Fatty Acid Synthesis -28
Outline of Fatty Acid Synthesis
Stages in fatty acid synthesis
Unsaturated and longer fatty acids
Regulation of synthesis
Basics of Fatty Acid Synthesis
Key Precursor: Two-carbon molecule, acetyl CoA.
Challenges:
Linking separate two-carbon units.
Reducing carbon atoms in the chain (acetyl CoA has a carbonyl group).
Stages of Fatty Acid Synthesis
Transfer of Acetyl CoA:
Acetyl CoA is transferred from mitochondria to cytoplasm as citrate.
Activation of Acetyl CoA:
Acetyl CoA is converted into malonyl CoA in preparation for chain addition.
Elongation:
Repetitive addition and reduction of two-carbon units occur.
First Stage: Getting Acetyl CoA to the Cytoplasm
Acetyl CoA, produced in mitochondria, is transported as citrate.
Citrate Formation: Acetyl CoA condenses with oxaloacetate in the mitochondrial matrix to form citrate.
Citrate is cleaved in the cytoplasm by ATP-citrate lyase, releasing acetyl CoA.
Additional Requirement for Synthesis: Reducing Power
Requires NADPH in addition to two-carbon units and ATP.
NADPH sources include:
Oxaloacetate conversion to malate and decarboxylation.
Pentose phosphate pathway.
Second Stage: Activation of Acetyl CoA
Acetyl CoA must be carboxylated to form malonyl CoA:
Catalyzed by acetyl CoA carboxylase I (a biotin enzyme).
Formation of malonyl CoA is the committed step in fatty acid synthesis.
Third Stage: Elongation
Involves ACP (acyl carrier protein):
Acetyl CoA and malonyl CoA react with ACP to elongate the fatty acid chain.
Core Steps in Elongation:
Condensation:
Malonyl CoA condenses with acetyl CoA, extending the chain by two carbons; carbon dioxide is lost.
Reduction:
Convert C-3 keto group to methylene (-CH2-) using NADPH as reducing power.
Dehydration:
Reduction:
The chain continues to grow until a 16-carbon acyl ACP is formed, cleaved by thioesterase.
Energetic Accounting
Stoichiometry:
Required reactions for malonyl CoA synthesis, net stoichiometry for palmitate synthesis from acetyl CoA is tabulated yet crucial for understanding energy requirements.
Enzymatic Machinery
Organization of fatty acid synthesis varies:
In E. coli: Components encoded on separate genes.
In Animals: All components are part of a single polypeptide chain.
Synthase is a homodimer divided into:
Selecting and Condensing Compartment: Activation/Condensation.
Modification Compartment: Reduction/Dehydration.
Clinical Insights
β-Hydroxybutyric Acid:
An intermediate in fatty acid synthesis and degradation.
γ-Hydroxybutyric Acid:
An isomer with different effects; used as a drug (GHB), poses toxicity risks.
Long Fatty Acids
Fatty acid synthase primarily processes fatty acids of lengths up to 16 carbons.
For > 16 carbons:
Separate enzymes on the endoplasmic reticulum required.
Unsaturated Fatty Acids
Fatty acid synthase produces saturated fatty acids;
Double bonds added by ER enzymes.
Mammals cannot form double bonds beyond C-9, leading to essential fatty acids like linoleate.
Arachidonic Acid and Eicosanoids
Arachidonate (20-carbon fatty acid) is a precursor for eicosanoids, functionally important cellular signal molecules.
Regulation of Fatty Acid Synthesis
Responds to energetic conditions:
Acetyl CoA carboxylase 1 is the key regulatory enzyme.
Phosphorylation by AMP-dependent kinase inactivates the carboxylase.
Citrate activates carboxylase; palmitoyl CoA inhibits it, providing feedback based on fatty acid status.
Hormonal regulation also involved (glucagon, epinephrine decrease activity; insulin increases activity).
Ethanol and Fatty Acid Metabolism
Ethanol metabolism can lead to increased NADH, creating effects such as:
Reduced gluconeogenesis.
Inhibition of fatty acid oxidation, leading to increased fatty acid synthesis and further acidosis.
Key Concepts to Remember
Key precursor in fatty acid synthesis: acetyl CoA.
Fatty acid extension occurs in the cytoplasm.
Acetyl CoA activation for birth into fatty acid chains is crucial (acetyl CoA carboxylase responsible).
Fatty acid synthesis comprises three main stages.