molecules in cellular reactions. They take part in complex checks and balances systems in many parts of the human body such as during the inflammatory response or relaying messages in the central nervous system. They are derived from oxidation of essential fatty acids, generally Omega-3 or Omega-6 polyunsaturated fatty acids. The name is derived from "eicosa" which means twenty in Greek. This is because eicosanoids are made of 20 carbon fatty acids called eicosatetraenoïc acid.
they are local hormones because they exist only for a short amount of time. they change the cell activities which they are sunthesized and of adjoining cells by binding to 7TM receptors. however, their effects are not uniformed and varies from cell to cell.
Biosynthesis of eicosanoids involves two steps: arachidonic acid release and its transformation into active products. Eicosanoids are not stored anywhere but rather created whenever required by the body. When a stimuli is triggered, such as cytokines, or growth factors, a phospholipase is released at the cell membrane and travels to the nuclear membrane. Here, the phoshpolipase catalyzes the break down of either a phospholipid or a diacyglycerol. This step releases a 20-carbon fatty acid. This fatty acid is a precursor to the different eicosanoids.
Two key enzymes starts the eicosanoid routes: cyclo-oxygenases lead to the formation of prostaglandins, while lipoxygenase produces hydroperoxides of arachidonic acid or catalyze the first step of leukotriene synthesis.
Arachidonic acid metabolism: cyclooxygenase pathway
catalyzes fatty acids to prostanoids by a 2 step process. two Oxygen molecules are added as two peroxide linkages, this leads to the formation of short lived, active intermediate PGG when a 5 member ring is forged in the middle of the fatty acid chain. secondly, one of the peroxide loses H and sheds a single oxygen, forming PGH.
Arachidonic acid metabolism: lipoxygenase pathway
Catabolism (inactivation) of eicosanoids
All arachidonic acid derivatives are quickly, in less than a few minutes, inactivated in the body by several complex reactions
Functions in the Human Body
Eicosanoids are stored in the gallbladder and are cycled between the intestines and liver via the enterohepatic circulation. The nature of the conjugates requires membrane transporters for cellular uptake and secretion, but once their main task is completed approximately 95% of the non-conjugated bile acids are reabsorbed passively throughout the small and large intestines. The conjugated bile acids require an apical sodium-dependent bile acid transporter. A further transporter molecule enables bile acids to exit the enterocyte, before they are returned to the liver bound to albumin in the portal blood stream, where they are absorbed by the sodium/taurocholate co-transporting polypeptide to complete the cycle. They are then re-secreted into bile together with newly synthesised bile acids to continue the process. In humans, a conjugated bile salt may complete this cycle from 4 to 12 times each day. The average pool of bile acids is roughly 2 g, and because of recycling, hepatic secretion into the duodenum is about 12g/day. A small proportion avoids hepatic extraction and enters the general circulation.