FATTY ACID OXIDATION

 

·        Occurs in mitochondria.

·        Biological fatty acids are mostly even number in C.  For unsaturated FAs, the double bonds are mostly cis.

·         Franz Knoop discovered in 1904: Losing a 2-C unit by oxidation (Fig. 19-9)

 

I.  OXIDATION OF EVEN CHAIN SATURATED FAs

 

A.   Activation and Entry into Mitochondria by Carnitine Shuttle

 

1.  Activation on mitochondrial outer membrane and endoplasmic reticulum by

     (Fatty) Acyl-CoA synthetases (or thiokinases)

·        Acetyl-CoA synthetase:       acetate, propionate, acrylate (C=C-COO-)

·        Medium chain acyl-CoA synthetase:       4-12 Cs

·       

Long-chain acyl-CoA synthetase:  12-22 Cs or more

 

 

The hydrolysis of PPi by inorganic pyrophosphatase provide the driving energy.

2.  Transfer to Carnitine

Acyl-CoA has a limited ability to cross mitochondrial inner membrane.

·        Carnitine palmitoyl transferase I


(on cytosolic face of mitochondrial inner membrane)

 

 

 

3.  Specific transfer of acyl carnitine into mitochondrial matrix. (see step 2 in Fig. 19-11)

4.  Converted back to acyl-CoA by

·        Carnitine palmitoyl transferase II

(on matrix face of mitochondrial inner membrane)

Acyl carnitine + CoASH → Acyl-CoA + Carnitine

5.  Transfer of carnitine back to cytosolic side.  (Step 4 in Fig. 19-11)


 

 

b-OXIDATION

All oxidation enzymes are in mitochondrial matrix.  (See Fig. 19-12)

1. Acyl-CoA dehydrogenase

·        Produces trans-Δ2-enoyl-CoA.   Note that naturally occurring unsaturated fatty acids are cis.

·        Has a bound FAD cofactor.

·        Jamaican vomiting sickness – eating unripe ackee fruit which contains an unusual amino acid hypoglycin A, which is a mechanism-based (or suicide) inhibitor against acyl-CoA dehydrogenase.

2. Enoyl-CoA hydratase

·       

Specifically produces 3-L-hydroxyacyl-CoA from trans-Δ2-enoyl-CoA.

 

 

·        Can also produce 3-D-hydroxyacyl-CoA from cis-Δ2-enoyl-CoA.

3. 3-L-Hydroxyacyl-CoA dehydrogenase (absolute stereospecificity for 3-L)

4. b-Ketoacyl-CoA thiolase

 

ENERGETIC CONSIDERATION

 

OXIDATION OF PALMITATE (16:0)

Palmitate + ATP + CoA → Palmitoyl-CoA + AMP + PPi (or 2 Pi)              - 1 ATP

Palmitoyl-CoA + 7 CoA + 7 FAD + 7 NAD+ + 7 H2O →

                                       8 Acetyl-CoA + 7 FADH2 + 7 NADH + 7 H+        

7 FADH2 →                                                                                       14 ATP

7 NADH →                                                                                        21 ATP

8 Acetyl-CoA → TCA →  8 ´ 12 =                                                       96 ATP (Each TCA cycle → 1 GTP + 3 NADH + 1 FADH2 = 12 ATP)

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                                                                                           Σ =          130 ATP

 

OXIDATION OF ODD-NUMBER FAs

 

(See Fig. 19-16; in some plants and marine organisms)

 

1.  R-CO-SCoA → → → Propionyl-CoA

2.  Propionyl-CoA carboxylase

CH3-CH2-CO-SCoA + ATP + *CO2 + H2O → (S)-Methylmalonyl-CoA + ADP + Pi

Text Box:

3.  Methylmalonyl-CoA racemase

     (S)-Methylmalonyl-CoA  ⇌  (R)-Methylmalonyl-CoA 

 

 

4.  Methylmalonyl-CoA mutase

     (R)-Methylmalonyl-CoA   ⇌  Succinyl-CoA  (HOO*C-CH2-CH2-CO-SCoA)

5.  TCA Cycle

 

OXIDATION OF UNSATURATED FAs

See Fig. 19-15.