Sepsis is the systemic response to a severe bacterial insult that can disrupt the inter-organ metabolic balance. One of the manifestations of this condition is hyperlactatemia (elevated blood lactate). Hyperlactatemia can result from increased lactate production, decreased lactate clearance, or both.
Muscle tissue represents a major source of lactate production in the body. A study conducted in animals (Vary and Hazen, Mol. Cell. Biochem., 198, 113, 1999) has shown that sepsis affects the proportions of muscle mitochondrial pyruvate dehydrogenase (PDH) in its phosphorylated versus dephosphorylated form. This finding was suggested as a possible mechanism for increased lactate production in muscle from sepsis-afflicted animals.
a) Write the reaction that is catalyzed by PDH.
b) What is the effect of phosphorylation/dephosphorylation on the activity of PDH?
c) Briefly explain how a change in PDH activity could account for hyperlactatemia? A sketch of the metabolic pathway involved would be helpful.
d) Based on your answers to parts (a) and (b), in what way do you think sepsis affected the phosphorylation status of the PDH enzyme (i.e., a greater proportion in the phosphorylated state or in the dephosphorylated state)?