A full-term female infant failed to gain weight and showed metabolic acidosis in the neonatal period. A physical examination at 6 months showed failure to thrive, hypotonia, small muscle mass, severe head lag, and a persistent acidosis (pH 7.0 to 7.2). Blood lactate, pyruvate, and alanine were greatly elevated. Treatment with thiamine did not alleviate the lactic acidosis. Which of the following enzymes is most likely deficient in this patient?
a) Alanine amino transferase
b) Phosphoenolpyruvate carboxy kinase
c) Pyruvate carboxylase
d) Pyruvate dehydrogenase
e) Pyruvate kinase
Hi. Pyruvate is central to this question.
- Pyruvate can be formed out of phosphoenolpyruvate by pyruvate kinase, this is a one way reaction.
- It can react away towards lactate (lactate dehydrogenase)
- It can react away towards acetyl-CoA, through the action of pyruvate dehydrogenase, which uses thiamine pyrophosphate as a coenzyme.
- It can react away towards oxaloacetate through the action of pyruvate carboxylase (one way reaction) and then to phosphoenolpyruvate (PEP carboxykinase, equilibrium)
- It can react away towards alanine (alanine aminotransferase, equilibrium).
So, there is a defective enzyme somewhere that causes pyruvate buildup. Alanine aminotransferase alleviates some of this and causes alanine buildup. Lactate dehydrogenases also alleviates some of this and causes lactate buildup. So these two are not defective.
Pyruvate kinase is a one way reaction towards pyruvate, so if thiw would be defective you would expect lower pyruvate concentrations. This is not the culprit either.
If pyruvate carboxylase were to be deficient, you would expect to be able to treat with thiamine, because this would generate more active pyruvate dehydrogenase complex and thus lower pyruvate concentrations. Also, this is only a major sink for pyruvate if the gluconeogenesis would be activated, so oxaloacetate concentration are not necessarily expected to be raised when pyruvtae concentrations rise.
Phosphoenolpyruvate carboxykinase equilibrates oxaloacetate and phosphoenolpyruvate, so doesn't seem to be directly involved with this problem.
The fact that thiamine makes no difference also points towards pyruvate dehydrogenase deficiency. If you look up this disease you will see that the symptoms match with the question.
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