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Fatty acid synthesis Dr. Nalini Ganesan M.Sc., Ph.D Associate Professor Department of Biochemistry SRMC & RI (DU) Porur, Chennai - 116 Harper’s biochemistry 24th ed, Pg 218 Fatty acid Synthesis • Known as lipogenesis • Extramitochondrial • Highly active process • Elongation takes place in microsomes •Takes place primarily in liver & lactating mammary glands • To lesser extent in adipose tissue & kidney Harper’s biochemistry 24th ed, Pg 218 Biomedical importance • Reduced importance in humans • Critical diseases of this pathway has not been reported because of this. • Variation in its activity between individuals may have an effect on the nature and extent of obesity. • Inhibition of lipogenesis is the lesion in Type I diabetes mellitus Harper’s biochemistry 24th ed, Pg 218 -219 Rate controlling step in Fatty acid synthesis Production of Malonyl CoA CH3-CO~s-CoA Enz-biotin -* COO- -OO *C-CH2-CO~S-CoA Enz-biotin ADP + Pi ATP + HCO3- + Enz-biotin Enz – Acetyl CoA Carboxylase Biochemistry – Pamela - 2nded- Pg175 Allosteric regulation of acetyl CoA carboxylase Citrate + Protomer (inactive) Polymer (active) Malonyl CoA, Palmitoyl CoA Biochemistry – Pamela - 2nded- Pg174 Production of cytoplasmic Acetyl CoA Mitochondrial acetyl CoA is produced from • Oxidation of pyruvate •Degradation of fatty acids •Degradation of ketones bodies •Degradation of amino acids Coenzyme A portion of acetyl Co A cannot cross mitochondrial membrane Acetyl CoA combines with Oxaloacetate to form Citrate Citrate enters into the cytoplasm and gets cleaved by citrate lyase. Provision of acetyl CoA Harper’s biochemistry 24th ed, Pg 216 Fatty acid synthase complex • Multienzyme complex • Dimer with head to tail arrangement • Each monomer have seven enzymes • Encoded by single gene Harper’s biochemistry 24th ed, Pg 216 Fatty acid synthase complex • Contains acyl carrier protein (binds to acyl radical) • ACP contains pantothenic acid • Performs the role of CoA • Performs with great efficiency • Three domains Condensing unit - Acetyl transferase Malonyl transferase α ketoacyl synthase Reduction unit - ACP β ketoacyl reductase dehydrase Releasing unit - Thioesterase www.rpi.edu/dept/bcbp/molbiochem/MBweb/ Fatty acid synthase complex Harper’s biochemistry, 24th ed. Pg218 Biosynthesis of long chain fatty acids CO2 Acetyl-CoA Malonyl CoA C2 Acetyl-CoA Carboxylase C3 Acetyl Transacylase HS-Pan- 1 -Cys-SH MalonylCoA Transacylase - 1 -Cys –S~CO-CH3 HS-Cys- 2 -Pan-SH - 2 -Pan –S~CO-CH -COO2 Fatty Acid synthase multienzyme complex Acyl(acetyl)-malonylenzyme Harper’s biochemistry, 24th ed. Pg218 Biosynthesis of long chain fatty acids Acyl(acetyl)-malonylenzyme - 1 -Cys –S~CO-CH3 - 2 -Pan –S~CO-CH2-COO- 3-ketoacyl synthase CO2 1 - 1 -Cys –SH 3-ketoacyl enzyme - 2 -Pan –S~CO-CH2-CO-CH3 3-ketoacyl reductase D(-)3-hydroxyacyl enzyme NADPH + H+ NADP+ 2 - 1 -Cys –SH - 2 -Pan –S~CO-CH2-CHOH-CH3 Harper’s biochemistry, 24th ed. Pg 218 Biosynthesis of long chain fatty acids - 1 -Cys –SH D(-)3-hydroxyacyl enzyme - 2 -Pan –S~CO-CH2-CHOH-CH3 Hydratase H2O 3 - 1 -Cys –SH 2,3 unsaturated acyl enzyme - 2 -Pan –S~CO-CH=CH-CH3 Enoyl reductase NADPH + H+ NADP+ 4 - 1 -Cys –SH Acylenzyme - 2 -Pan –S~CO-CH2CH2-CH3 Harper’s biochemistry, 24th ed. Pg 218 Biosynthesis of long chain fatty acids Acyl enzyme Transferred from 2nd position of FAS complex to the 1st Undergoes steps 1 –4 six more times to form palmitate Thioesterase Palmitate + FAS Harper’s biochemistry, 24th ed. Pg 219 Overall equation for the synthesis of palmitate from acetyl CoA and malonyl CoA CH2CO.S.CoA+ 7HOOC.CH2.CO.S.CoA + 14NADPH + 14H+ CH3(CH2)14COOH + 7 CO2 + 6H2O + 8CoASH + 14NADP+ Harper’s biochemistry 24th ed, Pg 219 Sources of NADPH • HMP pathway • Malic enzyme • Cytosolic isocitrate dehydrogenase Harper’s biochemistry 24th ed, Pg 219 Fate of palmitate after biosynthesis Acylglycerol Cholesterol esters Esterfication ATP + CoA Palmitate AMP + PPi Palmityl CoA Acyl-CoA Synthase Chain elongation desaturation Acyl CoA Harper’s biochemistry 24th ed, Pg 221 Fatty acid elongation • Takes place in microsomes • Malonyl CoA donates acetyl CoA • Fatty acids having more than 10 carbon atoms acts as a primer • Fasting abolishes elongation • Elongation process is very active during myelination in brain Harper’s biochemistry 24th ed, Pg 221 -222 Regulation of lipogenesis • Nutritional state Main factor Depressed under conditions of restricted calorie intake High fat diet Deficiency of insulin Harper’s biochemistry 24th ed, Pg 221 -222 Regulation of lipogenesis •Short term mechanism Allosteric and covalent modification of enzymes Acetyl CoA carboxylase & Pyruvate dehydrogenase •Long term mechanism Changes in gene expression governing rates of synthesis of enzymes Harper’s biochemistry 24th ed, Pg 221 -222 Regulation of lipogenesis • Hormones Insulin – Stimulates lipogenesis by increasing the transport of glucose into cells Activates pyruvate dehydrogenase & acetyl CoA carboxylase Depresses cAMP levels inhibits lipolysis in adipose tissue Glucagon & Epineprine antagonizes the action of insulin • Fatty acid synthase Complex and acetyl CoA carboxylase are adaptive enzymes THANK YOU