Lecture 19

• Fatty Acid Biosynthesis


  • Occurs by different pathways
  • Catalyzed by different sets of enzymes
  • Occur in different cellular compartments (in eukaryotes)

  
• Acetyl-CoA carboxylase


  Catalyzes the irreversible formation of malonyl-CoA from acetyl-CoA

  
• Fatty acid synthase


  Catalyzes assembly of long carbon chains of fatty acids in the cytosol through a repeating four-step sequence

  
• Fatty Acid Synthase I (FAS I)


  • Found in mammals
  • 7 active sites are in separate domains within single multifunctional polypetptide chain
  • Forms a single product

  
• The first group added is an acetyl-CoA, but subsequent rounds of addition need malonyl-CoA

  
• The acetyl-CoA is the group at the "methyl" end of the finished fatty acid (i.e., the additions occur what will be the carboxyl end of the fatty acid)

  
• Although the malonyl portion of malonyl-CoA has 3 carbons, one of these is lost as CO2, and therefore the chain grows 2 carbons at a time

  
• Although the chain is being reduced to the methylene carbons

  
• 4'-phosphopantetheine


  • A prosthetic group of ACP that serves as a flexible arm
  • In coenzyme A
  • Carrier reaction intermediates from and to active sites

  
• Thioesterase (TE)


  Hydrolyzes (using a H2O molecule) the thioester linkage between palmitate and ACP to release free palmitate

  
• Citrate synthase


  Catalyzes the formation of citrate from acetyl-CoA and oxaloacetate

  
• Citrate transporter


  Transports citrate through the inner mitochondrial membrane

  
• Citrate lyase


  Catalyzes the cleavage of citrate to generate acetyl-CoA and oxaloacetate (requires ATP)

  
• Fatty acid elongation systems


  Lengthen palmitate to form long saturated fatty acids

  
• Fatty acyl-CoA desaturase


  Catalyzes an oxidative reaction that introduces a double bond into a fatty acid chain

  
• Essential fatty acids


  Must be obtained from dietary plant material (e.g. linoleate and α-linolenate for mammals)

  
• Aspirin


  Irreversibly inactivates the cyclooxygenase activity of both COX isozymes

  
• NSAIDs


  Also inhibit both COX and isozymes
• Glycolipids


  • Cerebrosides and gangliosides
  • Sugar donor = UDP-sugar
  • Head-group sugar is attached directly to the C-1 hydroxyl of sphingosine in glycosidic linkage

  
• Synthesis of Cholesterol


  1. Synthesis of mevalonate from acetate

  2. Conversion of mevalonate to 2 activates isoprenes

  3. Condensation of 6 activated isoprene units to form squalene

  4. Conversion of squalene to the four-ringed steroid nucleus

  
• Acetyl-CoA acetyltransferase


  Catalyzes the condensation of two acetyl-CoA molecules

  
• HMG-CoA synthase


  Catalyzes the condensation of acetyl-CoA with acetoacetyl-CoA to form β-hydroxy-βmethylglutaryl-CoA (HMG-CoA)

  
• HMG-CoA reductase


  An integral membrane protein of the smooth ER that catalyzes the reduction of HMG-CoA to mevalonate
• Squalene monooxygenase


  Adds one oxygen atom from O2 to the end of the squalene chain to form squalene 2,3-epoxide

  
• Apolipoproteins


  Specific carrier proteins

  
• Plasma lipoproteins


  Macromolecular complexes of apolipoproteins and various combinations of phospholipids, cholesterol, cholesteryl esters, and triacylglycerols
• The Exogenous Pathway


  1. The pathway from dietary cholesterol to the liver

  2. Chylomicrons are synthesized from dietary fats in the ER of enterocytes and enter the bloodstream

  3. ApoC-II activates lipoprotein lipase in tissues to release FFAs

  4. Chylomicron remnants move through the bloodstream to the liver

  5. Receptors in the liver bind to the apoE in the remnants and mediate uptake of these remnants by endocytosis

  
• The Endogenous Pathway


  1. The pathway from liver to extrahepatic organ

  2. VLDL are synthesized containing TAG and Cholesterol Esters

  3. ApoC-II activates lipoprotein lipase in tissues to release FFAs

  4. LDL delivers cholesterol to extrahepatic organs (mostly in the form of cholesterol esters)

  5. LDL receptors are present in many different types of cells (it's how cells take up cholesterol in the LDL particle)

  
• Very-low-density lipoprotein (VLDL)


  • Lipoproteins that carry cholesteryl esters or triacylglycerols from the liver to muscle and adipose tissue
  • ApoC-II activates lipoprotein lipase to release FFAs from triacylglycerols on VLDL

  
• Low-density lipoprotein (LDL)


  • Formed by triacylglycerol loss in VLDL
  • Rich in cholesterol and cholesteryl esters
  • Carries cholesterol to extrahepatic tissues and macrophages

  
• LDL receptors


  Receptors in the hepatocyte plasma membrane that take up LDL not taken up by peripheral tissues and cells
• High-density lipoprotein (HDL)


  • Lipoproteins that originate in the liver and small intestine as small, protein-rich particles
  • Contain lecithin-cholesterol acyltransferase (LCAT) to catalyze the formation of cholesteryl esters
  • Mediates cholesterol scavenging and transport back to the liver ("reverse cholesterol transport")
  • Protects against heart disease

  
• HMG-CoA reductase is most active when dephosphorylated
• Familial hypercholesterolemia


  • Characterized by extremely high blood levels of cholesterol
  • Typically due to a defective LDL receptor
  • Cholesterol accumulates in foam cells and contributes to the formation of atherosclerotic plaques