Chem 454: Biochemistry II University of Wisconsin-Eau Claire Chem 454: Biochemistry II University of Wisconsin-Eau Claire Chapter 22. Fatty Acid Metabolism.

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Presentation transcript:

Chem 454: Biochemistry II University of Wisconsin-Eau Claire Chem 454: Biochemistry II University of Wisconsin-Eau Claire Chapter 22. Fatty Acid Metabolism

Text 2 Fatty acids play several important roles: Building blocks for phospholipids and glycolipids Target proteins to membranes High energy source of fuel Fatty acid derivatives are used as hormones and intracellular messengers Fatty acids play several important roles: Building blocks for phospholipids and glycolipids Target proteins to membranes High energy source of fuel Fatty acid derivatives are used as hormones and intracellular messengers Introduction

Text 3 Overview of fatty acid synthesis Introduction

Text 4 Triglycerides are a highly concentrated store of energy 9 kcal/g vs 4 kcal/g for glycogen Glycogen is also highly hydrated, 2 g H 2 O/g glycogen Triglycerides are a highly concentrated store of energy 9 kcal/g vs 4 kcal/g for glycogen Glycogen is also highly hydrated, 2 g H 2 O/g glycogen 1. Triglycerides

Text 5 Dietary triacylglycerols must be broken down before being absorbed by the intestines. Bile salts, which act as detergents, are used to solublize the triacylglycerols Dietary triacylglycerols must be broken down before being absorbed by the intestines. Bile salts, which act as detergents, are used to solublize the triacylglycerols 1.1 Pancreatic Lipases

Text 6 Dietary triacylglycerols must be broken down before being absorbed by the intestines. Bile salts, which act as detergents, are used to solublize the triacylglycerols Dietary triacylglycerols must be broken down before being absorbed by the intestines. Bile salts, which act as detergents, are used to solublize the triacylglycerols 1.1 Pancreatic Lipases

Text 7 Pancreatic lipases hydrolyze the ester bonds of the triacylglycerols while in the micelles. 1.1 Pancreatic Lipases

Text 8 In the intestinal mucosal cells, the fatty acids and monoacylglycerides are resynthesized into triacylglycerides and packaged into chylomicrons. Chylomicrons and lymph are dumped via the thoracic duct into the left subclavian vein 1.1 Chylomicrons

Text Chylomicrons Chylomicrons and lymph are dumped via the thoracic duct into the left subclavian vein. Want to know more about lymphatic system? Try here: /Notes7%20Lymphatic%20Anatomy.htm /Notes7%20Lymphatic%20Anatomy.htm

Text 10 Three stages of processing Triglycerols are degraded to fatty acids and glycerol in the adipose tissue and transported to other tissues. Fatty acids are activated and transported into the mitochondria. Fatty acids are broken down into two-carbon acetyl–CoA units and fed into the citric acid cycle. Three stages of processing Triglycerols are degraded to fatty acids and glycerol in the adipose tissue and transported to other tissues. Fatty acids are activated and transported into the mitochondria. Fatty acids are broken down into two-carbon acetyl–CoA units and fed into the citric acid cycle. 2. Utilization of Fatty Acids as Fuel

Text 11 In the adipose tissue, lipases are activated by hormone signaled phosphorylation 2.1 Breakdown of Triacylglycerols

Text 12 The lipases break the triacylglycerols down to fatty acids and glycerol The fatty acids are transportred in the blood by serum albumin The lipases break the triacylglycerols down to fatty acids and glycerol The fatty acids are transportred in the blood by serum albumin 2.1 Breakdown of Triacylglycerols

Text 13 The glycerol is absorbed by the liver and converted to glycolytic intermediates. 2.1 Breakdown of Triacylglycerols

Text 14 Acyl CoA synthetase reaction occurs in the on the mitochondrial membrane. 2.2 Activation of Fatty Acids

Text 15 Carnitine carries long-chain activated fatty acids into the mitochondrial matrix 2.3 Transport into Mitochondrial Matrix

Text 16 Carnitine carries long-chain activated fatty acids into the mitochondrial matrix 2.3 Transport into Mitochondrial Matrix

Text Transport into Mitochondrial Matrix A Miracle???

