Question

Sodium fluoroacetate \(\left(\mathrm{FH}_{2} \mathrm{CCOO}^{-} \mathrm{Na}^{+}\right)\) is highly toxic. Patients with fluoroacetate poisoning accumulate citrate and fluorocitrate in their cells. Which enzyme is inhibited by fluoroacetate for this to occur? Explain.

Short answer

The enzyme inhibited by fluoroacetate is aconitase.

Step-by-step solution

Understanding the Problem

This problem involves identifying the enzyme inhibited by sodium fluoroacetate that leads to the accumulation of citrate and fluorocitrate. Sodium fluoroacetate is known to disrupt processes in the citric acid cycle.

Recall the Citric Acid Cycle

The citric acid cycle (Krebs cycle) is a series of chemical reactions used by all aerobic organisms to release stored energy through the oxidation of acetyl-CoA derived from carbohydrates, fats, and proteins. Citrate is one of the intermediates in this cycle.

Identify Key Reactions

In the citric acid cycle, citrate is synthesized from acetyl-CoA and oxaloacetate by the enzyme citrate synthase. Fluorocitrate, formed from fluoroacetate by cellular enzymes, is known to disrupt the cycle.

Determine the Point of Inhibition

Fluorocitrate specifically inhibits the enzyme aconitase. Aconitase is responsible for converting citrate to isocitrate in the citric acid cycle. By inhibiting this enzyme, fluorocitrate causes an accumulation of citrate and ultimately a disruption of the cycle.

Conclusion

Fluoroacetate poisoning leads to the accumulation of citrate and fluorocitrate in cells due to the inhibition of aconitase by fluorocitrate. This inhibition blocks the conversion of citrate to isocitrate, halting the citric acid cycle.

Key concepts

Citric Acid Cycle

The citric acid cycle, also known as the Krebs cycle, is a critical metabolic pathway that plays a key role in cellular respiration in aerobic organisms. This cycle is responsible for oxidizing acetyl-CoA, derived from carbohydrates, fats, and proteins, to produce energy. During the process, various substrates are converted step-by-step to release energy stored in molecular bonds, which is then used to form energy-rich molecules such as ATP, NADH, and FADH2.
Here's how it works in a nutshell:

• The cycle begins with the combination of acetyl-CoA and oxaloacetate to form citrate.
• The citrate then undergoes a series of enzyme-catalyzed transformations.
• These transformations release carbon dioxide and transfer electrons to NADH and FADH2, ultimately generating ATP.

In addition to energy production, the citric acid cycle provides intermediates for biosynthetic processes, making it essential for cell function and energy metabolism.

Fluorocitrate

Fluorocitrate is a potent metabolite formed from fluoroacetate, a toxic compound. Once inside the body, fluoroacetate undergoes metabolic transformations to become fluorocitrate, a powerful inhibitor of the citric acid cycle. This transformation involves multiple cellular enzymes that add a fluorine atom, creating an altered molecule that meddles with the cycle.
Fluorocitrate’s impact is profound:

• It is structurally similar to citrate, allowing it to interact with the same enzymes within the citric acid cycle.
• Despite its similarity to citrate, fluorocitrate acts as a decoy, disrupting normal metabolic processes.
• This disruption leads to an accumulation of citrate, affecting the cycle and energy production.

The accumulation of unmetabolized citrate highlights fluorocitrate’s role as a metabolic poison. Blocking essential enzymes can lead to serious physiological consequences, making fluorocitrate a focal point in understanding toxicological effects of fluoroacetate poisoning.

Aconitase Inhibition

Aconitase is a crucial enzyme in the citric acid cycle, responsible for the conversion of citrate into isocitrate. This transformation is essential for the continuation of the cycle and the effective production of cellular energy. Aconitase catalyzes the isomerization of citrate to isocitrate through a stereospecific process that involves removal and addition of water.
When fluorocitrate inhibits aconitase, the conversion is blocked:

• Citrate accumulates since it cannot be converted further down the cycle.
• This blockage prevents the production of isocitrate, a vital step leading to the generation of NADH and ATP.
• Consequently, cellular respiration is hampered, leading to energy deficits in the body.

The inhibition of aconitase by fluorocitrate underscores the delicate balance needed for cellular processes. Disruption of even a single enzyme can cascade into broader metabolic deficiencies, illustrating the critical nature of aconitase in energy metabolism and the profound effects of its inhibition.