Fatty acid synthesis. Dr. Nalini Ganesan M.Sc., Ph.D Associate Professor Department of Biochemistry SRMC & RI (DU) Porur, Chennai - 116

Transcription

1 Fatty acid synthesis Dr. Nalini Ganesan M.Sc., Ph.D Associate Professor Department of Biochemistry SRMC & RI (DU) Porur, Chennai 116

2 Harper s biochemistry 24 th 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

3 Harper s biochemistry 24 th 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

4 Harper s biochemistry 24 th ed, Pg Rate controlling step in Fatty acid synthesis Production of Malonyl CoA CH 3 CO~sCoA Enzbiotin * COO Enzbiotin OO*CCH 2 CO~SCoA ADP + Pi ATP + HCO 3 + Enzbiotin Enz Acetyl CoA Carboxylase

5 Biochemistry Pamela 2 nd ed Pg175 Allosteric regulation of acetyl CoA carboxylase Citrate + Protomer (inactive) Polymer (active) Malonyl CoA, Palmitoyl CoA

6 Biochemistry Pamela 2 nd ed 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.

7 Provision of acetyl CoA

8 Harper s biochemistry 24 th ed, Pg 216 Fatty acid synthase complex Multienzyme complex Dimer with head to tail arrangement Each monomer have seven enzymes Encoded by single gene

9 Harper s biochemistry 24 th 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

10 Fatty acid synthase complex

11 Harper s biochemistry, 24 th ed. Pg218 Biosynthesis of long chain fatty acids CO 2 AcetylCoA Malonyl CoA C 2 AcetylCoA Carboxylase C 3 HSPan HSCys 1 2 CysSH PanSH Fatty Acid synthase multienzyme complex Acetyl Transacylase 1 2 MalonylCoA Transacylase Cys S~COCH 3 Pan S~COCH 2 COO Acyl(acetyl)malonylenzyme

12 Harper s biochemistry, 24 th ed. Pg218 Biosynthesis of long chain fatty acids Acyl(acetyl)malonylenzyme 1 Cys S~COCH 3 2 Pan S~COCH 2 COO 3ketoacyl synthase CO Cys SH 3ketoacyl enzyme 2 Pan S~COCH 2 COCH 3 3ketoacyl reductase D()3hydroxyacyl enzyme 1 2 NADPH + H + NADP + Cys SH Pan S~COCH 2 CHOHCH 3 2

13 Harper s biochemistry, 24 th ed. Pg 218 Biosynthesis of long chain fatty acids D()3hydroxyacyl enzyme 1 2 Cys SH Pan S~COCH 2 CHOHCH 3 Hydratase H 2 O 3 2,3 unsaturated acyl enzyme 1 2 Cys SH Pan S~COCH=CHCH 3 Enoyl reductase NADPH + H + NADP Cys SH Acylenzyme 2 Pan S~COCH 2 CH 2 CH 3

14 Acyl enzyme Harper s biochemistry, 24 th ed. Pg 218 Biosynthesis of long chain fatty acids Transferred from 2 nd position of FAS complex to the 1 st Undergoes steps 1 4 six more times to form palmitate Thioesterase Palmitate + FAS

15 Harper s biochemistry, 24 th ed. Pg 219 Overall equation for the synthesis of palmitate from acetyl CoA and malonyl CoA CH 2 CO.S.CoA+ 7HOOC.CH 2.CO.S.CoA + 14NADPH + 14H + CH 3 (CH 2 ) 14 COOH + 7 CO 2 + 6H 2 O + 8CoASH + 14NADP +

16 Harper s biochemistry 24 th ed, Pg 219 Sources of NADPH HMP pathway Malic enzyme Cytosolic isocitrate dehydrogenase

17 Harper s biochemistry 24 th ed, Pg 219 Fate of palmitate after biosynthesis Acylglycerol Cholesterol esters ATP + CoA AMP + PPi Esterfication Palmitate Palmityl CoA AcylCoA Synthase Chain elongation desaturation Acyl CoA

18 Harper s biochemistry 24 th 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

19 Harper s biochemistry 24 th ed, Pg Regulation of lipogenesis Nutritional state Main factor Depressed under conditions of restricted calorie intake High fat diet Deficiency of insulin

20 Harper s biochemistry 24 th ed, Pg 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

21 Harper s biochemistry 24 th ed, Pg 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

22 THANK YOU