IC18 Lipid and amino acid metabolism (AY2425)
Page 1: Introduction
Presenter: A/Prof Chew Eng Hui
Affiliation: Department of Pharmacy, Faculty of Science
Contact: phaceh@nus.edu.sg
Course Content: IC18: Lipid and amino acid metabolism
Page 2: Learning Outcomes
Overview of key topics:
Lipolysis and fatty acid oxidation (Part 1)
Ketogenesis (Part 1)
Oxidative degradation of amino acids (Part 2)
Chemical reactions in the urea cycle (Part 2)
Page 3: Fatty Acids as Energy Storage
Fatty acids are more efficient for long-term energy storage compared to carbohydrates:
Long alkyl chain, highly reduced (-CH2- groups), yielding more energy per gram.
Glycerol backbone can also be utilized as fuel, preventing wastage.
Water insoluble, forming oil droplets, maintaining osmotic balance in cells.
Generally inert, minimizing toxic reactions with other cellular components.
Page 4: Importance of Fats
Energy from triglycerides can contribute up to 80% of the energy needs for vital organs like heart and liver.
Despite concerns about body fat, fats are essential in diet.
Page 5: Lipoproteins
Terminology:
VLDL, LDL, HDL: Lipoproteins transporting cholesterol and triglycerides in the bloodstream.
Page 6: Lipolysis
Mechanism of fat mobilization when energy is needed:
Hormone-sensitive lipase controls breakdown of triglycerides in adipocytes.
Stimulatory hormones (epinephrine, norepinephrine, glucagon, ACTH) promote lipolysis.
Mechanism involves G-protein-coupled receptor activation, leading to increased cAMP and activation of protein kinases which lead to triglyceride hydrolysis.
Results in production of free fatty acids (FFAs) and glycerol.
Page 7: FFA Liberation and Transport
Free fatty acids from lipolysis:
Leave adipocytes, bound to serum albumin, enter target cells via specific transporters.
FFAs undergo β-oxidation, contributing to the citric acid cycle, while glycerol is soluble and enters circulation.
Page 8: Fates of Glycerol and FFAs
Glycerol (5% of triglyceride energy):
Phosphorylated to glycerol-3-phosphate, enters glycolysis.
Fatty Acids (95% of triglyceride energy):
Converted to acyl-CoA, undergo β-oxidation.
Page 9: FFA Activation
FFAs need to be activated to acyl-CoA for transport into the mitochondria:
Requires coexistence with ATP to form acyl-adenylate and subsequently acyl-CoA through a two-step reaction.
Page 10: Acyl-CoA Transport into Mitochondria
Acyl-CoA transport necessitates:
Carnitine and carnitine acyltransferase, which facilitate acyl group transfer and transport across the inner mitochondrial membrane.
Page 11: β-Oxidation Overview
β-oxidation consists of 4 enzyme-catalyzed reactions, taking place in the mitochondrial matrix.
Cleavage of fatty acids occurs two carbons at a time, producing acetyl-CoA.
Page 12: Continued β-Oxidation
The process repeats, shortening fatty acyl-CoA until completely degraded to acetyl-CoA.
Each round yields 1 acetyl-CoA, 2 electron pairs, and 4 protons.
Page 13: Overall Oxidation Process
The overall reaction for fatty acid oxidation involves combining equations from β-oxidation, the citric acid cycle, and oxidative phosphorylation.
Page 14: Example—Oxidation of Stearic Acid
Stearic acid (C18) yields more ATP than 3 molecules of glucose (C6), validating higher energy yield of fatty acids.
Page 15: Oxygen and Water Production
For every stearic acid oxidized, 26 O2 and 17 H2O molecules produced, highlighting metabolic water contributions.
Page 16: Discussion Question
Why do grizzly bears hibernate and camels store fats in their humps?
Page 17: Odd-Numbered Fatty Acids
β-oxidation of odd-numbered fatty acids produces propionyl-CoA, which is converted to succinyl-CoA for TCA cycle entry.
Page 18: Monounsaturated Fatty Acids
Naturally occurring fatty acids have cis double bonds which require isomerization before β-oxidation can proceed.
Page 19: Polyunsaturated Fatty Acids
Double bonds in wrong positions require additional enzymes (e.g., 2,4-dienoyl-CoA reductase) for proper metabolism, utilizing NADPH.
Page 20: Ketogenesis Overview
Ketogenesis occurs primarily in the liver and kidneys, producing ketone bodies during states of high lipid intake or low carbohydrate availability.
