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Ch.21 Lipid Biosynthesis, :star: Fatty Acid Synthesis, :star: Synthesis…

- - - - produces reducing power (NADH, FADH2)
      - takes place in the mitochondria
      - produces acetyl-CoA
    - - requires acetyl-CoA and malonyl-CoA
      - requires reducing power from NADPH
      - takes place in cytosol in animals, chloroplast in plants
    - - Mitochondria
        
        • NO fatty acid oxidation
        
        • Fatty acid oxidation
        
        • Acetyl-coA production
        
        • Ketone body synthesis
        
        • Fatty acid elongation
      - Endoplasmic reticulum
        
        • Phospholipid synthesis
        
        • Sterol synthesis (late stages)
        
        • Fatty acid elongation
        
        • Fatty acid desaturation
      - Cytosol
        
        • NADPH production
        (pentose phosphate pathway; malic enzyme)
        
        • [NADPH] / [NADP+] high
        
        • Isoprenoid and sterol synthesis (early stages)
        
        • Fatty acid synthesis
  - - - • Fatty acids are built in several passes, processing one acetate unit at a time.
      - • The acetate is coming from activated malonate in the form of malonyl-CoA.
      - • Each pass involves reduction of a carbonyl carbon to a methylene carbon.
      - :star: MalonyI-CoA Is Formed from Acetyl-CoA and Bicarbonate
        
        Reaction carboxylates acetyl-CoA
        
        Catalyzed by acetyl-CoA carboxylase
        
        The enzyme has three subunits:
        
        • One unit has biotin covalently linked to Lys.
        
        • Biotin carries C02.
        
        • In animals, all three subunits are on one polypeptide chain.
        
        HC03- (bicarbonate) is the soluble source of C02.
    - - Sources of NADPH:
        
        in adipocytes: pentose phosphate pathway and malic enzyme
        —NADPH made as malate converts to pyruvate + C02
        
        in hepatocytes and mammary gland: pentose phosphate pathway
        — NADPH made as glucose-6-phosphate converts to ribulose 6- phosphate.
        
        in plants: photosynthesis
- - - - Least dense of lipoproteins (contains most TAG)
      - Have apoB-48, apoE, and apoC-ll
    - - Contains TAG and cholesteryl esters in high concentrations
      - Contain apoB-100, apoC-l, apoC-ll, apoC-lll, and apoE
    - - LDL is enriched in cholesterol/chloesteryl esters.
      - ApoB-IOO is the major apolipoprotein.
      - Produced by removal of TAG from VLDL
    - - Produced from enzymatic conversion of LDL and VLDL cholesterol to cholesteryl esters
      - HDLs are high in protein, including apoA-l.
  - - - ApoC-II activates lipoprotein lipase to allow free fatty acid release for fuel in adipose tissue, heart, and skeletal muscle.
      - When fats are depleted, remnants go to the liver for absorption via apoE- mediated endocytosis.
    - - Again, apoC-ll activates lipoprotein lipase to release free fatty acids.
      - Adipocytes take up the FFAs, reconvert them to TAGS, and store them in lipid droplets.
      - Muscle uses the TAG for energy.
    - - Muscle and adipose tissue have LDL receptors and recognize apoB-100.
      - Myocytes and adipocytes take up cholesterol via receptor-mediated endocytosis.
    - - HDL picks up cholesterol from the cells and returns to liver, where it can be metabolized (e.g., bile salts).
      - Also catalyzes conversion of remnant cholesterol of LDL and VLDL to cholesteryl esters
- - - - COX-I catalyzes synthesis of prostaglandins that regulate gastric mucin secretion.
      - COX-2 catalyzes synthesis of prostaglandins that mediate pain, inflammation, and fever.
        — NSAlDs (aspirin, ibuprofen, acetaminophen) inhibit COX-2.
        
        NSAlDs Inhibit Cyclooxygenase (COX) Activity
        
        • Aspirin (acetylsalicylate) is an irreversible inhibitor.
        
        — blocks active site in both COX isozymes
        
        — acetylates a Ser in active site
        
        • Ibuprofen and naproxen are competitive inhibitors.
        
        — resemble substrate; also block active site in both Isozymes
- - - - Note that malonyl- COA and acetyl-CoA have already been attached to complex via thioester linkages to enzyme and have shed their COA attachments.
- - - - • one of many ways to ensure that fat synthesis and xidation don't occur simultaneously
- - - - • Citrate is made from acetyl-CoA in mitochondria (acetyl-CoAmt).
      - • Citrate signals excess energy to be converted to fat.