Beta Oxidation of lipids

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LIPID METABOLISM : 

LIPID METABOLISM Dr. V. Siva Prabodh MD Associate Professor Dept. of Biochemistry NRI Medical College

Dietary Fatty Acids : 

2 Dietary Fatty Acids Comprise 30-60% of caloric intake in average American diet Triacylglycerols, phospholipids, sterol esters Principal sources: dairy products, meats

Digestion of Dietary Triacylglycerols : 

3 Digestion of Dietary Triacylglycerols Occurs in duodenum Facilitated by Bile salts (emulsification) Alkaline medium (pancreatic juice) Pancreatic lipases OH OH TAG MAG Intestinal lipases Glycerol + Fatty Acids Blocked by Orlistat (“Fat Blocker”)

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4 Epithelial Cell (Intestinal Wall) Intestinal lumen MAG Glycerol Fatty Acids TAG Lipoprotein Chylomicrons Lymphatics Blood (bound to albumin) Adipose Tissue And Muscle

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5 Adipocytes

Lipid Metabolism : 

Lipid Metabolism

Lipid Metabolism : 

Lipid Metabolism

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9 Adipose Cell Hormone (Adrenalin, Glucagon, ACTH) Receptor (7TM) ATP c-AMP Adenylyl Cyclase Activates Activates lipase Triacylglycerols Glycerol + Fatty acids Blood Lipolysis Insulin blocks this step

Lipid Metabolism : 

Lipid Metabolism

Beta Oxidation of Fatty acids : 

Beta Oxidation of Fatty acids Beta Oxidation is the process where energy is produced from Lipids. Beta oxidation is the oxidation over the β -Carbon of hydrocarbon chain of fatty acids by a sequential cleavage of two carbon atoms.

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The break down of a fatty acid to acetyl-CoA Occurs in the mitochondria STRICTLY AEROBIC Acetyl-CoA is fed directly into the Krebs cycle Overproduction causes KETOSIS

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→ β -oxidation takes place in Mitochondria → Fatty acids which are participating in β-oxidation undergo activation to form Fatty acyl CoA → Activation of fatty acid takes place in cytoplasm, requires 2 high energy bonds and enzyme is Thiokinase or fatty acyl Co A synthetase. → The activated fatty acids which are present in cytoplasm enters into mitochondria with the help of Carnitine. CARNITINE is β – hydroxy trimethyl amonium butrate It is synthesized from Lysine and Methionine in Liver & Kidney.

Lipid Metabolism : 

Lipid Metabolism

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Transport into Mitochondria depends on Carnitine FA~CoA FA~Carnitine FA~Carnitine Carnitine Translocase

β – oxidation proper : 

β – oxidation proper There are 4 steps in β – oxidation Step I – Oxidation by FAD linked dehydrogenase Step II – Hydration by Hydratase Step III – Oxidation by NAD linked dehydrogenase Step IV – Thiolytic clevage Thiolase

Beta Oxidation : 

Beta Oxidation

Beta Oxidation : 

Beta Oxidation

Beta Oxidation : 

Beta Oxidation

Beta Oxidation : 

Beta Oxidation

Beta Oxidation : 

Beta Oxidation Palmitic (16 c)

Beta Oxidation : 

Beta Oxidation Palmatic acid(16 c) 7 8

Energetics: : 

Energetics: Palmitic acid (16 C) needs 7 cycles of beta-oxidation, which gives rise to 8 molecules of Acetyl Co A 8 acetyl Co A x 12 = 96 ATP 7 FADH2 x 2 = 14 ATP 7 NADH x 3 = 21 ATP Total 131 ATP In initial activation Palmic acid → Palmitoyl Co A requires 2 high energy phosphates, so net is 131 – 2 = 129 ATP

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24 American Golden Plover

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25 Arctic Tern

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26 Camel

Acetyl CoA : 

Acetyl CoA

Regulation: : 

Regulation: Availability of FFA regulates β-oxidation. The availability of FFA is controlled by Glucagon : Insulin ratio Glucagon Increases FFA level Insulin decreases FFA level (2) CAT – I regulates entry of Fatty acyl Co A into mitochondria. Malonyl Co A Inhibits CAT – I activity.

Disorders of β-Oxidation : 

Disorders of β-Oxidation SIDS : Sudden Infant death syndrome. Unexpected death in healthy Infants, usually overnight. Deficiency: Medium chain acyl Co A dehydrogenase. The sudden death is due to blockade of β-Oxidation due to absence of MCAD. ■ Jamaican vomiting sickness: Symptoms: Severe hypoglycemia Vomitings Convulsion, coma & death Causes : Hypoglycin A which is present in Unripe ackee fruit. Hypoglycin A inhibits Acyl CoA dehydrogenase and thus β-Oxidation is blocked.

Beta Oxidation of Odd chain Carbon Fatty Acids : 

32 Beta Oxidation of Odd chain Carbon Fatty Acids 5 Cycles 5 CH3COSCoA + CH3CH2COSCoA Propionyl CoA D-Methylmalonyl CoA L-Methylmalonyl CoA Succinyl CoA TCA Cycle Propionyl CoA Carboxylase ATP/CO2 Epimerase Mutase Vit. B12

β-Oxidation of odd chain fatty acids : 

β-Oxidation of odd chain fatty acids In odd chain fatty acids in the last and final β-Oxidation cycle, a three carbon fragment is left behind (Propionyl CoA) Fate of Propionyl CoA: Propionyl CoA ↓ D-Methylmalonyl CoA ↓ α – Methylmalonyl CoA ↓ Succinyl CoA

Disorder related to β-Oxidation in odd chain fatty acids. : 

Disorder related to β-Oxidation in odd chain fatty acids. ═ Methylmalonic acidemia - Due to deficiency of Vit – B12 - Due to deficiency of Mutase enzymes In both the cases, α – Methylmalonyl CoA is not converted to Succinyl Co A. So, Methylmalonyl CoA is converted to Methyl malonic acid which is accumulated in blood and excreted through urine ═ Metabolic acidosis CNS damage Growth retardation are seen

β-Oxidation in Peroxisomes : 

β-Oxidation in Peroxisomes Peroxisomes are cell organelles. Initial steps of β-Oxidation for long chain Fatty acids takes place in Perosixomes. FADH2 which are generated because of β-Oxidation in perosixomes does not enter into ETC to generate ATP These FADH2 combine with O2 directly to generate H2O2 FADH2 + O2 FAD + H2O2 H2O2 H2O + ½ O2

Disorders related to β-Oxidation in Peroxisomes : 

Disorders related to β-Oxidation in Peroxisomes Zelweger syndrome: Rare disorder Absence of Peroxisomes, so very long chain fatty acids are not oxidized. Accumulation of very long chain fatty acids in tissues like brain, liver & Kidney. This syndrome also known as Cerebrohepato renal syndrome.

α – Oxidation of fatty acids : 

α – Oxidation of fatty acids Removal of one carbon unit at a time by oxidation of α – carbon of fatty acids is known as α – oxidation α – oxidation takes place over the fatty acids where a group is attached on the β- carbon Eg : Phytanic acid (derived from phytol present in chloroform,milk and animal fats) α – oxidation takes place in endoplasmic reticulum, Hydroxylation followed by oxidation of α-carbon . Minor pathway requires cytochrome P450, NADPH & O2 doesn't produce energy

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Refsums disease: Deficiency of Phytanic acid oxidase or α -hydroxylase Phytanic acid accumulation in tissues. Symptoms : Severe neurological disorders like polyneuropathy,retinitis pigmentosa and cerebellar ataxia.

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Thank you