2024 SFI Nakai Fats and Ketones Bioenergetics VI Handout PDF

SCIENTIFIC FOUNDATIONS I Bioenergetics VI Metabolism of Fat and Ketone Bodies Dr. Hiroshi Nakai Room 331 Basic Science...

SCIENTIFIC FOUNDATIONS I Bioenergetics VI Metabolism of Fat and Ketone Bodies Dr. Hiroshi Nakai Room 331 Basic Science A Preliminary Look at Diabetic Ketoacidosis Patients with diabetes can undergo a dangerous condition called diabetic ketoacidosis (DKA) that accompanies hyperglycemia. Patients with type 1 diabetes cannot produce insulin at all: DKA Patients with type 2 can produce some insulin: DKA and hyperosmolar hyperglycemic state (HHS), a condition without ketoacidosis Adipose tissue of patients with HHS release much less fatty acids than those with DKA. Consider why this may be the case. I. b Oxidation A. Oxidation of a saturated fatty acid 1) Acyl-CoA dehydrogenase: Oxidation linked to transfer of electrons to the mitochondrial respiratory chain. 2) Enoyl-CoA hydratase: Addition of water to the double bond 3) b-hydroxacyl-CoA dehydrogenase: NAD+ is the electron acceptor 4) Acyl-CoA acetyltransferase (thiolase): Reaction with coenzyme A that cleaves off the carboxy-terminal 2 carbons, releasing acetyl-CoA 5) This is repeated until the final oxidation step in which two acetyl-CoA molecules are generated. Bioenergetics V – Page 1 Copyrighted illustrations mostly from Lehninger unless otherwise indicated. All other materials ©2019 Hiroshi Nakai. This document may not be printed, posted, or shared without explicit permission.  Fatty Acid Oxidation Acetyl-CoA Production (β- oxidation) Oxidation of acetyl-CoA Oxidative Phosphorylation β-Oxidation: Acyl-CoA Dehydrogenase Three isozymes: for very long, medium, and short chain Bioenergetics V – Page 2 Copyrighted illustrations mostly from Lehninger unless otherwise indicated. All other materials ©2019 Hiroshi Nakai. This document may not be printed, posted, or shared without explicit permission.  Path of Electrons from Acyl-CoA Dehydrogenase Acyl-CoA Dehydrogenase is bound to the mitochondrial inner membrane ETF = Electron- Transferring Flavoprotein Addition of Water to the Double Bond Bioenergetics V – Page 3 Copyrighted illustrations mostly from Lehninger unless otherwise indicated. All other materials ©2019 Hiroshi Nakai. This document may not be printed, posted, or shared without explicit permission.  Dehydrogenation of L-β-Hydroxyacyl-CoA Release of Acetyl-CoA B. Oxidation of a monounsaturated fatty acid 1) D3,D2-enoyl-CoA isomerase Bioenergetics V – Page 4 Copyrighted illustrations mostly from Lehninger unless otherwise indicated. All other materials ©2019 Hiroshi Nakai. This document may not be printed, posted, or shared without explicit permission.  Oxidation of a Mono- unsaturated Fatty Acid C. Complete Oxidation of odd-number fatty acids 1) Odd number fatty acids are not stored in human cells. However, they arise in the diet since they are common in plants and some marine organisms. 2) The basic problem is that propionyl-CoA is generated in the last step of b oxidation. 3) Oxidation of propionyl-CoA. Oxidation of Propionyl- CoA Bioenergetics V – Page 5 Copyrighted illustrations mostly from Lehninger unless otherwise indicated. All other materials ©2019 Hiroshi Nakai. This document may not be printed, posted, or shared without explicit permission.  Palmitate is the saturated fatty acid with 16 carbon units. Total yield during oxidation of palmitoyl-CoA to CO2 and H20: 108 ATP molecules II. Synthesis of Ketone Bodies A. Acetone, acetoacetate, and D-b-hydroxybutyrate Bioenergetics V – Page 6 Copyrighted illustrations mostly from Lehninger unless otherwise indicated. All other materials ©2019 Hiroshi Nakai. This document may not be printed, posted, or shared without explicit permission.  Ketone Bodies Acetoacetate and D-β- hydroxybutyrate are negatively charged metabolic fuel Synthesized in the liver mitochondria and distributed to peripheral tissue Acetone is more of a byproduct, usually produced in small amounts and exhaled B. Ketogenesis Ketogenesis Synthesized from acetyl-CoA produced by β oxidation Begins with condensation of two acetyl-CoA catalyzed by thiolase (reversal of last step in β oxidation) Bioenergetics V – Page 7 Copyrighted illustrations mostly from Lehninger unless otherwise indicated. All other materials ©2019 Hiroshi Nakai. This document may not be printed, posted, or shared without explicit permission.  