Energy Metabolism II Fatty Acid Oxidation PDF

Energy metabolism II: fatty acid Jorge Miguel, MD. oxidation W E MAKE DOCTORS Main bibliography Today's lecture is based on: The full book can be found in Clinical Key in your digital resources....

Energy metabolism II: fatty acid Jorge Miguel, MD. oxidation W E MAKE DOCTORS Main bibliography Today's lecture is based on: The full book can be found in Clinical Key in your digital resources. AMBOSS Threads Recommended pre- lecture Today’s lecture Further reading How can I prepare for future lectures? Learning objectives Explain the classification and nomenclature of fatty acids. Saturated and unsaturated fatty acids. Geometric isomerism. Outline the sequence of reactions involved in the oxidation of fatty acids. Release of the free fatty acids from the adipose tissue. Peroxisomal catabolism of fatty acids. Activation of fatty acids. Transport inside the mitochondrion (carnitine shuttle). Fatty acid β-oxidation cycle. Describe the general features of pathways for the oxidation of odd-chain and branched-chain fatty acids. α-oxidation. Explain the rationale for the pathway of ketogenesis and identify the major intermediates and products of this pathway. Describe the regulatory mechanisms for the fatty acid oxidation.  Lipids This introduction focuses on the structure of fatty acids, triglycerides and phospholipids. Baynes, J. W., & Dominiczak, M. H. (2019). Medical Biochemistry (6th ed.). Elsevier.  Lipids This introduction focuses on the structure of fatty acids, triglycerides and phospholipids. Phospholipids are the major lipids in biological membranes Baynes, J. W., & Dominiczak, M. H. (2019). Medical Biochemistry (6th ed.). Elsevier.  Lipids This introduction focuses on the structure of fatty acids, triglycerides and phospholipids. Triglycerides are the storage form of lipids in adipose tissue Baynes, J. W., & Dominiczak, M. H. (2019). Medical Biochemistry (6th ed.). Elsevier.  Lipids This introduction focuses on the structure of fatty acids, triglycerides and phospholipids. Fatty acids exists in free form and as components of more complex lipids, the simplest form of lipids, found primarily in plasma Baynes, J. W., & Dominiczak, M. H. (2019). Medical Biochemistry (6th ed.). Elsevier. Fatty Acids Fatty acids are short to very long straight carbon chain alkanoic acids, most of them with 16 to 18 carbons. Baynes, J. W., & Dominiczak, M. H. (2019). Medical Biochemistry (6th ed.). Elsevier. Fatty Acids They may be saturated or unsaturated, the latter containing up to five doble bonds. Fatty acids with a single double bond are described as monounsaturated Those with two or more double bonds are described as polyunsaturated. Commonly classified into two groups: ω-3 and ω-6 fatty acids depending on whether the first double bond appears 3 or 6 carbons from the terminal methyl group. Baynes, J. W., & Dominiczak, M. H. (2019). Medical Biochemistry (6th ed.). Elsevier. Baynes, J. W., & Dominiczak, M. H. (2019). Medical Biochemistry (6th ed.). Elsevier.  Fatty acid oxidation Fatty acids are a crucial energy source in the postabsorptive and fasted states when glucose supply is limiting Fats are the major source of energy in liver and skeletal muscle and in other tissues (heart, and kidney), with two major exceptions: brain and red cells. Baynes, J. W., & Dominiczak, M. H. (2019). Medical Biochemistry (6th ed.). Elsevier. Fatty acid oxidation Fatty acids are important nutrients, and their storage as triglycerides in adipose tissue allows humans to tolerate extended periods of starvation or fasting and other metabolically challenging conditions such as febrile illness and exercise. Mitochondrial fatty acid β-oxidation (FAO) is the major pathway for the degradation of fatty acids and is essential for maintaining energy homeostasis in the human body. Baynes, J. W., & Dominiczak, M. H. (2019). Medical Biochemistry (6th ed.). Elsevier. Fatty acid oxidation Fat metabolism is controlled primarily by the rate of triglyceride hydrolysis (lipolysis) in adipose tissue, which is regulated by hormonal mechanisms involving insulin, glucagon, epinephrine, and cortisol. These hormones coordinate the metabolism of carbohydrates, lipids, and