Fatty Acid Synthesis PDF

Almaaqal University Fatty Acid Synthesis Dr/ Wael Sobhy Darwish Biochemistry PhD  Fatty Acid Synthesis There are 2 mechanisms for fatty acids synthesis: cytoplasmic and microsomal. Cytoplasmic system (extra-mitocho...

Almaaqal University Fatty Acid Synthesis Dr/ Wael Sobhy Darwish Biochemistry PhD  Fatty Acid Synthesis There are 2 mechanisms for fatty acids synthesis: cytoplasmic and microsomal. Cytoplasmic system (extra-mitochondrial) or (de novo) - The main product of this pathway is palmitate (16C). SITE 1. Intracellular location: Cytosol. 2. Organ location: Many tissues including liver, adipose tissue, lung and kidney. Requirements This pathway needs the following substrates: acetyl CoA, NADPH+H and group of enzymes called fatty acid synthase complex.  1. Acetyl CoA: It is provided mainly by glucose through pyruvate (glycolysis). Acetyl CoA is formed in mitochondria and fatty acid synthesis occurs in cytosol. The acetyl CoA cannot diffuse to cytosol because mitochondrial membrane is impermeable to it.  Fatty Acid Synthesis occurs in three stages 1. The first stage of fatty acid synthesis is transfer of acetyl CoA out of the mitochondria into the cytoplasm. Citrate is transported into the cytoplasm and cleaved into oxaloacetate and acetyl CoA. 2. The second state is the activation of acetyl CoA to form malonyl CoA. 3. The third stage is the repetitive addition and reduction of two carbon units to synthesize C16 fatty acid. Synthesis occurs on an acyl carrier protein, a molecular scaffold.  Fatty acid synthesis consist of a series of condensation, Reduction, Dehydration, and Reduction reactions Steps of Fatty Acids Synthesis  Regulation Of Fatty Acid Synthesis The key enzyme of cytoplasmic pathway is acetyl CoA carboxylase enzyme. 1- Insulin: Stimulates fatty acid synthesis 2- Glucagon and epinephrine: Inhibits fatty acid synthesis through cyclic AMP and it also stimulates lipolysis 3- Long chain acyl CoA: Inhibits Fatty acid synthesis 4- Citrate: stimulates fatty acid synthesis through stimulation of acetyl CoA carboxylase. Microsomal Pathway For F.A. Synthesis This is probably the main site for the elongation of existing long chain fatty acid molecules i.e.production of fatty acids longer than 16 carbon atoms. A. The elongated molecules (C10-C16) are derived from: 1. Palmitate: by cytoplasmic pathway. 2. Fatty acids of diet. B. The microsomal pathway needs malonyl CoA as acetyl donor and NADPH+H+ as coenzyme. C. Function: This system becomes active during myelination of nerves in order to provide C22 and C24 fatty acids which are present in sphingolipids  Lipogenesis Synthesis of triacylglycerols from fatty acids (acyl CoA) and glycerol (glycerol-3-phosphate). STEPS 1. Activation of fatty acids into fatty acyl CoA 2. Synthesis of glycerol phosphate In liver, kidney, intestine, and muscle 3. Synthesis of triacylglycerol: By reaction between acyl CoA and glycerol phosphate.  Regulation Of Lipogenesis 1. After meal, lipogenesis is stimulated: Insulin is secreted which stimulates glycolysis. Glycolysis supplies dihydroxyacetone phosphate that converted into glycerol phosphate in adipose tissue. 2. During fasting lipogenesis inhibited: as anti-insulin hormones e.g. glucagon is secreted. These inhibit lipogenesis and stimulate Lipolysis.  Fatty liver Definition: Fatty liver disease is a build-up of fats in the liver that can damage the organ and lead to serious complications.  Normally liver cells contain only 5 % of fats. The fatty liver is formed when fat level increases above 5 % in the liver cells. Liver has the ability to take up fatty acids from the blood and esterify it to fat. This fat (Triglycerides) along with the endogenously synthesized triglycerides are incorporated into VLDL & transported out of the liver to the extra-hepatic tissues. This is a very finely balanced process. Fatty liver is formed due to imbalance in the rate of triacylglycerol synthesis and export. Excessive accumulation of fat in the liver causing fibrosis, then cirrhosis and finally hepatic cancer  Fatty liver is seen in two conditions: 1) Increased synthesis of triacylglycerol in liver 2) In the metabolic block of VLDL formation 1. Increased synthesis of triacylglycerol in liver: Causes: diabetes mellitus, starvation, high fat diet, high calorie intake, alcoholism etc. Diabetes mellitus & starvation: Increased mobilization of fat from adipose tissues by increased lipolysis leading to increased levels of free fatty acids in the blood and subsequent increased uptake of fatty acids by liver and synthesis of excess amount of fat, which exceeds the rate of VLDL formation and capacity of fat disposal from liver. This results in the accumulation of fat in the liver leading to fatty liver.