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Siva Prabodh MD Associate Professor Dept. of Biochemistry NRI Medical College Biosynthesis of Fatty acids : Biosynthesis of Fatty acids The excess dietary Carbohydrates & Proteins can be converted to fatty acids and are stored as Tri acyl Glycerol. Denovo synthesis of Fatty acids takes place in Liver, Kidney, adipose tissue and Lactating Mammary glands. Site: Cytoplasm of the cell Requirements: Acetyl CoA – source of Carbon atoms NADPH – provides reducing equivalents ATP – energy Slide 3: ═ Fatty acid synthesis in 3 stages Production of Acetyl CoA & NADPH Conversion of acetyl CoA to Malonyl CoA Reactions of Fattyacid synthase complex. Production of Acetyl CoA & NADPH : Production of Acetyl CoA & NADPH Acetyl CoA is produced in mitochondria from oxidation of pyruvate fatty acids degradation of Amino acids Ketone bodies Mitochondrial membrane is impermeable to Acetyl CoA Slide 5: Transfer of Acetyl CoA from mitochondria to cytoplasm ═ In mitochondria Acetyl CoA + Oxaloacetate to form Citrate ═ Citrate is freely transferable ═ In cytoplasm Citrate is cleaved to Acetyl CoA & Oxaloacetate oxaloacetate ↓ Malate NADPH Malic enzyme Pyruvate Slide 6: 6 Mitochondrial membrane Cytosol Mitochondria Glucose Pyruvate Pyruvate Acetyl CoA Oxalo- acetate Citrate Citrate Acetyl CoA Pyruvate Dehydrogenase ATP-Citrate Lyase Malate Oxaloacetate Malic enzyme Malate dehydrogenase Note: Acetyl CoA cannot be converted to glucose Citrate As Carrier of Acetate Groups Sources of NADPH : Sources of NADPH ↑ Malic enzyme (Malate → Pyruvate) 2) HMP Shunt NADPH Formation of Malonyl CoA : Formation of Malonyl CoA Acetyl CoA is carboxylated to Malonyl CoA by Acetyl CoA Carboxylase ATP dependent Biotin as a coenzyme This step is the regulating step for Fatty acid synthesis Reactions of Fatty acid synthase complex: : Reactions of Fatty acid synthase complex: Fatty acid synthase is a Multi enzyme complex. It is a dimer with two identical units. Each unit contains 7 enzymes and a protein (acyl carrier protein) Each unit produces one fatty acid Steps in Fatty acid synthase complex : Steps in Fatty acid synthase complex Acetyl CoA is transferred to ACP by Acetyl CoA ACP transacylase (CoA is removed). The two carbon unit acetate which is attached to ACP is shifted to cysteine residue of keto acyl synthase enzyme. Slide 12: 2) Now Malonyl CoA is transferred to ACP by Malonyl CoA ACP transacylase where Co A is removed Slide 13: 3) The acetyl unit (2) which is attached to cysteine combines with malonyl unit (3 ‘C’) where Co2 is released to form keto acyl, ACP, Enzyme is keto acyl synthase. Slide 14: 4) Ketoacyl ACP undergoes reduction to form β-hydroxy acyl ACP, enzyme is keto Acyl reductase NADPH provides Hydrogens. Slide 15: 5) β-hydroxy acyl ACP undergoes dehydration where one water molecule is removed to form Enoyl ACP (double bond between 2 & 3 Carbons) enzyme is dehydratase. Slide 16: 6) Enoyl ACP undergoes reduction to form acyl ACP or butryl ACP, enzyme is enoyl ACP reductase, NADPH provides Hydrogens. Slide 17: 7) The 4 carbon butryl acid attached to ACP is shifted to cysteine residue and reactions 2 – 6 are repeated Formation of Butyryl ACP : 18 Formation of Butyryl ACP CH3COCH2CO-S-ACP CH3CCH2CO-S-ACP OH H Acetoacetyl ACP -D-Hydroxybutyryl ACP -Ketoacyl ACP reductase NADPH + H+ NADP+ CH3C=C-CO-S-ACP H H -Hydroxyacyl ACP dehydratase - H2O eonyl ACP CH3CH2CH2CO-S-ACP Butyryl ACP 2,3-trans- Enoyl ACP reductase NADPH + H+ NADP+ Slide 20: For 1 cycle carbon chain length increase by 2 carbons (2) Acetyl acid 1 cycle (4) Butyric acid 2 cycle (6) Caproic acid 3 cycle (8) Caprylic acid Palmatic acid Synthesis: : Palmatic acid Synthesis: It is a 16 carbon compound. It requires 8 Acetyl CoA requires 7 cycles. In the 1 step acetyl CoA is added directly, but in each cycle 2 carbons are added in the form of malonyl CoA 8 Acetyl CoA + 7 ATP + 14 NADPH H+ Palmitic acid + 8 CoA + 7 ADP + Pi + 7 H2o Regulation of Fatty acid Synthesis : Regulation of Fatty acid Synthesis