Metabolism
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Muscle weakness and hypoketotic coma on fasting
Key points from this exercise:
Fatty acids (as fatty acyl CoA esters) undergo oxidation at the beta-carbon. The steps are:
dehydrogenation to form a carbon-carbon dounble bond between teh alpha and beta-carbons, lined to reduction of FAD
addition of water across te double bond to yield a hydroxyl group at the beta-carbon
oxidation of the hydroxyl group to an oxo group, linked to the reduction of NAD
cleavage by formation of a thiester to CoA at the new oxo-group, yilding acetyl CoA and a fatty acyl CoA that is two carbons shorter than the staryting compound.
Each cycle of beta-oxidation yields ~ 4 x ATP, but there is an initial cost of 2 x ATP to form palmitoyl CoA from palmitate
complete oxiadtion of palmitate to acetyl CoA yields 26 x ATP
complete oxiadtion of palmitate to carbon dioxide and water yields 106 x ATP
The intermediates of the beta-oxidation pathway are not detected in tissues, suggesting that the enzymes are closely associated in a multi-enzyme complex. However, traces of medium- and short-chain fatty acyl CoA are found when loing-chain fatty acyl CoA is being oxidised, suggesting that there are three separate sets of nzymes, with specificity for long-, medium- and short-chain fatty acyl CoA.
In the long-chain hydroxyacyl CoA dehydrogenase three of the enzymes of beta-oxidation are found in a single trifunctional protein. A large subunit catalyses hydroxylation of the unsaturated fatty acyl CoA and dehydrogenation of the hydroxy-derivative, and a small subunit catalyses the cleavage by CoASH. THis trifunctional protein and the fatty acyl CoA dehydrogenase are bound to the matrix face of the inner mitochondrial membrane.
Children who have a genetic defect of the long-chain trifunctional protein suffer from hypoketotic coma in fasting because they are unbable to oxidised the long-chain fatty acids released from adipose tissue to form acetyl CoA as a substrate for ketone body synthesis. They can metabolism medium- and short-chain fatty acids normally.