Synthesis of Fatty Acids and Triacylglycerol

Transcription

1 Fatty Acid Synthesis Synthesis of Fatty Acids and Triacylglycerol Requires Carbon Source: Reducing Power: NADPH Energy Input: ATP Why Energy? Why Energy? Fatty Acid Fatty Acid + n(atp) ΔG o : -ve Fatty Acid ΔG o : +ve ΔG o : -ve Fatty Acid + n(adp) ΔG o : -ve 1

2 FA Degradation and Synthesis Acyl CoA (n) Oxidation Hydration Acyl CoA (n+2) reduction dehydration Carboxylation of Produces Malonyl CoA O O O װ װ װ CH 3 -C-CoA - OC-CH 2 -C-CoA Oxidation Thyolysis Acyl CoA (n-2) + reduction condensation Acyl CoA (n) + Malonyl CoA CO 2 ATP ADP + Pi Carboxylase Biotin-Containing Enzyme Fatty Acid Synthase Catalyzes the remaining steps Multifunctional Enzyme Complex Dimer of two Identical Chains Each has Seven Catalytic Activities One activity is Condensing Enzyme with SH One Domain is inked to Phosphopantetheine With Reactive -SH 2 phosphate s Ribose Adenine Pantothenic acid 2

3 Fatty Acid Synthase Catalyzes the remaining steps Multifunctional Enzyme Complex Dimer of two Identical Chains Each has Seven Catalytic Activities One activity is Condensing Enzyme with SH One Domain is inked to Phosphopantetheine With Reactive -SH Carries Intermediates during Catalysis (Acyl, Acetyl and Malonyl Groups) Known as Acyl Carrier Protein (ACP) Fatty Acid Synthesis (Overview) Acetyl-CE (Acyl-CE) + Malonyl ACP (n) (3) Ketoacyl ACP (n+2) Acyl ACP CO 2 CH 3 CO~S-CE Acetyl (Acyl) + OOC-CH 2 -CO~ACP Malonyl-ACP O CH 3 C-CH 2 -CO~ACP Ketoacyl- ACP CO 2 HS-CE H 2 O Reduction of the Ketoacyl Group O CH 3 C-CH 2 -CO~ACP Ketoacyl- ACP NADPH OH l CH 3 CH-CH 2 - CH 3 CH=CH- NADPH CH 3 CH 2 -CH 2 -CO~ACP 3

4 Synthesis of Palmitate by Fatty Acid Synthase Synthesis of Palmitate by Fatty Acid Synthase (Cont.) Synthesis of Palmitate (net reaction) How many cycles of synthesis (Condensation)? * 7 How many Malonyl CoA? * 7 How many? * 1 How Many NADPH? * 14 Production of Cytosolic for FA Synthesis Inner mitochondrial membrane is immpermiable to 4

5 Return of Oxaloacetate NADH NAD + Pyruvate + CO2 NADPH NADP + Malate NAD + Regulation of FA Oxidation & Synthesis OXIDATION SYNTHESIS Allosteric Regulation of Carboxylase Supply of Fatty Acids -Hormonal Control Entry into Mitochondria Availability of NAD + Regulation of AcCoA Carboxylase -Allosteric Mechanism - Phosphorylation Amounts of Enzymes 5

6 Hormone-Mediated, Covalent Regulation of Carboxylase ACC Regulation of FA Oxidation & Synthesis OXIDATION Supply of Fatty Acids -Hormonal Control Entry into Miochondria Availability of NAD + SYNTHESIS Regulation of AcCoA Carboxylase -Allosteric Mechanism - Phosphorylation Amounts of Enzymes Regulation of FA Oxidation Elongation of Fatty Acids Fatty Acids -in Endoplasmic Reticulum - Similar Sequence of Reactions - Different Enzymes NADH - Fatty Acyl CoA - Fatty Acyl Carnitine Malonyl CoA ACC Malonyl CoA + Acyl CoA (n) 2NADPH + H + 2NADP + Acyl CoA (n+2) n = 16 or more carbons 6

7 Elongation of Fatty Acids in Mitochondria + Acyl CoA (n) NADH + H+ NAD+ Acyl CoA (n+2) NADPH NADP+ Introduction of Double Bonds Synthesis of Monounsaturated FA - Oleic Acid 18:Δ 9 - Palmitoleic 16:Δ 9 In endoplasmic reticulum No double bond can be introduced beyond carbon 9 in human n = less than16 carbons Introduction of Double Bonds (Cont.) Stearoyl CoA Palmitoyl CoA NADPH + O 2 Introduction of Double Bonds (Cont.) Formation and Modification of Polyunsaturated FA -Elongation NADP+ + 2H 2 O Oleoyl CoA Palmitoleoyl CoA Δ 9 Desaturase; Cytochrome b 5 - Desaturation Additional double bonds can be introduced by: Δ 4 Desaturase Δ 5 Desaturase Δ 6 Desaturase 7

8 Modification of Polyunsaturated FA inoleic 18:2Δ 9,12 Desaturation Biosynthesis of Triacylglycerol & Phosphoacylglycerol 18:3Δ 6,9,12 ω? Elongation 20:3Δ 8,11,14 ω? Desaturation G Y C E R O FATTYACID G Y C E R O PHOSPHATE ACOHO 20:4Δ 5,8,11,14 ω? Arachidonic TRIACYGYCERO PHOSPHOACYGYCERO Phosphotadic Acid is Common Intermediate G Y C E R O P HO S P H ATE Biosynthesis of Triacylglycerol Requires Acyl~CoA (Active form of FA) Glycerol Phosphate Why Active form? TAG + H 2 O DAG + FA ΔG ve DAG + FA TAG + H 2 O ΔG +ve P H O S P H O A C Y G Y C E R O DAG + Acyl~CoA TAG ΔG ve 8

9 Production of Glycerol Phosphate - Glycerol + ATP --- Glycerol 3 Phosphate Enz: Glycerol Kinase Not in Adipose tissue Production of Glycerol Phosphate CH 2 OH CH 2 OH I I C = O C HOH I I CH 2 OPO 3 CH 2 OPO 3 NADH NAD + 9

10 Glucose DHAP Glycerol- P FA~CoA TAG Glycerol + Fatty Acids 10