Lecture 37

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Stony Brook University**We aren't endorsed by this school

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BIO 361

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Biology

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Dec 17, 2024

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Lecture 37: Fatty Acid Metabolism 3Overview of Fatty Acid Biosynthesis●Occurs in thecytoplasm, primarily in the liver (also adipose tissue).○Beta-oxidationoccurs in themitochondrial matrixduring low-energy states.○Fatty acid biosynthesisoccurs during high-energy states.●Convertsacetyl-CoAintopalmitate(16-carbon fatty acid).●Key precursors:○Acetyl-CoA(from citrate transported from the mitochondria).○NADPH(generated from the citrate to oxaloacetate to pyruvate conversion).Tricarboxylate Transport System●Acetyl-CoA, the precursor for fatty acid biosynthesis, cannot cross the mitochondrialmembrane.●Transport Mechanism:○Acetyl-CoA is converted tocitratein the mitochondrial matrix.○Citrate is transported to the cytosol via a specific transporter.○In the cytosol,ATP-citrate lyaseconverts citrate back intoacetyl-CoA.●Additional Outcomes:○Generates a cytosolic pool of acetyl-CoA for biosynthesis.○ProducesNADPH, essential for fatty acid synthesis.Key Enzymes in Fatty Acid Biosynthesis1.Acetyl-CoA Carboxylase (ACC):○Convertsacetyl-CoAtomalonyl-CoA.○Found in the cytoplasm; large enzyme with multiple domains.○Requiresbiotinas a cofactor to attach CO2 to acetyl-CoA.○Activated by cytosolic citrate, indicative of a high-energy state.■Promotes polymerization of ACC, increasing activity.2.Fatty Acid Synthase (FAS/FASN):○Convertsmalonyl-CoAtopalmitate.○Multifunctional, dimeric enzyme with multiple domains.○Contains anacyl-carrier protein (ACP)cofactor:■Ensures intermediates remain attached to the enzyme.■Transports the growing fatty acid chain through each domain.

Biosynthesis of Malonyl-CoA●Committed stepin fatty acid biosynthesis.●Converts acetyl-CoA intomalonyl-CoAvia ACC:○CO2 from bicarbonate is attached to acetyl-CoA.○Requires ATP.●Regulation:○Malonyl-CoA inhibits β-oxidationby directly inhibiting CPT1, preventing fattyacids from entering mitochondria for oxidation.Fatty Acid Synthase (FAS) Mechanism●Reactions:○MAT (Malonyl/Acetyl CoA-ACP Transferase): Transfersacetyl-CoA/malonyl-CoA to ACP.○KS (Keto Synthase): Condenses malonyl-ACP and acetyl-ACP, releasing CO2.○KR (Keto Reductase): Reduces β-keto group to a hydroxyl group using NADPH.○DH (Hydroxylacyl Dehydratase): Removes water to form a trans double bond.○ER (Enoyl Reductase): Reduces the double bond to form a saturated fatty acid.○TE (Thioesterase): Releasespalmitatefrom ACP.●Cycle Overview:○Begins with acetyl-CoA and malonyl-CoA.○Adds 2 carbons per cycle to the growing fatty acid chain.○Repeats untilpalmitate (16:0)is formed.○Balanced Equation:8Acetyl-CoA+14NADPH+7ATP→Palmitate+14NADP++8CoA+7ADP+7Pi+6H2OFatty Acid Elongation and Desaturation●Fatty acids can be elongated beyond 16 carbons (e.g., 18, 20 carbons).●Desaturases introduce double bonds but are limited toΔ9in mammals.○Fatty acids likelinoleic acidareessentialbecause they have double bondsbeyond Δ9 and must be obtained from the diet.Lipid Biosynthesis in the Liver●Glucose provides the primary precursor for fatty acid biosynthesis:○Glucose → Pyruvate → Acetyl-CoA → Citrate → Cytosolic acetyl-CoA.

●Liver incorporates triglycerides and cholesterol intoVLDL:○VLDL transports triglycerides and cholesterol esters to other tissues.○Analogous to chylomicrons.Regulation of Fatty Acid Biosynthesis●Reciprocal Regulation of Biosynthesis and Oxidation:○Insulinpromotes biosynthesis (high-energy state).○Glucagonpromotes β-oxidation (low-energy state).●AMP-Activated Protein Kinase (AMPK):○Signals low energy states (high AMP, low ATP).○Inactivates ACCvia phosphorylation, reducing fatty acid biosynthesis.Acetyl-CoA Carboxylase and Cancer●ACC expression is elevated in cancer cells:○Fatty acids promote cancer cell proliferation.○ACC knockout results in smaller tumor growth.●FAS Overexpression:○Promotes tumor growth in cancers like prostate cancer.○Inhibition of FAS reduces tumor growth.Key Enzymes and FunctionsEnzymeFunctionAcetyl-CoA Carboxylase (ACC)Converts acetyl-CoA to malonyl-CoA (committed step).Fatty Acid Synthase (FAS)Multifunctional enzyme synthesizing palmitate.Palmitoyl ThioesteraseReleases palmitate from FAS.Fatty Acyl-CoA DesaturaseIntroduces double bonds in fatty acids.

Summary of Reciprocal RegulationProcessFed StateFasting StateLipogenesisActivated by insulinInhibited by glucagon/epinephrineβ-OxidationInhibited bymalonyl-CoAActivated due to low malonyl-CoA