Why does fluorocitrate inhibit aconitase?

Fluorocitrate is converted to fluoro-cis-aconitate and then to 4-hydroxy-trans-aconitate (HTn) which binds tightly to aconitase and inhibits its action. It does this by displacing the double bond closest to the Fe and preventing the hydration of the double bond.

What does fluoroacetate do to cellular respiration?

Fluoroacetate enters the tricarboxylic acid (Krebs) cycle in place of acetate and is converted to fluorocitrate, which competitively inhibits aconitase and thereby prevents the conversion of citrate to isocitrate. This leads to citrate accumulation, reducing glucose metabolism, energy stores, and cellular respiration.

What enzyme does fluoroacetate inhibit?

Fluoroacetate (FA; CH2FCOOR) is highly toxic towards humans and other mammals through inhibition of the enzyme aconitase in the tricarboxylic acid cycle, caused by ‘lethal synthesis’ of an isomer of fluorocitrate (FC). FA is found in a range of plant species and their ingestion can cause the death of ruminant animals.

Why is fluoroacetate an effective pesticide?

It is well suited as a pesticide because it is virtually tasteless and odourless, which enables it to be easily disguised within bait material targeted towards a specific pest species [3].

What happens if aconitase is inhibited?

The inhibition of aconitase can lead to accumulation of citrate because aconitase mediates its conversion to isocitrate.

What is the function of aconitase?

Aconitase (aconitate hydratase; EC 4.2. 1.3) is an enzyme that catalyses the stereo-specific isomerization of citrate to isocitrate via cis-aconitate in the tricarboxylic acid cycle, a non-redox-active process.

Why is it called 1080?

History and production. The effectiveness of sodium fluoroacetate as a rodenticide was reported in 1942. The name “1080” refers to the catalogue number of the poison, which became its brand name. The salt is synthesized by treating sodium chloroacetate with potassium fluoride.

How does fluoroacetate inhibit TCA cycle?

Fluoroacetate combines with coenzyme A (CoA-SH) to form fluoroacetyl CoA, which can substitute for acetyl CoA in the tricarboxylic acid cycle and reacts with citrate synthase to produce fluorocitrate, a metabolite of which then binds very tightly to aconitase, thereby halting the cycle.

What is the science behind 1080?

Once in water, the sodium bond (Na+) dissociates, leaving fluoroacetate in solution. Therefore after ingestion, 1080 works the same as naturally occurring fluoroacetate [2]. Once within the body, the Na+ bond dissociates, and the fluoroacetate is converted to fluorocitrate.

Is aconitase reversible?

Aconitase from pig (PDB 7acn) is a single polypeptide (Mr 83kD) that catalyzes the reversible isomerization of citrate and isocitrate.

Is Fumarase an iron sulfur protein?

Iron-sulfur clusters are the traces of biological evolution in the early anaerobic earth. Dehydratases that contain [4Fe–4S] clusters, such as fumarase, aconitase and isopropylmalate isomerase (IPMI), are such proteins [[12], [13], [14], [15]].

How is fluorocitrate inhibited by the enzyme aconitase?

The mechanism of the inhibitory effects of fluorocitrate on the enzyme aconitase [citrate (isocitrate)hydrolyase, EC 4.2.1.3] has been a long-standing problem in biochemistry.

Which is more toxic fluoroacetate or fluorocitrate?

It has been known for many years that fluoroacetate and fluorocitrate when metabolized are highly toxic, and that at least one effect of fluorocitrate is to inactivate aconitase.

How is fluoroacetic acid converted to a toxic metabolite?

This product combines with oxaloacetate in the Krebs cycle and is converted to fluorocitrate, a toxic metabolite. Several species, such as the Western Australian opossum, are known to be capable of rapid defluorination of fluoroacetate, which reduces the conversion of fluoroacetate to fluorocitrate.

How is fluoroacetate eliminated from the human body?

Fluoroacetate is converted to the ultimate toxicant, fluorocitrate. Fluoroacetate is distributed to lipid-rich organs, such as the liver, brain, and kidneys. Fluoroacetate is primarily eliminated through urine. Up to 50% of the fluoroacetate is excreted unchanged in the urine by 72 h following administration.