NSC 408: Lipogenesis (Fatty Acid Synthesis) Notes
Lipogenesis (Fatty Acid Synthesis)
Introduction to Lipogenesis
Definition: Lipogenesis refers to the process of synthesizing fatty acids, primarily for energy storage in the form of triglycerides.
Course Context: This topic is covered in NSC 408.
Reference: Flexbook Read 6.33.
Primary Product: The main product of de novo fatty acid synthesis in humans is palmitate, which is a saturated fatty acid with carbons.
Synthesis Process: The synthesis of palmitate involves a series of reactions that are repeated times. Each repetition extends the fatty acid chain length by carbons.
Cellular Location: The initial steps of fatty acid synthesis occur in the cytosol (matrix). Key components and organelles mentioned in relation to this location include the outer membrane, inner membrane, intermembrane space, cristae, ribosome, granules, ATP synthase particles, and DNA, indicating the broader cellular context.
The First Committed Step: Malonyl CoA Formation
Reaction: The crucial first step in fatty acid synthesis is the conversion of Acetyl CoA into Malonyl CoA.
Enzyme: This reaction is catalyzed by Acetyl CoA Carboxylase (ACC).
Co-enzyme: Biotin serves as a co-enzyme for Acetyl CoA Carboxylase, typically involved in the transfer of carboxyl groups.
Source of Acetyl CoA for Lipogenesis:
Glycolysis: Products of glycolysis, particularly pyruvate, can be converted to Acetyl CoA.
Ketogenic Amino Acids: Certain amino acids, categorized as ketogenic, can be catabolized to produce Acetyl CoA.
Regulation of Acetyl CoA Carboxylase (ACC)
Acetyl CoA Carboxylase is a key regulatory enzyme in fatty acid synthesis, controlling the rate of the overall pathway.
Covalent Modification:
Insulin: High levels of insulin, typically observed after a meal, activate ACC, promoting fatty acid synthesis and storage.
Glucagon: High levels of glucagon, typically observed during fasting, inactivate ACC, inhibiting fatty acid synthesis.
Allosteric Regulation:
Citrate: Acts as an allosteric activator of ACC. High citrate levels signal an abundance of energy substrates (derived from carbohydrates and amino acids) that can be diverted for fat synthesis (citrate moves from mitochondria to cytosol).
Palmitoyl CoA: Acts as an allosteric inactivator of ACC. Palmitoyl CoA, a product of fatty acid synthesis, exerts feedback inhibition when its concentration is high, signaling that sufficient fatty acids have been produced.
Steps of Fatty Acid Synthesis by Fatty Acid Synthase (FAS)
Fatty Acid Synthase (FAS): This is a multi-enzyme complex responsible for catalyzing a series of reactions that convert Acetyl CoA and Malonyl CoA into long-chain fatty acids.
Key Enzymatic Reactions within the FAS Complex: The process involves a repetitive cycle of steps:
Reduction: Involves the use of reducing equivalents (usually NADPH) to reduce a carbonyl group.
Dehydration: Removal of water to form a double bond.
Reduction: Further reduction of the double bond to a saturated bond, again using reducing equivalents.
Biosynthesis of Palmitic Acid ()
Overall Process: The synthesis of palmitic acid, a -carbon saturated fatty acid (denoted as ), involves specific contributions from its precursors.
Carbon Origin:
Carbons & : These two carbons at the methyl end of palmitic acid (the primer unit) are derived directly from Acetyl CoA.
Carbons : The remaining carbons are derived from Malonyl CoA molecules. Each Malonyl CoA contributes two carbons per cycle, but the initial carboxylation of Acetyl CoA to Malonyl CoA means all carbons ultimately originate from Acetyl CoA.
Limitations and Essential Fatty Acids
Dietary Requirement: The body has limitations in synthesizing all types of fatty acids required for physiological functions.
Essential Fatty Acids: We need to consume essential fatty acids from our diet because the human body lacks the enzymes necessary to introduce double bonds at certain positions (e.g., beyond carbon and from the carboxyl end) in the fatty acid chain. These essential fatty acids are crucial for various biological processes and cannot be synthesized de novo.
Metabolic Connections: Lipogenesis and the TCA Cycle
Glucose as a Precursor:
Glucose is metabolized through glycolysis to produce Pyruvate.
Pyruvate is then converted into Acetyl-CoA (e.g., through pyruvate dehydrogenase complex).
Acetyl-CoA is the direct precursor for Malonyl-CoA (the first committed step of lipogenesis) and also serves as the entry point into the TCA Cycle (Krebs Cycle).
Role of Citrate:
Acetyl-CoA condenses with Oxaloacetate to form Citrate in the TCA cycle within the mitochondria.
When energy is abundant, citrate can be transported from the mitochondria to the cytosol.
In the cytosol, Citrate acts as a crucial allosteric activator of Acetyl CoA Carboxylase, thereby linking high energy status to increased fatty acid synthesis.
Amino Acid Interconnections: Various amino acids feed into glycolysis and the TCA cycle intermediates, influencing the availability of Acetyl-CoA for lipogenesis.
Glucogenic Amino Acids: Alanine, Glycine, Threonine, Cysteine, Serine, Tryptophan, Aspartate, Asparagine, Methionine, Valine, Histidine, Glutamine, Arginine, Proline. These can be converted into glucose or TCA cycle intermediates like pyruvate, oxaloacetate, ketoglutarate, succinyl-CoA, or fumarate, thereby contributing to glucose synthesis or energy production.
Ketogenic Amino Acids: Lysine, Leucine. These are degraded completely to Acetyl-CoA or acetoacetate, thus contributing directly to ketone body formation or fatty acid synthesis.
Both Glucogenic and Ketogenic Amino Acids: Tryptophan, Tyrosine, Phenylalanine, Isoleucine, Threonine. These amino acids can yield both glucose precursors and acetyl-CoA or acetoacetate through different catabolic pathways.
Overall Significance: The intricate connections demonstrate how excess intake of carbohydrates or proteins (amino acids) can lead to an abundance of Acetyl-CoA, which the cell can then efficiently convert into fatty acids for long-term energy storage during periods of caloric surplus.