HMG-CoA Synthase Condensation with a third acetyl-CoA HMG-CoA Lyase Removal of an acetyl-CoA unit to form acetoacetate Bioenergetics V – Page 8 Copyrighted illustrations mostly from Lehninger unless otherwise indicated. All other materials ©2019 Hiroshi Nakai. This document may not be printed, posted, or shared without explicit permission.  Formation of D-β-Hydroxybutyrate C. Use of ketone bodies as fuel 1. One step different from the biosynthesis pathway is the b-ketoacyl-CoA transferase. This step cannot be catalyzed in the liver such that ketone bodies cannot be used by liver as fuel. Bioenergetics V – Page 9 Copyrighted illustrations mostly from Lehninger unless otherwise indicated. All other materials ©2019 Hiroshi Nakai. This document may not be printed, posted, or shared without explicit permission.  Use of Ketone Bodies as Fuel Two of the reactions for converting ketone bodies to acetyl- CoA is simply the reverse of the synthesis reaction β-ketoacyl-CoA transferase is missing in the liver β-Ketoacyl-CoA Transferase Activation of acetoacetate by transfer of CoA from succinyl-CoA This reaction is not catalyzed in the liver III. Fatty Acid Synthesis Bioenergetics V – Page 10 Copyrighted illustrations mostly from Lehninger unless otherwise indicated. All other materials ©2019 Hiroshi Nakai. This document may not be printed, posted, or shared without explicit permission.  Fatty Acid Synthesis Site of synthesis: Cytoplasm Starting material for synthesis: Acetyl-CoA Source of Acetyl-CoA units: Mitochondria Problem: Acetyl-CoA cannot be transported across the mitochondrial inner membrane A. Site of synthesis: The cytoplasm B. Starting material: Acetyl-CoA; this is the step that is hormonally regulated. C. Export of acetyl-CoA units from the mitochondria Bioenergetics V – Page 11 Copyrighted illustrations mostly from Lehninger unless otherwise indicated. All other materials ©2019 Hiroshi Nakai. This document may not be printed, posted, or shared without explicit permission.  D. The committed first step of fatty acid synthesis: acetyl-CoA carboxylase. 1. Attached biotin, a prosthetic group that functions in carboxylation reactions. 2. Biotin carboxylase 3. Transcarboxylase 4. Note that the product of this reaction, malonyl-CoA inhibits CAT I. Acetyl-CoA Carboxylase Committed first step of fatty acid synthesis Major target of hormonal regulation in the liver E. Fatty Acid Synthase 1. 7 activities residing in one large peptide in vertebrates 2. Malonyl-CoA is used to add two carbon units at a time to the C-terminus of an acyl chain. The starting acyl chain is the acetyl group from Acetyl-CoA. a) A thioester linkage is formed between the acetyl group from acetyl-CoA and a cysteine residue on the protein. b) Malonyl-CoA will be attached to the Acyl Carrier Protein (ACP) domain. This domain is characterized by a bound prosthetic group 4’- phosphopantetheine covalently attached to a serine residue. The panthothenic acid and b-mercaptoethylamine moiety is identical to coenzyme A except that it is attached to the protein rather than to an adenylate nucleotide. c) Condensation of the activated acyl chain with the malonyl group results in decarboxylation and the extension of the fatty acid chain by two carbon units. d) The b-keto product is reduced by steps identical to b-oxidation in reverse except that NADPH is used as reducing agent. e) The newly extended acyl chain is translocated to the cysteine residue where the acetyl group was first attached. Another malonyl group is transferred to the ACP domain, and the cycle begins again. Bioenergetics V – Page 12 Copyrighted illustrations mostly from Lehninger unless otherwise indicated. All other materials ©2019 Hiroshi Nakai. This document may not be printed, posted, or shared without explicit permission.  Fatty Acid Synthase Bioenergetics V – Page 13 Copyrighted illustrations mostly from Lehninger unless otherwise indicated. All other materials ©2019 Hiroshi Nakai. This document may not be printed, posted, or shared without explicit permission.  Bioenergetics V – Page 14 Copyrighted illustrations mostly from Lehninger unless otherwise indicated. All other materials ©2019 Hiroshi Nakai. This document may not be printed, posted, or shared without explicit permission.  Bioenergetics V – Page 15 Copyrighted illustrations mostly from Lehninger unless otherwise indicated. All other materials ©2019 Hiroshi Nakai. This document may not be printed, posted, or shared without explicit permission.  Bioenergetics V – Page 16 Copyrighted illustrations mostly from Lehninger unless otherwise indicated. All other materials ©2019 Hiroshi Nakai. This document may not be printed, posted, or shared without explicit permission.