Acetyl CoA Carboxylase →Important step in FA Synthesis Acetyl CoA → Malonyl CoA This enzyme is activated by citrate Inhibited by Palmitoyl CoA This enzyme is also activated by Insulin Inactivated by Glucagon, epinephrine & nor epinephrine. Diet also influences fatty acid synthesis. Orlistat: A Fatty Acid Synthase (FAS) Inhibitor : 23 Orlistat: A Fatty Acid Synthase (FAS) Inhibitor Anti-obesity (Inhibits pancreatic lipase in gut) Inhibits thioesterase domain of FAS Anti-cancer (experimental): FAS overexpressed in several tumor types; inhibition induces apoptosis Synthesis of TAG : Synthesis of TAG (I) Stage :→ Synthesis of Glycerol – 3 – phosphate a) In liver Glycerol is converted to Glycerol – 3 – phosphate by Glycerol Kinase Glycerol Glycerol – 3- phosphate b) In liver & adipose tissue from Glycolysis DHAP is converted to Glycerol -3 – phospate by Glycerol – 3- Phosphate dehydrogenase DHAP Glycerol – 3 – Phosphate (II) Stage : Addition of acyl groups (fatty acids) to Glycerol – 3 – Phosphate Acyl transferases catalyes the transfer acyl groups Slide 25: Glycerol – 3 – Phosphate Lysophosphatidic acid phosphatidic acid Diacyl glycerol Fatty acyl CoA CoA Fatty acyl CoA CoA P1 Phosphatase Fatty acyl CoA CoA Triacyl glycerol Synthesis of Phospholipids : Synthesis of Phospholipids Phospholipid synthesis takes place in smooth endoplasmic reticulum. Precursors are 1,2 Diacylglycerol and phosphotidic acid. For 1,2 Diacylglycerol, Phosphocholine is transferred from CDP-Choline to form Phosphotidyl choline For 1,2, Diacylglycerol, phosphoethanolamine is transferred from CDP ethanolamine to form Phosphotidyl ethanolamine Phosphotidyl serine is formed from phosphitidyl ethanolamine, where serine is inserted in exchange with ethanolamine Slide 29: Phosphotidyl Ionositol and cardiolipins are formed from phosphotidic acid Degradation of phospholipids : Degradation of phospholipids Phospholipids are hydrolysed (degraded) by phospholipases. They cleave the ester bonds. Phospholipase A1 – cleaves FA at C1 of phospholipid Phospholipase A2 – Cleaves FA at C2 of phospholipid Phospholipase B – Cleaves FA at C2 of Lysophospholipid Phospholipase C – Cleaves the bond between phosphate and glycerol at C3 of phospholipid Phospholipase D – Removes the Nitrogen base from ` phospholipid. Degradation of sphingomyelin : Degradation of sphingomyelin Spingomyelin → (Ceramide – phosphoryl choline) Spingomyelinase hydrolyse spingomyelin and seperates ceramide and phosphoryl choline Ceramide → ( Spingosine – FFA) Ceramidase hydrolyse ceramide, which seperates sphingosine and FFA. Disorders related to metabolism of Spingomyelins : Disorders related to metabolism of Spingomyelins (1)Niemann – Pick disease: - Inherited disorder Enzyme deficiency – Sphingomyelinase Accumulation of Sphingomyelins in Liver & Spleen Hepatomegaly – Splenomegaly Severe Mental Retardation Fatal in Early childhood (2) Faber’s disease Deficiency of Ceramidase Accumulation of ceramide Skeletal deformation, subcutaneous nodules, dermatitis and Mental retardation Fatal in Early life Synthesis of Cerebosides : Synthesis of Cerebosides Metabolic disorders related to cerebrosides : Metabolic disorders related to cerebrosides Gauchers disease - Deficiency of β – Glucosidase - Accumulation of Glucocerobroside in tissues - Hepatomegaly, Splenomegaly, Osteoporosis, Pigmentation of skin, Anemia, Mental Retardation 2) Krabbe’s disease - Deficiency of β – galactosidase - Accumulation of galactocerebrosides Characterized by Absence of MyelinSheath in Nervous tissue. - Mental Retardation, convulsions, blindness, deafness etc. Synthesis of Gangliosides : Synthesis of Gangliosides Disorders related to Ganglioside Metabolism : Disorders related to Ganglioside Metabolism Tay Sach’s disease: Deficiency of Hexosamidase A accumulation of Gangloside (GM) Gangliosidosis : Deficiency of galactosidase accumulation of Ganglioside (GM1) Slide 40: Thank you You do not have the permission to view this presentation. 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