Branched Chain Amino Acid Metabolism
1) All of the steps of these complex pathways are ones you have seen before. These pathways borrow
heavily from the Krebs cycle and fatty acid oxidation.
2) The first three steps of BCAA catabolism are chemically the same. They are a transamination, an keto acid dehydrogenase (oxidative decarboxylation, like pyruvate dehydrogenase) and a
dehydrogenation, like that in the Krebs cycle, or FA oxidation. In fact, the first two enzymes of the
pathway are the same for all three of the BCAA’s.
3) Valine is glucogenic, leucine is ketogenic, and isoleucine is both.
First three steps:
Leucine catabolism continues via a standard carboxylation reaction (biotin cofactor), followed by
hydration to give HMGCoA. You should remember how this can be converted into 3 AcCoA molecules
(think ketone body metabolism).
Valine catabolism continues with a hydration of the double bond (like beta oxidation) followed by
hydrolysis of the CoA ester (to drive the pathway forward) then two successive oxidations, the last one
of which is driven to completion by decarboxylation. This yields propionyl CoA, which is converted to
succinyl CoA as we have discussed (carboxylation followed by B-12-dependent mutase reaction).
Isoleucine catabolism requires that we convert the five carbon thioester into AcCoA and propionyl CoA.
This is accomplished by a sequence that is the exact analogue of beta oxidation. Oxidation of the
alcohol to a ketone give a beta-keto ester that is the same intermediate obtained by degradation of odd
chain fatty acids. Thiolase completes the sequence by cleaving this into the two required CoA esters.
Since AcCoA is ketogenic and propionyl CoA is glucogenic (because it is converted into succinyl CoA),
isoleucine is both ketogenic and glucogenic.