Fatty Acid Oxidation

Question 1

Clinical Aspects

Answer 1

• Ketoacidosis
• Hypoglycemia
  
  • carnitine deficiency
  • Mitochondiral FA oxidation deficiency
• Accumulation of VLCFA & branched FA in peroxisomal FA oxidation deficiency

Question 2

Overview of FA Oxidation and Ketone Metabolism

Answer 2

Question 3

Different FA Chain lengths

Answer 3

• Very Long Chain: >20
• Long Chain: 12-20
• Medium Chain: 6-12
• Short Chain: <6

Question 4

Activation of FA to FA-CoA

Answer 4

• FA Carboxylic acid attacks alpha phosphate of ATP
  
  • Fatty acyl CoA synthetase
  • Pyrophosphate hydrolyzed off
• Sulfur of CoASH attachs the new mixed anhydride
  
  • Fatty acyl CoA synthease
  • AMP removed
• Fatty Acyl CoA created
• Irreversible reaction
• Location:
  
  • LCFA:i. ER, outer mitochondrial membranes, peroxisomal membranes
  • VLCFA: peroxisomes
  • MCFA: a. mitochondrial matrix of liver and kidney cells

Question 5

Fates of FA-CoA

Answer 5

1. Energy: beta oxidation or ketogenesis
2. Membrane lipids: phospholipids or sphingolipids
3. Storage: triacylglycerols

Question 6

Carnitine

Answer 6

• Transport of LCFA into mitochondria requires carnitine carrier
• Zwitterionic alcohol

Question 7

Transport into Mitochondrial Matrix

5 steps

Answer 7

• FACoA crosses outer mito membrane
• FACoA+Carnitine—>CoA+FA-carnitie
  
  • Carnitine palmitoyl-transferase I (CPT I)
• FA-carnitine transported thru inner mitchondiral membrane
  
  • carnitine acylcarnitine translocase: brings FA-carnitine in and carnitine out
• FA-carnitine+CoA—>FACoA+carnitine
  
  • CPT II
• FA-CoA undergoes beta oxidation
• Carnitine shuttled to inter membrane space

Question 8

Beta Oxidation of saturated LCFA

Palmitoyl CoA—>Acetyl CoA

Answer 8

1. FA-CoA—>trans Δ2 fatty enol CoA

• acyl CoA dehydrogenase
• FAD—>FADH2+1.5ATP

2. trans Δ2 fatty enol CoA—>Lβ hydroxy acyl CoA
   * enoyl CoA hydratase (uses H2O)
3. Lβ hydroxy acyl CoA—>β-keto acyl CoA

• NAD+ —>NADH+2.5ATP
• β hydroxy acyl CoA dehydrogenase

4. β-keto acyl CoA—>acetyl CoA+FACoA(n-2 of original)
   * β-keto thiolase

Question 9

Beta Oxidation of Unsaturated FA

2 additional enzymes required

Answer 9

• Normal β oxidation until cis DB encountered
  
  • B/t 3&4: not recognized by hydratase
• enoyl CoA isomerase switches it to trans
• More β oxidation until 5-4 cis DB conjugated w/ 3-2 cis DB encountered: not recognized by hydratase
• 2,4 dienyl reductase reduces conjugate DB to single cis DB
  
  • NADPH—>NADP+ H+
• Resulting 4-3 cis DB must be isomerized to 3-2 DB by enoyl CoA isomerase
• Normal β oxidation to acetyl CoA

Question 10

Energy yeild for Unsaturated FA

Answer 10

• Less b/c FADH2 is produced
• NADPH epended costing 2.5 ATP

Question 11

Odd Chain Length FA

4 steps

Answer 11

1. Normal β oxidation until propionyl CoA formed (3C)
2. Propionyl CoA+HCO3- –>D-methylmalonyl CoA
   
   • Propinoyl CoA carboylase
   • carboxylation of α carbon
   • ATP required
   • Biotin required
3. D-methylmalonyl CoA–>L-methylmalonyl CoA
   
   • methylmalonyl CoA epimerase
   • Changes steriochemistry
4. L-methylmalonyl CoA–>Succinyl CoA
   
   • methylmalonyl CoA mutase
   • B12 coenzyme
   • goes to TCA cycle, gluconeogenesis, or further oxidation

Question 12

Regulation of β Oxidation

Answer 12

• Location:
  
  • FA oxidation occurs in the mitochondrial matrix
  • FA synthesis occurs in the cytoplasm
• Levels of ATP and NADH: inhibits β Oxidation
• Restricted by mitochondrial supply of CoASH
• CPT I is inhibited by malonyl CoA
  
  • High AMP: AMP-PK inhibits malonyl CoA formation from acetyl CoA carboxylase → CPT I stays active
• Strictly aerobic
• Increase in ADP: increases NAD+/NADH ratio
  
  • increases rates of all reactions using NAD
• Increase in AMP:
  
  • increases fatty acid transport into the mitochondrial matrix
  • iv. activates glucose transport into cell