3. Fatty acid metabolism

Beta-Oxidation

How energy is extracted from Fatty Acids

The process of fatty acid degradation is known as β-oxidation, which occurs in the Mitochondrial matrix.

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Transport Review

  1. Fatty Acids are stored in lipocytes and mobilized by lipase enzymes
  2. Fatty Acids are transported from lipid droplets to the blood stream via bound proteins
  3. Once in the bloodstream, Fatty Acids are bound to serum albumin and transported to the tissues
  4. In the tissues, Fatty Acids are grabbed by transport proteins and delivered to mitochondria where they are metabolized

Acyl-Cranitine Shuttle (ACS)

Fatty Acids (such as palmitate) cannot be transported freely across the cell membrane because of their negative charge. In order to traverse the OM and IM membranes, they are modified by Acyl-cranitine shuttle .

This occurs in the following steps. First, the Acyl-COA synthetase, found in the outer membrane, attaches CoA-SH to the palmitate (or whatever FA) forming a fatty acyl-CoA. For example, palmitoyl-CoA. Cost: 2 ATP, but note this is because 1 ATP->AMP, meaning it takes two phosphate groups.

Next, acyl-CoA (e.g., palmitoyl-CoA) reacts with carnitine to form a fatty acyl-carnitine (e.g., palmitoylcarnitine), catalyzed by carnitine acyl transferase (CCAT), a.k.a., catnitine palmitoyl transferase (CPT1),  which is also located in the outer membrane.

CPT1 acts as a gatekeeper for all FA entering the IMS.

The acyl-carnitine (palmitoylcarnitine) is then transported the IMS via the transporter porin. Porin enters the IM via the IM membrane translocase.

Once in the matrix, the palmitoylcarnitine needs to be transferred back to a molecule of CoA, a reaction catalyzed by an enzyme CPT2 (attached to the IM membrane). Carnitine is then released and palmitoyl-CoA is formed. The FA is ready for breakdown.

Regulation of ACS

CPT1 is allosterically regulated by malonyl-CoA, a building block of FA synthesisHere, it inhibits FA oxidation (breakdown) proving that FA synthesis and β-oxidation are reciprocally regulated by malonyl-CoA.

AMPK, on the other hand, inhibits FA synthesis and promotes β-oxidation.

Recall that AMPK phosphorylates and inhibits ACC when energy supplies are low

=> less malonyl-CoA is formed

=> FA synthesis slows down

=> CPT1 is no longer inhibited increasing β-oxidation.

This is another example of reciprocal regulation helping the cell respond to a low energy crisis.

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