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Chapter 19: Problem 5

In a tissue where the TCA cycle has been inhibited by fluoroacetate, what difference in the concentration of each TCA cycle metabolite would you expect, compared with a normal, uninhibited tissue?

Short Answer

Expert verified
Fluoroacetate disrupts the TCA cycle leading to an increased concentration of citrate and reduced concentration of subsequent metabolites in the TCA cycle compare to a normal, uninhibited tissue.

Step by step solution

01

Understand the TCA cycle

The TCA cycle, also known as citric acid cycle or Krebs cycle, is a series of chemical reactions used by all aerobic organisms to release stored energy from carbohydrates, fats and proteins. The cycle consists of several steps involving different metabolites. Each step is facilitated by a specific enzyme. In our context, fluoroacetate primarily inhibits aconitase.
02

Identify the effect of fluoroacetate

Fluoroacetate inhibits the TCA cycle by converting to fluorocitrate, which inhibits aconitase. Aconitase facilitates the conversion of citrate to isocitrate in the TCA cycle.
03

Understand the impact on metabolite concentration

Due to inhibition of aconitase, the conversion of citrate to isocitrate is halted. It means the concentration of citrate will increase. As most subsequent reactions in the cycle are dependent on the prior one, the concentration of the downstream metabolites (those following isocitrate) will decrease.
04

Review the effect on entire cycle

The individual concentration of each TCA cycle metabolite downstream of citrate will decrease due to lack of their precursor molecule. On the contrary, citrate concentration will increase as it no longer can convert to isocitrate because of aconitase inhibition.

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Most popular questions from this chapter

(Integrates with Chapter \(15 .\) ) The serine residue of isocitrate dehydrogenase that is phosphorylated by protein kinase lies within the active site of the enzyme. This situation contrasts with most other examples of covalent modification by protein phosphorylation, where the phosphorylation occurs at a site remote from the active site. What direct effect do you think such active-site phosphorylation might have on the catalytic activity of isocitrate dehydrogenase? (See Barford, D., 1991. Molecular mechanisms for the control of enzymic activity by protein phosphorylation. Biochimica et Biophysica Acta \(1133: 55-62 .\)

Aconitase is rapidly inactivated by \(2 R, 3 R\) -fluorocitrate, which is produced from fluoroacetate in the citrate synthase reaction. Interestingly, inactivation by fluorocitrate is accompanied by stoichiometric release of fluoride ion (i.e., one F-ion is lost per aconitase active site \() .\) This observation is consistent with "mechanism-based inactivation" of aconitase by fluorocitrate. Suggest a mechanism for this inactivation, based on formation of 4 -hydroxy-trans-aconitate, which remains tightly bound at the active site. To assess your answer, consult this reference: Lauble, H., Kennedy, M., et al., 1996. The reaction of fluorocitrate with aconitase and the crystal structure of the enzyme-inhibitor complex. Proceedings of the National Academy of Sciences \(93: 13699-13703\)

The malate synthase reaction, which produces malate from acetylCoA and glyoxylate in the glyoxylate pathway, involves chemistry similar to the citrate synthase reaction. Write a mechanism for the malate synthase reaction and explain the role of CoA in this reaction.

Describe the effect on the TCA cycle of (a) increasing the concentration of \(\mathrm{NAD}^{+},\) (b) reducing the concentration of \(\mathrm{ATP}\), and (c) increasing the concentration of isocitrate.

In most cells, fatty acids are synthesized from acetate units in the cytosol. However, the primary source of acetate units is the TCA cycle in mitochondria, and acetate cannot be transported directly from the mitochondria to the cytosol. Cells solve this problem by exporting citrate from the mitochondria and then converting citrate to acetate and oxaloacetate. Then, because cells cannot transport oxaloacetate into mitochondria directly, they must convert it to malate or pyruvate, both of which can be taken up by mitochondria. Draw a complete pathway for citrate export, conversion of citrate to malate and pyruvate, and import of malate and pyruvate by mitochondria. a. Which of the reactions in this cycle might require energy input? b. What would be the most likely source of this energy? c. Do you recognize any of the enzyme reactions in this cycle? d. What coenzymes might be required to run this cycle?
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