FA Oxidation Lecture 2 PDF

FA oxidation Professor Dr/ Yasser Elghobashy Medical Biochemistry and Molecular Biology  Fatty acid oxidation Oxidation of fatty acids gives the maximum amount of energy among food stuffs, where 1 gm fat gives ≈ 9 Kcal. Sources of FA:- 1- Diet 2- Mobilization fro...

FA oxidation Professor Dr/ Yasser Elghobashy Medical Biochemistry and Molecular Biology  Fatty acid oxidation Oxidation of fatty acids gives the maximum amount of energy among food stuffs, where 1 gm fat gives ≈ 9 Kcal. Sources of FA:- 1- Diet 2- Mobilization from adipose tissue by lipolysis. Types of fatty acid oxidation include:- 1- Beta (β) oxidation (the most common type) 2- Alpha (α) oxidation 3- Omega (ω) oxidation  β-Oxidation Site:- Intracellular site  Mitochondria Organ site  Liver, kidney, heart Steps of β-oxidation:- It includes 3 steps 1. Activation of FA to form acyl CoA: – Fatty acids must be activated in the cytoplasm before being oxidized in the mitochondria. – Activation is catalyzed by acyl-CoA synthetase or thiokinase. ATP AMP+PPi Fatty acid Acyl CoA COASH 2. Transport of Acyl CoA by carnitine shuttle into the mitochondria: The inner mitochondrial membrane is impermeable to acyl CoA, but it can be transported by special mechanism called carnitine shuttle. Carnitine shuttle:- – Carnitine is a β-hydroxy -γ-trimethyl ammonium butyrate. – It involves 3 enzymes:- 1. Carnitine acyl transferase I:- in outer mitochondrial membrane 2. Carnitine acylcarnitine translocase:- in inner mito membrane 3. Carnitine acyl transferase II:- in inner mito membrane 3. Oxidation: occurs in the mitochondrial matrix  Regulation of FA oxidation β-oxidation of fatty acids is increased when glucose oxidation is decreased as in diabetes mellitus and starvation. Starvation ↓ blood glucose ↑ anti-insulin hormones ↑ lipolysis ↑ FFAs ↑ β- oxidation β-oxidation is inhibited by insulin and feeding carbohydrate which increase glucose oxidation and decrease release of FA.  Energy produced from β-oxidation of palmitic acid β-oxidation of palmitic acid is repeated 7 times to produce 8 acetyl CoA Each cycle produces 1- One molecule of FADH2 2ATP by the respiratory chain 2- One molecule of NADH+H+ 3ATP by the respiratory chain Then the total energy produced by 7 times = 7 X 5 = 35 ATP One molecule of acetyl CoA produces 12 ATP by Kreb's cycle, so 8 molecules of Acetyl CoA produces = 8 X 12 = 96 ATP In activation of FA to acyl CoA 2 high energy bonds are consumed, these are equivalent to 2 molecules of ATP. Net energy produced by β-oxidation of palmitic acid = Energy gained – Energy consumed = (35+96) – 2 =131 – 2 = 129 ATP  Note; There is a general formula for calculation of energy of even No FA:- Energy = [(N/2 - 1) x 5 ATP] + [(N/2 x 12 ATP] - 2 ATP N = number of carbon atoms  Oxidation of odd number fatty acids Fatty acids with an odd number of carbon atoms are oxidized by the pathway of beta-oxidation, producing acetyl-COA until a 3-carbon residues remain (propionyl COA). Propionyl COA is converted to succinyl COA which is a member of the citric acid cycle to produce glucose by gluconeogenesis.  α - oxidation This type of FA oxidation occurs in α position because β position is occupied by methyl group. It is characterized by:- – It occurs mainly in the brain but also occurs in liver tissue. – It is a minor pathway of FA oxidation. – One carbon atom is removed at a time from α position. – It doesn't require COASH and doesn't generate energy. Importance:- – Metabolism of dietary methylated fatty acids e.g phytanic acid – Phytanic acid is present in the tissues of ruminants and in dairy products. – It has a methyl group at the β position that prevents β oxidation, so it undergoes α -oxidation as follow.  Metabolism of ketone bodies During high rates of FA oxidation, primarily in the liver, large amounts of acetyl-CoA are generated that exceed the capacity of the TCA cycle, and result in the synthesis of ketone bodies (ketogenesis). The ketone bodies include 3 substances: Acetoacetic acid CH3-CO-CH2-COOH β-hydroxybutyric acid CH3-CHOH-CH2-COOH Acetone CH3-CO-CH3  Importance of ketone bodies Ketone bodies are important fuels in extrahepatic tissues especially during fasting and starvation. Notes: - – The brain uses ketone bodies after 5 – 10 days of starvation. – The liver can't utilize ketone bodies as a source of energy because it doesn't contain enzymes of ketone bodies oxidation. – The total blood concentration of ketone bodies does not exceed 2 mg/dl.  Ketone body synthesis (Ketogenesis) Definition: ketogenesis is the synthesis of ketone bodies from active acetate. Site: occur in the mitochondria of liver cells. Ketone bodies are synthesized from acetyl CoA. Steps: - Formation of acetoacetyl CoA: It is formed by 2 ways; 1. Condensation of 2 molecules of acetyl CoA 2. Or formed in the course of β-oxidation (last 4 carbons)  Acetoacetic acid is formed from acetoacetyl COA by 2 pathways: 1. Simple deacylation by deacylase enzyme: Deacylase Acetoacetyl CoA Acetoacetate H2O CoA 2. By formation of 3-hydroxy-3-methyl glutaryl COA (HMG- COA). Acetoacetic acid is then undergoes; – Either spontaneous decarboxylation to give acetone – Or reduced to give β-hydroxybutyrate  Regulation of ketogenesis Ketogenesis is increased by the following: 1. Lipolysis of triacylglycerol in adipose tissue: – FAs are the precursors of ketone bodies in the liver. – They arise from the lipolysis of triacylglycerol in adipose tissue. – The liver can extract up to 30% of FAs passing through it. – So, increased lipolysis → ↑FFAs → ↑ uptake by the liver → ↑ ketone bodies formation. 2. Increased activity of carnitine palmitoyl transferase -I in the liver: – Carnitine palmitoyl transferase-I activity regulates the entry of long- chain acyl COA into the mitochondria prior to beta-oxidation. – Malonyl CoA is a potent inhibitor of CPT-1. – In the fed state: acetyl CoA carboxylase is activated (due to ↑ insulin /glucagon ratio) → ↑ malonyl CoA → inhibition of CPT-1 → inhibition of β-oxidation → ↓ ketogenesis. – In starvation: excessive lipolysis (due to decreased insulin/glucagon ratio) → ↑↑ FFAs → inhibition of acetyl CoA carboxylase → ↓ malonyl CoA → releive of the inhibitory effect on CPT-1 → ↑ β- oxidation thus acetyl CoA is increased → ↑ production of ketone bodies. 3. Increased level of serum free fatty acids.