Chapter 16: Pyruvate Dehydrogenase Complex and the TCA Cycle
In exercising skeletal muscles, pyruvate oxidation in the TCA cycle is stimulated by which of the following?
A. allosteric activation of isocitrate dehydrogenase by NADH
B. allosteric activation of malate dehydrogenase by NAD+
C. increased product inhibition of citrate synthase by oxaloacetate
D. phosphorylation of α-ketoglutarate dehydrogenase to an inactive form
E. stimulation of pyruvate dehydrogenase activity by Ca2+
Answer E: Muscle contraction results in release of stored calcium ion from sarcoplasmic reticulum. The released calcium allosterically inhibits the activity of the PDH kinases. Reduced activity of PDH kinases results in reduced phosphorylation of the PDHc thus, allowing for greater oxidation of pyruvate.
The pyruvate dehydrogenase complex (PDHc) is a multi-subunit enzyme whose activity is regulated by both allosteric effectors and covalent modification. Which of the following exerts a positive influence on the activity of PDHc toward pyruvate?
Answer C: The level of active PDHc is controlled by its state of phosphorylation. A family of enzymes called the PDH kinases phosphorylates the PDHc. In order to return the PDHc to full activity following PDH kinase-mediated phosphorylation, the phosphates are removed by PDH phosphatase.
A 24-year-old woman presents with diarrhea, dysphagia, jaundice, and white transverse lines on the fingernails (Mees lines). The patient is diagnosed with arsenic poisoning. Arsenic is known to inhibit which of the following enzymes of TCA cycle?
C. α-ketoglutarate dehydrogenase
E. succinate dehydrogenase
Answer C: Arsenic is toxic at many levels due to its broad specificity of enzyme inhibition. The mode of action of arsenic-containing compounds, primarily arsenic trioxide, is via it reacting with biological ligands that possess available sulfur groups. Arsenic interferes with the activity of the TCA cycle by inhibiting the α-ketoglutarate dehydrogenase complex, which requires the activity of the sulfhydryl group associated with the dihydrolipoamide moiety of the enzyme complex.
Which of the following vitamins is needed for the synthesis of a cofactor required for the conversion of succinate to fumarate?