Metabolism
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An unconscious child with keto-acidosis and a skin rash
Key points from this exercise:
Biotin provides the prosthetic group for carboxylases; it is covalently bound to the side-chain amino group of a lysine residue in the protein as biocytin (biotinyl-lysine), and acts as the carrier for carbon dioxide in carboxylation reactions.
There are four carboxylases involved in human metabolism: acetyl COA carboxylase, pyruvate carboxylase, propionyl CoA carboxylase and methylcrotonyl CoA carboxylase.
A single enzyme, holocarboxylase synthetase, catalyses the insertion of biotin into all four apo-carboxylases, and genetic defects of holocarboxylase synthetase lead to failure of all four carboxylases, with clinical signs of functional biotin deficiency and urinary excretion of a variety of abnormal organic acids.
Biotin is normally recovered from carboxylases when they are catabolised by hydrolysis of biocytin, catalysed by biotinidase.
Genetic defects of biotinidase lead to failure of all four carboxylases, with clinical signs of functional biotin deficiency and urinary excretion of a variety of abnormal organic acids.
Lack of pyruvate carboxylase activity leads to depletion of oxaloacetate and reduced citric acid cycle activity, and increased synthesis of ketone bodies, which cannot be metabolised because of the lack of oxaloacetate.
Lack of acetyl CoA carboxylase means that acetyl COA arising form glycolysis in the fed state cannot be utilised for fatty acid synthesis - it will again be used for ketone body synthesis, leading to ketosis even in the fed state.
Click here for more information on holocarboxylase synthetase deficiency.
Click here for more information on biotinidase deficiency