Text 18 Each round in fatty acid degradation involves four reactions 1. oxidation to trans-∆ 2 -Enoly-CoA Each round in fatty acid degradation involves four reactions 1. oxidation to trans-∆ 2 -Enoly-CoA 2.4 Fatty acid oxidation

Text 19 Each round in fatty acid degradation involves four reactions 2. Hydration to L–3– Hydroxylacyl CoA Each round in fatty acid degradation involves four reactions 2. Hydration to L–3– Hydroxylacyl CoA 2.4 Fatty acid oxidation

Text 20 Each round in fatty acid degradation involves four reactions 3. Oxidation to 3–Ketoacyl CoA Each round in fatty acid degradation involves four reactions 3. Oxidation to 3–Ketoacyl CoA 2.4 Fatty acid oxidation

Text 21 Each round in fatty acid degradation involves four reactions 4. Thiolysis to produce Acetyl–CoA Each round in fatty acid degradation involves four reactions 4. Thiolysis to produce Acetyl–CoA 2.4 Fatty acid oxidation

Text 22 Each round in fatty acid degradation involves four reactions The process repeats itself Each round in fatty acid degradation involves four reactions The process repeats itself 2.4 Fatty acid oxidation

Text 23 Each round in fatty acid degradation involves four reactions 2.4 Fatty acid oxidation

Text 24 The complete oxidation of the sixteen carbon palmitoyl–CoA produces 106 ATP's 2.5 ATP Yield

Text 25 Unsaturated fatty acids (monounsaturated) 3.1 Special Cases

Text 26 Unsaturated fatty acids (polyunsaturated) 3.1 Special Cases

Text Odd-Chain

Text Peroxisomes (skip)

Text Ketone Bodies Use of fatty acids in the citric acid cycle requires carbohydrates for the the production of oxaloacetate. During starvation or diabetes, OAA is used to make glucose Fatty acids are then used to make ketone bodies (acetoacetate and D–3–hydroxybutarate) Use of fatty acids in the citric acid cycle requires carbohydrates for the the production of oxaloacetate. During starvation or diabetes, OAA is used to make glucose Fatty acids are then used to make ketone bodies (acetoacetate and D–3–hydroxybutarate)

Text Ketone Bodies Ketone bodies, acetoacetate and 3– hydroxybutarate are formed from Acetyl– CoA

Text 31 The liver is the major source of ketone bodies. It is transported in the blood to other tissues Acetoacetate in the tissues Acetoacetate is first activated to acetoacetate by transferring the CoASH from succinyl–CoA. It is then split into two Acetyl–CoA by a thiolase reaction The liver is the major source of ketone bodies. It is transported in the blood to other tissues Acetoacetate in the tissues Acetoacetate is first activated to acetoacetate by transferring the CoASH from succinyl–CoA. It is then split into two Acetyl–CoA by a thiolase reaction 3.6 Ketone Bodies as a Fuel Source

Text 32 Even though the citric acid cycle intermediate oxaloacetate can be used to synthesize glucose, Acetyl–CoA cannot be used to synthesize oxaloacetate. The two carbons that enter the citric acid cycle as Acetyl–CoA leave as CO 2. Even though the citric acid cycle intermediate oxaloacetate can be used to synthesize glucose, Acetyl–CoA cannot be used to synthesize oxaloacetate. The two carbons that enter the citric acid cycle as Acetyl–CoA leave as CO Fatty Acids Cannot be Used to Synthesize Glucose

Text 33 Fatty acid are synthesized and degraded by different pathways. Synthesis takes place in the cytosol. Intermediates are attached to the acyl carrier protein (ACP). In higher organisms, the active sites for the synthesis reactions are all on the same polypeptide. The activated donor in the synthesis is malonyl– ACP. Fatty acid reduction uses NADPH + H +. Elongation stops at C 16 (palmitic acid) Fatty acid are synthesized and degraded by different pathways. Synthesis takes place in the cytosol. Intermediates are attached to the acyl carrier protein (ACP). In higher organisms, the active sites for the synthesis reactions are all on the same polypeptide. The activated donor in the synthesis is malonyl– ACP. Fatty acid reduction uses NADPH + H +. Elongation stops at C 16 (palmitic acid) 4. Fatty Acid Synthesis.

