Biosynthesis Of Fatty Acids PDF

Physical Pharmacy Biosynthesis of Fatty Acids Biosynthesis Of Fatty Acids Biomedical Importance: Fatty acids are synthesized by an extramitochondrial system, which is responsible for the complete synthesis of palmitate from acetyl-CoA in the cytosol. In most mammals, glucose is the primary substrate...

Physical Pharmacy Biosynthesis of Fatty Acids Biosynthesis Of Fatty Acids Biomedical Importance: Fatty acids are synthesized by an extramitochondrial system, which is responsible for the complete synthesis of palmitate from acetyl-CoA in the cytosol. In most mammals, glucose is the primary substrate for lipogenesis, but in ruminants it is acetate, the main fuel molecule produced by the diet. Critical diseases of the pathway have not been reported in humans. However, inhibition of lipogenesis occurs in type 1 (insulin-dependent) diabetes mellitus, and variations in the activity of the process affect the nature and extent of obesity. Biosynthesis Of Fatty Acids Biomedical Importance: Unsaturated fatty acids in phospholipids of the cell membrane are important in maintaining membrane fluidity. A high ratio of polyunsaturated fatty acids to saturated fatty acids (P:S ratio) in the diet is considered to be beneficial in preventing coronary heart disease. Animal tissues have limited capacity for desaturating fatty acids, and require certain dietary polyunsaturated fatty acids derived from plants. These essential fatty acids are used to form eicosanoic (C20) fatty acids, which give rise to the eicosanoids prostaglandins, thromboxanes, leukotrienes, and lipoxins. Biosynthesis Of Fatty Acids Biomedical Importance: Prostaglandins mediate inflammation, pain, and induce sleep and also regulate blood coagulation and reproduction. Nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin and ibuprofen act by inhibiting prostaglandin synthesis. Leukotrienes have muscle contractant and chemotactic properties and are important in allergic reactions and inflammation. Biosynthesis Of Fatty Acids Biomedical Importance: Biosynthesis Of Fatty Acids The Main Pathway For De Novo Synthesis Of Fatty Acids (Lipogenesis) Occurs In The Cytosol: This system is present in many tissues, including liver, kidney, brain, lung, mammary gland, and adipose tissue. Its cofactor requirements include NADPH, ATP, Mn2+, biotin, and HCO3– (as a source of CO2). Acetyl-CoA is the immediate substrate, and free palmitate is the end product. Biosynthesis Of Fatty Acids Production Of Malonyl-CoA Is The Initial & Controlling Step In Fatty Acid Synthesis: Bicarbonate as a source of CO2 is required in the initial reaction for the carboxylation of acetyl-CoA to malonyl-CoA in the presence of ATP and acetyl-CoA carboxylase. Acetyl-CoA carboxylase has a requirement for the B vitamin biotin (Figure 1). The enzyme is a multienzyme protein containing a variable number of identical subunits, each containing biotin, biotin carboxylase, biotin carboxyl carrier protein, and transcarboxylase, as well as a regulatory allosteric site. Biosynthesis Of Fatty Acids Production Of Malonyl-CoA Is The Initial & Controlling Step In Fatty Acid Synthesis: The reaction takes place in two steps: 1. Carboxylation of biotin involving ATP and 2. Transfer of the carboxyl group to acetyl-CoA to form malonyl-CoA. Biosynthesis Of Fatty Acids Production Of Malonyl-CoA Is The Initial & Controlling Step In Fatty Acid Synthesis: Biosynthesis Of Fatty Acids Figure 1 – Biosynthesis of malonyl-CoA. (Enz, acetyl-CoA carboxylase) Biosynthesis Of Fatty Acids The Fatty Acid Synthase Complex Is A Polypeptide Containing Seven Enzyme Activities: In bacteria and plants, the individual enzymes of the fatty acid synthase system are separate, and the acyl radicals are found in combination with a protein called the acyl carrier protein (ACP). However, in yeast, mammals, and birds, the synthase system is a multienzyme polypeptide complex that incorporates ACP, which takes over the role of CoA. It contains the vitamin pantothenic acid in the form of 4'-phosphopantetheine. Biosynthesis Of Fatty Acids The Fatty Acid Synthase Complex Is A Polypeptide Containing Seven Enzyme Activities: The use of one multienzyme functional unit has the advantages of achieving the effect of compartmentalization of the process within the cell without the erection of permeability barriers, and synthesis of all enzymes in the complex is coordinated since it is encoded by a single gene. In mammals, the fatty acid synthase complex is a dimer comprising two identical monomers, each containing all seven enzyme activities of fatty acid synthase on one polypeptide chain (Figure 2). Biosynthesis Of Fatty Acids Figure 2 Biosynthesis Of Fatty Acids The Fatty Acid Synthase Complex Is A Polypeptide Containing Seven Enzyme Activities: Initially, a priming molecule of acetyl-CoA combines with a cysteine —SH group catalyzed by acetyl transacylase (Figure 3, reaction 1a). Malonyl-CoA combines with the adjacent —SH on the 4'- phosphopantetheine of ACP of the other monomer, catalyzed by malonyl