* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Lecture 35 - Lipid Metabolism 1
Genetic code wikipedia , lookup
Nucleic acid analogue wikipedia , lookup
Point mutation wikipedia , lookup
Nicotinamide adenine dinucleotide wikipedia , lookup
Peptide synthesis wikipedia , lookup
Lipid signaling wikipedia , lookup
Mitochondrion wikipedia , lookup
Metalloprotein wikipedia , lookup
Microbial metabolism wikipedia , lookup
Amino acid synthesis wikipedia , lookup
Adenosine triphosphate wikipedia , lookup
Oxidative phosphorylation wikipedia , lookup
Evolution of metal ions in biological systems wikipedia , lookup
Basal metabolic rate wikipedia , lookup
Specialized pro-resolving mediators wikipedia , lookup
Biosynthesis wikipedia , lookup
Butyric acid wikipedia , lookup
Biochemistry wikipedia , lookup
Glyceroneogenesis wikipedia , lookup
Citric acid cycle wikipedia , lookup
Lipid Metabolism 1: Overview of lipid transport in animals, fatty acid oxidation, ketogenesis in liver mitochondria Bioc 460 Spring 2008 - Lecture 35 (Miesfeld) Prime rib contains large amounts of saturated fats in the form of triacylglycerols Adipose tissue is the primary triacylglycerol storage depot in animals, fats are an excellent form of redox energy Stored fat comes from the conversion of carbohydrates into fatty acids in the liver Key Concepts in Lipid Metabolism • Stored lipids is the primary source of energy in most organisms. • The three sources of triacylglycerols in animals are dietary lipids, stored triacylglycerols in adipose tissue, and fatty acids synthesized in the liver. -oxidation is the mitochondrial process by which fatty acids are oxidized to yield NADH, FADH2, and acetyl-CoA. • Ketogenesis takes place in liver mitochondria when acetyl-CoA levels are high and oxaloacetate levels are low. Overview of Lipid Transport in Animals Fat is stored in fat cells (adipocytes). Obesity, especially childhood obesity, can be due to both more fat storage per cell, and to a larger number of adipocytes. Not all fat is the same Review of lipid structures: Fatty acids are stored as triacylglycerols Glycerol Fatty acid #2 Fatty acid #1 Fatty acid #3 Glycerol esterification of fatty acids protects cell membranes from the amphipathic nature of fatty acids. Soap is made out of fatty acids and works well to remove oils from hands and clothes by forming micelles that trap the lipids in a water soluble particle. Homemade soap is made from animal fat Soap is made from fatty acids through a process called saponification. Fatty acids are amphipathic molecules that break up grease by partitioning the fat and water into micelles. Saponification neutralizes the fatty acid carboxylate group with Na+, however, Mg2+ and Ca2+ ions present in "hard" water cause the formation of fatty acid precipitates called soap scum. Lipid Metabolism Lipid Metabolism Pathway Questions 1. What purpose does fatty acid metabolism serve in animals? – Fatty acid oxidation in mitochondria is responsible for providing energy to cells when glucose levels are low. Triacylglycerols stored in adipose tissue of most humans can supply energy to the body for ~3 months during starvation. – Fatty acid synthesis reactions in the cytosol of liver and adipose cells convert excess acetyl CoA that builds up in the mitochondrial matrix when glucose levels are high into fatty acids that can be stored or exported as triacylglycerols. Pathway Questions 2. What are the net reactions of fatty acid degradation and synthesis for the C16 fatty acid palmitate? Fatty acid oxidation: Palmitate + 7 NAD+ + 7 FAD + 8 CoA + 7 H2O + ATP → 8 acetyl CoA + 7 NADH + 7 FADH2 + AMP + 2 Pi + 7 H+ Fatty acid synthesis: 8 Acetyl CoA + 7 ATP + 14 NADPH + 14 H+ → Palmitate + 8 CoA + 7 ADP + 7 Pi + 14 NADP+ + 6 H2O Pathway Questions 3. What are the key enzymes in fatty acid metabolism? Fatty acyl CoA synthetase – enzyme catalyzing the "priming" reaction in fatty acid metabolism which converts free fatty acids in the cytosol into fatty acyl-CoA using the energy available from ATP and PPi hydrolysis. Carnitine acyltransferase I - catalyzes the commitment step in fatty acid oxidation which links fatty acyl-CoA molecules to the hydroxyl group of carnitine. The activity of carnitine acyltransferase I is inhibited by malonylCoA, the product of the acetyl-CoA carboxylase reaction, which signals that glucose levels are high and fatty acid synthesis is favored. Pathway Questions 3. What are the key enzymes in fatty acid metabolism? Acetyl