Metabolism
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An unconscious child with hyperammonaemia and keto-acidosis
Key points from this exercise:
Propionyl CoA is normally metabolised by carboxylation to methylmalonyl CoA, followed by isomerisation to succinyl CoA, which is a citric acid cycle intermediate.
Genetic defects of propionyl CoA carboxylase lead to accumulation of propionyl CoA. In order to conserve CoA, which is formed from the vitamin pantothenic acid, propionyl CoA may be hydrolysed to yield free propionic acid. Alternatively, the propionyl moiety may be transferred onto carnitine; the resultant propionyl carnitine is then excreted in the urine.
The excretion of propionyl carnitine outstrips the body's capacity for carnitine synthesis, leading to carnitine depletion.
The major role of carnitine in the body is in the transport of fatty acids across the mitochondrial membrane for beta-oxidation. The depletion of carnitine leads to poor muscle tone and muscle weakness, because of the reliance of muscle on fatty acid metabolism.
Propionyl CoA is a poor substrate for, and hence a competitive inhibitor of some enzymes that utilise acetyl CoA:
citrate synthase, leading to the formation of methylcitrate, which cannot be metabolised further, and hence depletion of oxaloacetate and reduced citric acid cycle activity and reduced ATP formation
glutamate N-acetyltransferase, leading to much reduced synthesis of N-acetylglutamate, which is an obligatory activator of carbamoyl phosphate synthetase, the key enzyme for incorporation of ammonium into urea. This leads to potentially life-threatening hyperammonaemia.
Because of the impaired citric acid cycle activity, tissues are more than usually reliant on glycolysis, leading to hypoglycaemia.
In response to hypoglycaemia there is increased synthesis of ketone bodies, which cannot be metabolised through the citric acid cycle, leading to keto-acidosis.
See the exercise on Hyperammonaemic coma due to liver failure for a discussion of how intestinal bacterial fermentation of lactulose acidifies the intestinal contents and permits lowering of plasma ammonia.
See the exercise on Muscle weakness, heart failure and profound hypoglycaemia in a young girl for a discussion of the role of carnitine in fatty acid metabolism.
See the exercise on Experiments with isolated liver cells - the citric acid cycle and warming up post-operative patients for a discussion of the citric acid cycle.
For more on propionic acidaemia, see OMIM (On-line Mendelian Inheritance in Man) at http://omim.org/entry/606054)