Biosynthesis of Fatty Acids

Question 1

Differences between saturated and unsaturated fatty acids

Answer 1

• Saturated fatty acids contain no double bonds
• Unsaturated fatty acids contain one or more double bonds
  
  • Almost all double bonds in fatty acids are in cis configuration
  • One double bond = monounsaturated
  • More than one double bond = polyunsaturated
• Cis double bonds cause fatty acid to bend at that position
  
  • Decreases melting temperature of fatty acid
  • Long-chain fatty acids (LCFA) usually components of cell membranes
    
    • Double bonds increase membrane fluidity

Question 2

Fatty acid synthesis favored when energy sources are in excess - how and why?

Answer 2

• Eat a lot of carbs –> Insulin release –> ↑ fatty acid synthesis indirectly by promoting glucose utilization –> ↑ pyruvate flux
  
  • Results in formation of lots of acetyl CoA –> ↑ fatty acid biosynthesis.
• High levels of ATP inhibit isocitrate dehydrogenase –> blocks TCA cycle, causes accumulation of citrate to enhance fatty acid synthesis
• Long term consumption of excess calories –> ↑ in Acetyl CoA carboxylase synthesis
  
  • and vice versa
• High fat/low carb diet shuts down this pathway (pyruvate not formed)

Question 3

3 phases of fatty acid synthesis

Answer 3

1. Production of cytosolic Acetyl CoA
   
   • Acetyl portion of Acetyl CoA condenses with OAA, produces citrate. Citrate is then transported into the cytosol, then lysed and turned back into Acetyl-CoA
   • Mitochondrial acetyl CoA produced by oxidation of pyruvate and by catabolism of fatty acids, ketone bodies, and certain amino acids
2. Conversion of Acetyl CoA to Malonyl CoA by Acetyl CoA Carboxylase.
   
   • Rate limiting step, commitment step, and major regulatory step
3. Conversion of Malonyl CoA into palmitate by fatty acid synthase.
   
   • This is a 4 step process that repeats and adds 2 carbons each time
   • Acetyl CoA is used for the first cycle; Malonyl CoA is used for subsequent cycles
   • Ultimately forms palmitate

Question 4

Substrates for fatty acid synthesis

Answer 4

• Mainly Acetyl CoA in mitochondria
• More detailed: Substrate (acted on by enzyme in parentheses) → Product
  
  • Pyruvate (PDH) → Acetyl CoA (citrate synthase) → Citrate → Leaves mitochondria (ATP citrate lyase) → Cytosolic Acetyl CoA (Acetyl CoA Carboxylase) → Malonyl CoA (fatty acid synthase) → Palmitate → enters ER → can elongate or become desaturated → Tryglycerides and lipids

Question 5

Four regulators of fatty acid synthesis

Answer 5

1. Citrate
2. Palmitoyl CoA
3. Malonyl CoA
4. Insulin and glucagon

Question 6

MOA of citrate

Answer 6

• Citrate split into Acetyl CoA and OAA in cytosol
  
  • Acetyl CoA used for fatty acid synthesis
  • OAA converted to malate, then pyruvate –> produces NADPH to be used in fatty acid synthesis pathway
• Citrate also activates Acetyl CoA carboxylase
  
  • Causes polymerization of enzyme (conformational change) and increasing VMax

Question 7

MOA of palmitoyl CoA

Answer 7

• Acts as inhibitor of acetyl CoA carboxylase
• Cytosolic levels elevated during starvation or on high fat diets

Question 8

MOA of Malonyl CoA

Answer 8

• Product of acetyl CoA carboxylase
• Made under conditions favorable for fatty acid synthesis
• Potent inhibitor of carnitine acyltransferase I
  
  • Key regulatory step of fatty acid degradation

Question 9

MOA of insulin and glucagon (as regulators of fatty acid synthesis)

Answer 9

• Insulin promotes fatty acid synthesis indirectly by promoting glucose utilization (↑ pyruvate flux)
• Insulin can activate protein phosphatase –> dephosphorylates (activates) Acetyl CoA carboxylase
• Glucagon increases intracellular cAMP –> phosphorylation and inactivation of Acetyl CoA carboxylase
• Epinephrine has same effects as glucagon

**Regulation of Acetyl CoA carboxylase is key to regulation of fatty acid synthesis

Question 10

How does chronic alcoholism cause hyperlipidemia?

Answer 10

• Ethanol metabolized to acetate, mainly in liver
  
  • This reaction produces lots of NADH
• ↑ NADH/NAD+ slows citric acid cycle and fatty acid oxidation, promotes formation of glycerol-3-P from DHAP
• Glycerol-3-P + fatty acids –> triacylglycerols
• TAGs synthesized in liver normally packaged with cholesteryl esters, cholesterol, phospholipid, apolipoprotein B100 –> form VLDL for delivery to body
• At first, excess alcohol causes liver to secrete abnormally high levels of VLDLs
• Chronic liver dysfxn impairs protein synthesis including Apo-B100 —> liver becomes unable to produce/secrete VLDL, increasing hepatic fat buildup