Text 34 Formation of malonyl–CoA is the committed step in fatty acid synthesis. 4.1 Formation of Malonyl Coenzyme A

Text 35 The intermediates in fatty acid synthesis are covalently linked to the acyl carrier protein (ACP) 4.2 Acyl Carrier Protein

Text 36 In bacteria the enzymes that are involved in elongation are separate proteins; in higher organisms the activities all reside on the same polypeptide. To start an elongation cycle, Acetyl–CoA and Malonyl–CoA are each transferred to an acyl carrier protein In bacteria the enzymes that are involved in elongation are separate proteins; in higher organisms the activities all reside on the same polypeptide. To start an elongation cycle, Acetyl–CoA and Malonyl–CoA are each transferred to an acyl carrier protein 4.3 Elongation

Text 37 Acyl-malonyl ACP condensing enzyme forms Acetoacetyl-ACP. 4.3 Elongation

Text 38 The next three reactions are similar to the reverse of fatty acid degradation, except The NADPH is used instead of NADH and FADH 2 The D–enantiomer of Hydroxybutarate is formed instead of the L–enantiomer The next three reactions are similar to the reverse of fatty acid degradation, except The NADPH is used instead of NADH and FADH 2 The D–enantiomer of Hydroxybutarate is formed instead of the L–enantiomer 4.3 Elongation

Text 39 The elongation cycle is repeated six more times, using malonyl–CoA each time, to produce palmityl–ACP. A thioesterase then cleaves the palmityl–CoA from the ACP. The elongation cycle is repeated six more times, using malonyl–CoA each time, to produce palmityl–ACP. A thioesterase then cleaves the palmityl–CoA from the ACP. 4.3 Elongation

Text 40 Domain 1 Substrate entry (AT & MT) and condensation unit (CE) Domain 2 Reduction unit (DH, ER & KR) Domain 3 Palmitate release unit (TE) Domain 1 Substrate entry (AT & MT) and condensation unit (CE) Domain 2 Reduction unit (DH, ER & KR) Domain 3 Palmitate release unit (TE) 4.4 Multifunctional Fatty Acid Synthase

Text Multifunctional Fatty Acid Synthase

Text Multifunctional Fatty Acid Synthase A NEW STRUCTURE

Text Fatty Acid Synthase Mechanism

Text 44 The stoichiometry of palmitate synthesis: Synythesis of palmitate from Malonyl–CoA Synthesis of Malonyl–CoA from Acetyl–CoA Overall synthesis The stoichiometry of palmitate synthesis: Synythesis of palmitate from Malonyl–CoA Synthesis of Malonyl–CoA from Acetyl–CoA Overall synthesis 4.6 Stoichiometry of FA synthesis

Text 45 Acetyl–CoA is synthesized in the mitochondrial matrix, whereas fatty acids are synthesized in the cytosol Acetyl–CoA units are shuttled out of the mitochondrial matrix as citrate: Acetyl–CoA is synthesized in the mitochondrial matrix, whereas fatty acids are synthesized in the cytosol Acetyl–CoA units are shuttled out of the mitochondrial matrix as citrate: 4.7 Citrate Shuttle

Text 46 The malate dehydrogenase and NADP + –linked malate enzyme reactions of the citrate shuttle exchange NADH for NADPH 4.8 Sources of NADPH

Text Fatty Acid Synthase Inhibitors (skip)

Text Variations on a Theme (skip)

Text 49 Regulation of Acetyl carboxylase Global + insulin - glucagon - epinephrine Local + Citrate - Palmitoyl–CoA - AMP Regulation of Acetyl carboxylase Global + insulin - glucagon - epinephrine Local + Citrate - Palmitoyl–CoA - AMP 5. Regulation of Fatty Acid Synthesis

Text Regulation of Fatty Acid Synthesis

Text 51 Endoplasmic reticulum systems introduce double bonds into long chain acyl–CoA's Reaction combines both NADH and the acyl–CoA's to reduce O 2 to H 2 O. Endoplasmic reticulum systems introduce double bonds into long chain acyl–CoA's Reaction combines both NADH and the acyl–CoA's to reduce O 2 to H 2 O. 6. Elongation and Unsaturation

Text 52 Elongation and unsaturation convert palmitoyl–CoA to other fatty acids. Reactions occur on the cytosolic face of the endoplasmic reticulum. Malonyl–CoA is the donor in elongation reactions Elongation and unsaturation convert palmitoyl–CoA to other fatty acids. Reactions occur on the cytosolic face of the endoplasmic reticulum. Malonyl–CoA is the donor in elongation reactions 6.1 Elongation and Unsaturation

Text 53 Eicosanoid horomones are synthesized from arachadonic acid (20:4). Prostaglandins 20-carbon fatty acid containing 5-carbon ring Prostacyclins Thromboxanes Leukotrienes contain three conjugated double bonds Eicosanoid horomones are synthesized from arachadonic acid (20:4). Prostaglandins 20-carbon fatty acid containing 5-carbon ring Prostacyclins Thromboxanes Leukotrienes contain three conjugated double bonds 6.2 Eicosanoid Hormones

Text Eicosanoid Hormones

Text Eicosanoid Hormones

Text Eicosanoid Hormones