transacylase (reaction 1b), to form acetyl (acyl)-malonyl enzyme. The acetyl group attacks the methylene group of the malonyl residue, catalyzed by 3ketoacyl synthase, and liberates CO2, forming 3-ketoacyl enzyme (acetoacetyl enzyme) (reaction 2), freeing the cysteine —SH group. Biosynthesis Of Fatty Acids The Fatty Acid Synthase Complex Is A Polypeptide Containing Seven Enzyme Activities: Decarboxylation allows the reaction to go to completion, pulling the whole sequence of reactions in the forward direction. The 3-ketoacyl group is reduced, dehydrated, and reduced again (reactions 3, 4, 5) to form the corresponding saturated acyl-S-enzyme. A new malonyl-CoA molecule combines with the —SH of 4'-phosphopantetheine, displacing the saturated acyl residue onto the free cysteine —SH group. The sequence of reactions is repeated six more times until a saturated 16-carbon acyl radical (palmityl) has been assembled. Biosynthesis Of Fatty Acids Biosynthesis Of Fatty Acids The Fatty Acid Synthase Complex Is A Polypeptide Containing Seven Enzyme Activities: It is liberated from the enzyme complex by the activity of a seventh enzyme in the complex, thioesterase (deacylase). The free palmitate must be activated to acyl-CoA before it can proceed via any other metabolic pathway. Its usual fate is esterification into acylglycerols, chain elongation or desaturation, or esterification to cholesteryl ester. In mammary gland, there is a separate thioesterase specific for acyl residues of 𝐶8 , 𝐶10 , or 𝐶12 , which are subsequently found in milk lipids. Biosynthesis Of Fatty Acids The Fatty Acid Synthase Complex Is A Polypeptide Containing Seven Enzyme Activities: The equation for the overall synthesis of palmitate from acetyl-CoA and malonyl-CoA is: The acetyl-CoA used as a primer forms carbon atoms 15 and 16 of palmitate. The addition of all the subsequent C2 units is via malonyl-CoA. Propionyl CoA acts as primer for the synthesis of long-chain fatty acids having an odd number of carbon atoms, found particularly in ruminant fat and milk. Biosynthesis Of Fatty Acids The Main Source of NADPH for Lipogenesis Is the Pentose Phosphate Pathway: NADPH is involved as donor of reducing equivalents in both the reduction of the 3ketoacyl and of the 2,3-unsaturated acyl derivatives (Figure 3, reactions 3 and 5). The oxidative reactions of the pentose phosphate pathway are the chief source of the hydrogen required for the reductive synthesis of fatty acids. Significantly, tissues specializing in active lipogenesis—i.e., liver, adipose tissue, and the lactating mammary gland—also possess an active pentose phosphate pathway. Moreover, both metabolic pathways are found in the cytosol of the cell; so, there are no membranes or permeability barriers against the transfer of NADPH. Biosynthesis Of Fatty Acids The Main Source of NADPH for Lipogenesis Is the Pentose Phosphate Pathway: Other sources of NADPH include the reaction that converts malate to pyruvate catalyzed by the "malic enzyme" (NADP malate dehydrogenase) (Figure 4) and the extramitochondrial isocitrate dehydrogenas reaction (probably not a substantial source, except in ruminants). Biosynthesis Of Fatty Acids Acetyl-CoA Is the Principal Building Block of Fatty Acids: Acetyl-CoA is formed from glucose via the oxidation of pyruvate within the mitochondria. However, it does not diffuse readily into the extramitochondrial cytosol, the principal site of fatty acid synthesis. Citrate, formed after condensation of acetyl-CoA with oxaloacetate in the citric acid cycle within mitochondria, is translocated into the extramitochondrial compartment via the tricarboxylate transporter, where in the presence of CoA and ATP, it undergoes cleavage to acetyl-CoA and oxaloacetate catalyzed by ATP-citratlyase, which increases in activity in the well-fed state. Biosynthesis Of Fatty Acids Acetyl-CoA Is the Principal Building Block of Fatty Acids: The acetyl-CoA is then available for malonyl-CoA formation and synthesis to palmitate (Figure 4). The resulting oxaloacetate can form malate via NADH-linked malate dehydrogenase, followed by the generation of NADPH via the malic enzyme. The NADPH becomes available for lipogenesis, and the pyruvate can be used to regenerate acetyl-CoA after transport into the mitochondrion. Biosynthesis Of Fatty Acids Figure 4 Biosynthesis Of Fatty Acids Acetyl-CoA Is the Principal Building Block of Fatty Acids: This pathway is a means of transferring reducing equivalents from extramitochondrial NADH to NADP. Alternatively, malate itself can be transported into the mitochondrion, where it is able to re-form oxaloacetate. Note: that the citrate (tricarboxylate) transporter in the mitochondrial membrane requires malate to exchange with citrate. Biosynthesis Of Fatty Acids Acetyl-CoA Is the Principal Building Block of Fatty Acids: There is little ATP-citrate lyase or malic enzyme in ruminants, probably because in these species acetate (derived from carbohydrate digestion in the rumen and activated to acetyl-CoA extramitochondrially) is the main source of acetyl-CoA.