Beta Oxidation of Fatty Acids PDF

Fatty Acid Oxidation MEDICAL BIOCHEMISTRY OXIDIZATION OF FA AND KETONE BODIES Objectives: Student Learning Outcomes: Explain how fatty acids are a major fuel source, especially after fasting Describe the basic categories of fatty acids: VLC, LC, med chain FA, short chain FA Explain β-oxidation pathw...

Fatty Acid Oxidation MEDICAL BIOCHEMISTRY OXIDIZATION OF FA AND KETONE BODIES Objectives: Student Learning Outcomes: Explain how fatty acids are a major fuel source, especially after fasting Describe the basic categories of fatty acids: VLC, LC, med chain FA, short chain FA Explain β-oxidation pathway of fatty acids ADIPOSE TISSUE RELEASE FATTY ACIDS Glucagon and epinephrine stimulate adipocyte lipolysis via activation of adipose triglyceride lipase (ATGL): release of FA from TAGs stored in adipocyte fat droplets Coactivator of ATGL is called ABHD5 (α/βhydrolase domain containing protein 5) 3 LIPASES ARE REQUIRED TO RELEASE TAGS Adipose triglyceride lipase (ATGL) Hormone sensitive lipase (HSL) Monoglyceride lipase (MGL) ACTION OF LIPASES IN ADIPOSE TISSUES ABHD Fat droplet A perilipin HSL MGL glycerol Fatty acid monoglycerides Fatty acid ATGL diglycerides Fatty acid triglycerides OVERVIEW FATTY ACID METABOLISM Long-chain FA metabolism: Basically: FA released from adipose tissue and transported through blood Taken up by cells Activated in cytosol Transported through outer membrane of mito Transported through inner membrane of mito Fig. 1 CELLULAR UPTAKE OF FA Bound to albumin for transport in blood to peripheral tissues Membrane proteins that have high affinity for FA are: fatty acid receptor family 1. Fatty acid translocase (FAT) 2. Plasma membrane-associated FA binding protein (FABP) 3. Fatty acid transport proteins (FATPs) CONVERSION OF FA TO FATTY ACYL-COA: IN CYTOPLASM Activation of FA must occur prior to βoxidization Catalyzed by fatty acyl-CoA synthetase Large standard free energy change ΔG’0 = -15 kJ/mol Fig. 2 Step 1 Step 2 ΔG’0 = -19 kJ/mol FATES OF FATTY ACYL-COAS Fatty acyl CoA formation is prerequisite to FA metabolism Acyl CoA location reflects route: TAG & phospholipid synthesis in ER, Oxidation & plasmalogen synthesis in peroxisome, β-oxidation in mitochondria S H U T T L E I N TO M AT R I X O F M I TO C H O N D R I A CPTI transfers FA from FA-CoA to carnitine Translocase carries fatty acylcarnitine cross inner membrane CPTII transfers FA back to CoA -> FA-CoA Translocase returns carnitine STAGES OF FATTY ACID OXIDATION Stage 1: LCFA oxidized to acetyl residues (acetyl-CoA) = βoxidization Stage 2: acetyl groups are oxidized to CO2 via TCA cycle Stage 3: electrons derived from oxidization of steps 1 & 2 pass to O2 via ETC IN MITOCHONDRIA FA OXIDIZATION OCCURS 4 steps: 1. Oxidation: aceyl-CoA dehydrogenases (FAD) 2. Hydration: hydratase 3. Oxidation: dehydrogenase (NAD+) 4. Cleavage: acetyltransferase (thiolase) 4 BASIC STEPS OF Β OXIDIZATION OF SATURATED FA Step 1: dehydration of F-acyl-CoA è dbl bond between α and β C (C2-C3) = trans-Δ2-enoyl-CoA 1st step catalyzed by acylCoA dehydrogenases (Flavoproteins with FAD) 1. VLCAD (VLCFA 12-18C) 2. MCAD (MCFA 4-14) 3. SCAD (SCFA 4-8 C) FAD donates electrons to ETC 4 BASIC STEPS OF Β OXIDIZATION OF SATURATED FA Step 2 (hydration): water is added to dbl bond to form L stereoisomer of βhydroxy-acyl-CoA 2nd step catalyzed by enoyl-CoA hydratase 4 BASIC STEPS OF Β OXIDIZATION OF SATURATED FA Step 3: L-β-hydroxyacyl-CoA is dehydrogenated to from β-ketoacylCoA 3rd step catalyzed by β-hydroxyacylCoA dehydrogenase NAD+ is electron acceptor Enzyme is specific for L sterioisomer Where are we in the cell? NADH transfers electrons to ??? 4 BASIC STEPS OF Β OXIDIZATION OF SATURATED FA Step 4: β-ketoacyl-CoA reacts with free coenzyme A Results is split of carboxyl-terminal 2 C fragment to acetyl-CoA 4th step catalyzed by acyl-CoA acetyltransferase (thiolase) Acetyl-CoA enters TCA cycle DETAILS OF Β-OXIDATION PATHWAY C-C-C-C-C-C-C-C-C-C-C-C-C-C-C-C 4 steps repeat C-C-C-C-C-C-C-C-C-C-C-C-C-C Cleavage of the last 4-C fatty acyl-CoA (called butyryl-CoA) produces two acetyl-CoAs Even chained FA (palmitoyl-CoA 16C) is cleaved 7 times Produces: 7 FAD(2H) 7 NADH 8 acetyl-CoAs C-C-C-C-C-C-C-C-C-C-C-C C-C-C-C-C-C-C-C-C-C C-C-C-C-C-C-C-C C-C-C-C-C-C C-C-C-C C-C C-C Β-OXIDATION: FAD Details of FAD transfer to Electron transfer chain: FAD tightly bound to proteins sequential transfers: Acyl CoA dehydrogenase ETF (electron-transferring flavoprotein): ETF-QO (ETF coenzyme Q reductase): Co-Q in ETC Fig. 8 ENERGY YIELD IN Β-OXIDATION 1 mol of 16-C palmitate -> 8 Acetyl CoA 7 NADH x 2.5 ATP/NADH -> 17.5 ATP 7 FAD(2H) x 1.5 ATP/FAD(2H) -> 10.5 ATP If 8 Acetyl CoA oxidized through TCA, get 8 GTP, 24 NADH, 8 FAD(2H) -> 80 ATP (GTP, count all high energy bonds formed) KEY CONCEPTS Key concepts: Fatty acids are major fuels, during fasting F.A. released from adipose tissue are activated to fatty acyl CoA, transported to mitochondria: β-oxidation path generates ATP, 2-C Acetyl CoA from even-chain long-length chain fatty acids β-oxidation is regulated by NADH, Acetyl CoA