protein throughout the body. Baynes, J. W., & Dominiczak, M. H. (2019). Medical Biochemistry (6th ed.). Elsevier. The length of the fatty acid Short- and medium-chain fatty acids can cross the mitochondrial membrane by passive diffusion. Very long–chain fatty acids from the diet are shortened to long-chain fatty acids in peroxisomes. Long-chain fatty acids are the major components of storage triglycerides and dietary fats. Baynes, J. W., & Dominiczak, M. H. (2019). Medical Biochemistry (6th ed.). Elsevier. Fatty acid oxidation In the cytosol, fatty acids are activated to acyl- coenzyme A (CoA) esters by acyl-CoA synthetases before they can be transported into the mitochondrion via the carnitine shuttle. Baynes, J. W., & Dominiczak, M. H. (2019). Medical Biochemistry (6th ed.). Elsevier.  =O - R – CH2 – CH2 – C – OFatty acid ATP Thiokina ADP+P se i CoA- SH =O R – CH2 – CH2 – C – CoA-SH Fatty acyl-CoA  Fatty acid oxidation Thus, the fatty acid is first transferred to the small molecule, carnitine, by carnitine palmitoyl transferase- I (CPT-I), located in the outer mitochondrial membrane. CPT1, an integral outer-mitochondrial-membrane protein, catalyzes the transesterification of the acyl-CoA to acylcarnitine. Baynes, J. W., & Dominiczak, M. H. (2019). Medical Biochemistry (6th ed.). Elsevier.  =O R – CH2 – CH2 – C – CoA-SH Fatty acyl- CoA Thiokin CPT ase -I =O =O Carnitin CoA R – CH2 – CH2 – C – CoA-SH R – CH2 – CH2 – C – Fatty acyl- e Carnitine Fatty acyl- CoA carnitine Fatty acid oxidation An acyl-carnitine transporter, or translocase, in the inner mitochondrial membrane mediates transfer of the acyl- carnitine into the mitochondrion, where CPT- II regenerates the acyl-CoA, releasing free carnitine. Inside the mitochondria, CPT2, which is a peripheral inner-mitochondrial membrane protein, completes the cycle by reconverting the acylcarnitine into an acyl-CoA. Baynes, J. W., & Dominiczak, M. H. (2019). Medical Biochemistry (6th ed.). Elsevier.  =O R – CH2 – CH2 – C – CoA-SH Fatty acyl-CoA Thiokin CPT ase -I =O =O Carnitin CoA R – CH2 – CH2 – C – CoA-SH R – CH2 – CH2 – C – Fatty acyl- e Carnitine Fatty acyl- CoA carnitine CPT- Carnitin e acyl II transpor ter Carnitin CoA =O =O B- R – CH2 – CH2 – C – R – CH2 – CH2 – C e – CoA-SH Oxidati Carnitine Fatty acyl- Fatty acyl- on CoA carnitine  =O R – CH2 – CH2 – C – CoA-SH Fatty acyl-CoA Thiokin CPT ase -I =O =O Carnitin CoA R – CH2 – CH2 – C – CoA-SH R – CH2 – CH2 – C – Fatty acyl- e Carnitine Fatty acyl- CoA carnitine CPT- Carnitin e acyl II transpor ter Carnitin CoA =O =O B- R – CH2 – CH2 – C – R – CH2 – CH2 – C e – CoA-SH Oxidati Carnitine Fatty acyl- Fatty acyl- on CoA carnitine  =O R – CH2 – CH2 – C – CoA-SH Fatty acyl-CoA Thiokin CPT ase -I =O =O Carnitin CoA R – CH2 – CH2 – C – CoA-SH R – CH2 – CH2 – C – Fatty acyl- e Carnitine Fatty acyl- CoA carnitine CPT- Carnitin e acyl II transpor ter Carnitin CoA =O =O B- R – CH2 – CH2 – C – R – CH2 – CH2 – C e – CoA-SH Oxidati Carnitine Fatty acyl- Fatty acyl- on CoA carnitine  Fatty acid β-oxidation Although some tissues can synthesize carnitine, most carnitine is of dietary origin and is transported across the plasma membrane by the organic cation transporter OCTN2. The carnitine shuttle operates by an antiport mechanism in which free carnitine and the acyl- carnitine derivative move in opposite directions across the inner mitochondrial membrane. The shuttle is an important site in the regulation of fatty acid oxidation. The carnitine shuttle is inhibited by malonyl-CoA after the ingestion of carbohydrate-rich meals. Baynes, J. W., & Dominiczak, M. H. (2019). Medical Biochemistry (6th ed.). Elsevier.  =O R – CH2 – CH2 – C – CoA-SHFatty acyl- CoA FAD Acyl- CoA Dehydrogena se FADH2 =O R - CH = CH – C - CoA-SHEnoyl-CoA  =O R - CH = CH – C - CoA-SHEnoyl-CoA Enoyl- CoA H2O Hydratase H H -- -- =O R - C - C – C - CoA- SHOH H B-Hydroxy Acyl-  H H H =O -- -- Hydroxyacyl -- =O -CoA R - C - C – C - CoA- Dehydrogena R - C - C – C - - se SHOH H SH O H B-Hydroxy Acyl- B-Keto Acyl- CoA NAD+ + CoA NADH+H  H -- =O 11 R - CH2 – CH2 - C - C – C - - - CoA-SH O H B-Keto Acyl- CoA R - CH2 – CH2 CoA-SH - C =O - -Fatty Acyl- O CH3 – C - CoA- CoA Acetyl-CoA CoA Thiola se B-Keto Acyl- CoA Fatty acid oxidation In muscle, the acetyl-CoA is metabolized via the tricarboxylic acid (TCA) cycle and oxidative phosphorylation to produce ATP. Baynes, J. W., & Dominiczak, M. H. (2019). Medical Biochemistry (5th ed.). Elsevier. Fatty acid oxidation FAO not only fuels the tricarboxylic acid (TCA) cycle and oxidative phosphorylation, but also stimulates hepatic synthesis of the ketone bodies (3-hydroxybutyrate and acetoacetate). FAO was also shown to play significant roles in the pathophysiology of common disorders such as insulin resistance, diabetes, obesity, kidney fibrosis, and heart failure. Baynes, J. W., & Dominiczak, M. H. (2019). Medical Biochemistry (5th ed.). Elsevier. 16  Acetyl Acetyl Acetyl Acetyl Acetyl Acetyl Acetyl Acetyl CoA CoA CoA CoA CoA CoA CoA CoA NADH+H NADH+H NADH+H NADH+H NADH+H NADH+H NADH+H FADH2 FADH2 FADH2 FADH2 FADH2 FADH2 FADH2 Fatty acid Acetyl-CoA FADH2 NADH+H ATP total 16 carbons 8 (80 ATP) 7-7 (28 ATP) 108 Fatty acid oxidation One mole each of acetyl-CoA, FADH2 , and NADH is formed during each cycle, along with a fatty acyl-CoA with two fewer carbon atoms. Baynes, J. W., & Dominiczak, M. H. (2019). Medical Biochemistry (6th ed.). Elsevier. Fatty Acetyl FADH2 NADH+H ATP acid -CoA total 16 8 (80 7-7 (28 ATP) 108 carbon ATP) s NADH+ FADH2 Fatty acid oxidation In liver, acetyl-CoA is converted to ketone bodies (ketogenesis), which are water-soluble lipid derivatives that, like glucose, are exported for use in other tissues. Baynes, J. W., & Dominiczak, M. H. (2019). Medical Biochemistry (6th ed.). Elsevier. Fatty acid oxidation Peroxisomal catabolism of fatty acids  =O R – CH2 – CH2 – C – CoA-SHFatty acyl- CoA H2O2 FAD Acyl- CoA Dehydrogena se O2 + FADH2 H2O =O R - CH = CH – C - CoA-SHEnoyl-CoA  H2O2 Hidrogen peroxide Catalase O2 + Peroxisomal catabolism of fatty acids B-Oxidation Fatty acid oxidation During fasting, the nutritional glucose supply becomes progressively limiting, and glucose production is maintained through glycogen breakdown (glycogenolysis) and de novo glucose synthesis (gluconeogenesis). Glycogen stores are limited, and ultimately gluconeogenic precursors, which include lactate, pyruvate, glycerol, and specific amino acids, are the sole sources of glucose. Baynes, J. W., & Dominiczak, M. H. (2019). Medical Biochemistry (6th ed.). Elsevier.  Fatty acid oxidation Because proteolysis is mainly responsible for the net generation of gluconeogenic precursors, oxidation of fatty acids is essential as an alternative to prevent rapid erosion of protein mass. This adaptive response is mediated by the neuroendocrine system, which among other mechanisms increases adipose lipolysis. Baynes, J. W., & Dominiczak, M. H. (2019). Medical Biochemistry (6th ed.). Elsevier. β-oxidation disorders Baynes, J. W., & Dominiczak, M. H. (2019). Medical Biochemistry (6th ed.). Elsevier. Odd-chain fatty acids The oxidation of fatty acids with an odd number of carbons proceeds from the carboxyl end, like that of normal fatty acids, except that propionyl- CoA is formed by the last thiolase cleavage reaction. The propionyl-CoA is converted to succinyl-CoA by a multistep process involving three enzymes and two vitamins biotin and cobalamin. The succinyl-CoA enters directly into the TCA cycle. Baynes, J. W., & Dominiczak, M. H. (2019). Medical Biochemistry (6th ed.). Elsevier.  Acetyl Acetyl Acetyl Acetyl Acetyl Acetyl CoA CoA CoA CoA CoA CoA 15 Propion Succiny TCA ylCoA l CoA Cycle α-Oxidation α-Oxidation initiates oxidation of branched-chain fatty acids to acetyl-CoA and propionyl-CoA Phytanic acids are branched-chain polyisoprenoid lipids found in plant chlorophylls. Because the β-carbon of phytanic acids is at a branch point, it is not possible to oxidize this carbon to a ketone. The first and essential step in the catabolism of phytanic acids is α-oxidation to a pristanic acid, releasing the α-carbon as carbon dioxide. Refsum's disease is a rare neurologic disorder characterized by the accumulation of phytanic acid deposits in nerve tissues as a result of a genetic defect in α- oxidation. Baynes, J. W., & Dominiczak, M. H. (2019). Medical Biochemistry (6th ed.). Elsevier.  Thank you for your attention! Jorge Miguel, MD. W E MAKE DOCTORS