Question

2) A patient exhibits extreme lactic acidosis (buildup of lactate in the body). Genome sequencing reveals a mutation in the gene coding for the E1 subunit of the PDH complex. This mutation is known to increase the Km of PDH for TPP.
a) In two to three sentences, explain how this mutation could lead to extreme lactic acidosis.(2 pts)

b) For each of the statements below, identify whether you would recommend or not recommend the treatment. Then, explain your reasoning and/or possible effects on the individual.

Statement 1:
Provide the patient with a high carbohydrate diet. (2 pts)

Statement 2:
Administer thiamine, a precursor of TPP, to the patient. (2 pts)

Answer 1

a) Normally the E1 subunit of the PDH complex uses TPP and pyruvate to initiate the complex reaction that ultimately releases acetyl-CoA. The mutation-induced increase in K_m for TPP of the E1 downregulates the oxidative decarboxylation of pyruvate to acetyl-CoA. Consequently, further oxidation of the sugar is hindered and the accumulated pyruvate starts to be reduced by another enzyme called lactate dehydrogenase, which produces lactate as an end product plus replenishes the NAD⁺ lost in glycolysis.

b)

Statement 1: Not recommended.

Reason: All carbohydrates consumed ultimately gets converted to glucose in the digestive system. More glucose availability increases the rate of glycolysis and in turn, pyruvate production. Since further oxidation of pyruvate is slowed down by the mutation, inevitably lactate production by lactate dehydrogenase complex (LDH) soars up to keep the [NAD⁺] replenished (and thus carrying on glycolysis).

Statement 2: Recommended.

Reason: Thiamine supply upregulates TPP production. Abundant availability of TPP compensates for the low binding affinity of E1 for TPP, facilitating the smooth occurrence of oxidative decarboxylation of pyruvate by PDH. As pyruvate gets further oxidized to acetyl-CoA and enters the TCA cycle, NAD⁺ gets the opportunity to be replenished through the electron transport chain. Both unavailabilty of pyruavate for reduction and lack of need for NAD⁺ replenishment downregulates lactate production by LDH and thus helps the patient.