What enzyme is inhibited by fluorocitrate?
enzyme aconitase
The compound is incorporated into fluoroacetyl coenzyme A, which condenses with oxaloacetate to form fluorocitrate. This inhibits the enzyme aconitase, which inhibits conversion of citrate to cis-aconitic acid/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.
Which enzyme of the TCA cycle is inhibited by fluorocitrate?
Aconitase
Aconitase catalyzes the conversion of citrate to isocitrate and aconitase is inhibited by fluorocitrate. Inactivation of aconitase blocks the tricarboxylic acid cycle.
Why is fluoroacetate toxic?
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?
Fluoroacetate poisoning has been well-documented in animals since its application as a pesticide. Following oral administration and absorption through the gut, fluoroacetate is converted to fluorocitrate by citrate synthase (EC 4.1. 3.7) [31] which strongly binds to the aconitase enzyme (EC 4.2.
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 function of aconitase and how is it inhibited?
1. Aconitase. In addition to its participation in the citric acid cycle, the mammalian [4Fe-4S] aconitase is also a regulator of iron homeostasis. RNS inhibit aconitase activity by disrupting the [Fe–S] clusters.
What type s of reaction does aconitase catalyze?
Aconitase from pig (PDB 7acn) is a single polypeptide (Mr 83kD) that catalyzes the reversible isomerization of citrate and isocitrate. It is the second enzyme in the Citric acid cycle, which is a series of enzyme-catalysed chemical reactions that is crucial to aerobic cellular respiration and the production of ATP.
Is fluorocitrate toxic?
The classical explanation of the toxic action of fluorocitrate is that it inhibits the enzyme aconitase in the tricarboxylic acid cycle. Deactivation of aconitase results in decreased energy production by cells and ultimately death of the organism.
What are the effects of fluoroacetate poisoning in animals?
In mammals, fluoroacetate poisoning can cause death in a number of ways. Carnivores (dogs, cats, foxes) generally suffer failure of the central nervous system; herbivores (rabbits, cattle, sheep) suffer heart or lung failure; and in omnivores (pigs) the central nervous system, heart, or lungs can fail.
How does fluoroacetate affect glycolysis?
Citrate and fluorocitrate are allosteric inhibitors of phosphofructokinase-1 (PFK-1), a key enzyme in glycolysis. When PFK-1 is inhibited, cells are no longer able to metabolize carbohydrates, depriving them of energy. Alternatively, fluorocitrate interferes with citrate transport in the mitochondria.
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.
How big is the crystal structure of fluorocitrate?
The crystals grew within 8 weeks to a size of 1.0 × 0.8 × 0.3 mm and were characterized by precession photography. The crystals are monoclinic, space group B2, with unit cell dimensions of a = 185.9, b = 71.8, c = 72.2 Å, γ = 77.7°, and one molecule per asymmetric unit.
How is Fluorocitric acid incorporated into oxaloacetate?
The compound is incorporated into fluoroacetyl coenzyme A, which condenses with oxaloacetate to form fluorocitrate. This inhibits the enzyme aconitase, which inhibits conversion of citrate to cis -aconitic acid/isocitrate.
When was the toxic nature of fluoroacetate discovered?
The toxic nature of fluoroacetate was discovered over 50 years ago ( 1, 2) and citrate was found to accumulate in tissues poisoned with compounds that could provide the fluoroacetyl residue. On this basis Peters ( 3) and Martius ( 4) proposed that the inhibitory substance was a fluorotricarboxylic acid.
What happens when fluoride is added to aconitase?
When (+)- erythro -2-fluorocitrate is added to aconitase, the release of fluoride is stoichiometric with total substrate added, and HPLC analysis of the products indicates the formation of oxalosuccinate, and its derivative α-ketoglutarate.