Page 21: Ketone Body Production
Acetyl-CoA, from β-oxidation, is diverted to form acetoacetate and D-β-hydroxybutyrate to assist in continued metabolism during limited carbohydrate availability.
Page 22: Toxicity of Ketone Bodies
High levels of ketone bodies can be toxic, disrupting cellular pH and harming membranes due to acetone's solvent properties.
Page 23: Utilization of Ketone Bodies
Extrahepatic tissues convert ketone bodies back to acetyl-CoA for entry into the TCA cycle.
Page 24: Introduction to Amino Acid Metabolism
Transition into discussion on amino acid metabolism and the urea cycle.
Page 25: Circumstances for Amino Acid Degradation
Amino acids are oxidatively degraded in three situations:
Excess amino acids not needed for protein synthesis.
High protein diets.
Starvation or uncontrolled diabetes where carbohydrates are scarce.
Page 26: Pathways of Amino Acid Metabolism
Interconnections between amino acid metabolism and other metabolite pathways, linking to carbohydrate and fatty acid metabolism.
Page 27: Overview of Amino Acids Catabolism
Loss of amino groups during catabolism leads to formation of α-keto acids, which can enter TCA cycle; nitrogen is excreted as urea.
Page 28: Transamination Process
Amino group removal from amino acids through transamination forms α-keto acids, using α-ketoglutarate as an acceptor and leading to glutamate recycling.
Page 29: Role of Glutamate
Glutamate serves as an amino donor for various pathways post-deamination and is crucial for nitrogen recycling.
Page 30: Transaminases and Cofactor
Transaminase enzymes have vitamin B6 (pyridoxal phosphate) as a common cofactor, crucial for amino acid transamination reactions.
Page 31: Transamination Reaction Dynamics
Illustration of transamination reactions, typically involving α-ketoglutarate as the amino group acceptor.
Page 32: Oxidative Deamination in the Liver
Glutamate undergoes oxidative deamination in liver mitochondria, generating α-ketoglutarate and ammonium ions.
Page 33: L-Glutamate Dehydrogenase Regulation
Regulation of glutamate dehydrogenase is essential for managing amino acid conversion to energy, sensitive to cellular energy charge.
Page 34: Ammonia Transport in the Body
Muscle tissue converts glutamate’s amino group into alanine, which travels to the liver and contributes to glucose synthesis via the glucose-alanine cycle.
Page 35: Toxicity of Ammonia
Ammonia from amino acid breakdown is toxic and excess promotes osmotic effects and raises intracellular pH, necessitating effective disposal via the urea cycle.
Page 36: Urea Cycle Overview
The urea cycle converts ammonia into water-soluble urea, which is less toxic, utilizing ATP and primarily occurring in the liver.
Page 37: Urea Cycle Steps - Step 1
First step in the urea cycle: carbamoyl phosphate formation in the mitochondrial matrix, requiring ammonia and bicarbonate.
Page 38: Urea Cycle Steps - Step 2
Reaction of carbamoyl phosphate with ornithine to produce citrulline, catalyzed by ornithine transcarbamoylase.
Page 39: Urea Cycle Steps - Step 3
Citrulline moves to the cytosol, reacting with aspartate to generate argininosuccinate, introducing the second nitrogen for urea.
Page 40: Urea Cycle Steps - Steps 4 and 5
Argininosuccinate splits into fumarate and arginine; urea is released in the final step when arginine hydrolyzes back to ornithine.
Page 41: Fate of Fumarate
Fumarate continues into the TCA cycle, with multiple potential outcomes including glucose production and energy generation.
Page 42: Urea Cycle Regulation
Arginine activates the urea cycle through the formation of N-acetylglutamate, which stimulates carbamoyl phosphate synthetase I.
Page 43: Categorization of Amino Acids
Amino acids classified as ketogenic (yielding ketone bodies) or glucogenic (converting to glucose), influencing their metabolic fates.
Page 44: Summary of Amino Acids Metabolism
Overview of metabolic pathways involving amino acids, highlighting their catabolic and anabolic roles, and connections to the citric acid cycle.
Page 45: Essential vs Non-Essential Amino Acids
Essential amino acids: required in diet. Non-essential: synthesized by the body; this distinction is critical in nutrition.
Page 46: References
Reference: Principles of Biochemistry by Voet, Voet, and Pratt, 4th edition.