CoA carboxylase - catalyzes the commitment step in fatty acid synthesis using a biotin-mediated reaction mechanism that carboxylates acetyl-CoA to form the C3 compound malonyl-CoA. The activity of acetyl CoA carboxylase is regulated by both reversible phosphorylation (the active conformation is dephosphorylated) and allosteric mechanisms (citrate binding stimulates activity, palmitoyl-CoA inhibits activity). Fatty acid synthase - this large multi-functional enzyme is responsible for catalyzing a series of reactions that sequentially adds C2 units to a growing fatty acid chain covalently attached to the enzyme complex. The mechanism involves the linking malonyl-CoA to an acyl carrier protein, followed by a decarboxylation and condensation reaction that extends the hydrocarbon chain. Pathway Questions 4. What are examples of fatty acid metabolism in real life? A variety of foods are prominently advertised as "non-fat," even though they can contain a high calorie count coming from carbohydrates. Eating too much of these high calorie non-fat foods (e.g., non-fat bagels) activates the fatty acid synthesis pathway resulting in the conversion of acetyl-CoA to fatty acids, which are stored as triacylglycerols. Transport and storage of fatty acids and triacylglycerols Transport and storage of fatty acids and triacylglycerols The fatty acid oxidation pathway in mitochondria Fatty acid are transported into mitochondria by carnitine Carnitine acyltransferase I replaces CoA with carnitine to form fatty acyl carnitine which is translocated across the inner mitochondrial membrane by the carnitine translocating protein. Lastly, carnitine acyltransferase II release the carnitine and it is shuttled back across the membrane. -oxidation yields large amounts of ATP The energy conversion process of fatty acid --> ATP involves oxidation of fatty acids by sequential degradation of C2 units leading to the generation FADH2, NADH, and acetyl CoA. Palmitate (C16) The subsequent oxidation of these reaction products by the citrate cycle and oxidative phosphorylation generates lots of ATP. 106 ATP - WOW! -oxidation reactions OXIDATION The -oxidation pathway occurs at the carbon of the fatty acid, thereby releasing the C-1 carboxyl carbon and carbon as the acetate component of acetyl CoA. HYDRATION OXIDATION THIOLYSIS -oxidation reactions for palmitate (C16) Palmitoyl-CoA + 7 CoA + 7 FAD + 7 NAD+ + 7 H2O --> 8 acetyl CoA + 7 FADH2 + 7 NADH + 7 H+ ATP currency exchange ratios 31 NADH (31 x ~2.5 ATP) = ~77.5 ATP 15 FADH2 (15 x ~1.5 ATP) = ~22.5 ATP For a grand total = 100 ATP After subtracting the 2 ATP required for fatty acyl CoA activation (AMP --> PPi) And adding the 8 ATP obtained from eight turns of the citrate cycle; The total payout for the complete oxidation of palmitate is 106 ATP -oxidation is a chemical source of water for desert animals Besides the payout of ATP that comes from fatty acid oxidation, another benefit is the generation of H2O that occurs when O2 is reduced by the final reaction in the electron transport system, as well as, the formation of H2O in oxidative phosphorylation. 2 NADH + 2 H+ + O2 --> 2 H2O 2 FADH2 + O2 --> 2 H2O ADP + PO42- --> ATP + H2O Ketogenesis When fatty acid oxidation produces more acetyl-CoA than can be combined with OAA to form citrate, then the "extra" acetyl-CoA is converted to acetoacetyl-CoA and ketone bodies, including acetone. Ketogenesis (synthesis of ketone bodies) takes place primarily in the liver. Ketogenesis Acetyl-CoA derived from fatty acid oxidation enters the Citrate Cycle only if carbohydrate metabolism is properly balanced. When fatty acid oxidation produces more acetylCoA than can be combined with OAA to form citrate, then the "extra" acetyl-CoA is converted to acetoacetyl-CoA and ketone bodies, including acetone. Ketogenesis (synthesis of ketone bodies) takes place primarily in the liver. Ketones are an energy source for tissues How many total ATP from 2 acetyl-CoA? 6 NADH 2 FADH2 2 GTP 15 ATP 3 ATP 2 ATP 20 ATP Ok, now what happens to these two acetyl-CoA? per Acetyl-CoA PowerPoint slide from lecture 28 Ketogenesis occurs when glycogen stores are depleted such as during fasting and in undiagnosed diabetics Diabetics can have high levels of acetone in their blood which can be detected on their breath as a fruity odor. Acetone is a spontaneous breakdown product of acetoacetate (decarboxylation), or it is formed by enzymatic cleavage of acetoacetate by the enzyme acetoacetate decarboxylase.