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Renin Angiotensin Mechanism.

Inhibitors of ETC and oxidative phosphorylation / Uncouplers.

 

Definition of Inhibitors of ETC and oxidative phosphorylation.:

  • The compounds which inhibit ETC and hence affect oxidative phosphorylation.

  • These inhibitors bind to the respiratory chain, and not to the enzymes involved in ATP synthesis, which would normally accompany respiration.

  • Their actions may be mediated by 3 positions that are similar to energy transfer sites I, II, and III.

Examples of Inhibitors:

  1. Rotenone

    • Electron transport chain inhibitor that is non-toxic.

    • Obtained from the extracts of roots of tropical plants Derris elliptica. 

    • It binds in Complex I.

    • Mammals cannot be harmed by this substance since it is poorly absorbed. 

    • Fish are affected by their toxicity.

  2. Pieridine A

    • Antibiotics are used to treat infections (safer in Humans).

    • Strains of Streptomyces produce it.

    • It acts similarly to Rotenone.

  3. Barbiturates:

    • Coenzyme Q and NADH dehydrogenase are blocked, one of the reason of respiratory failure in barbiturate poisoning.

  4. Antimycin

    • Streptomyces produces antibiotics called antimycins. Antimycin is an electron transport chain inhibitor.

    • Site II is inhibited and electrons are prevented from flowing between cytochromes b and c1, preventing ATP synthesis coupled with the formation of a proton gradient.

  5. Dimercaprol

    • Similar to antimycins, it acts similarly.

  6. Hydrogen sulfide

    • The disagreeable odor of H2S provides a warning that it is toxic.

    • Oxidase is inhibited by H2S.

  7. Carbon monoxide

    • Oxygen and cytochrome oxidase is blocked.

    • Fer2+ is inhibited as well.

Definition of uncouplers:

  • An uncoupler is a substance that prevents electron transfer during phosphorylation of ADP. 

  • Compounds that uncouple ATP synthesis from electron transport through the cytochrome system are uncoupling agents. 

  • In this case, oxygen is consumed, but phosphorylation of ADP is inhibited, despite electron transport continuing to function.

Examples of Uncouplers:

  1. 2,4-Dinitrophenol

    • Oxidative phosphorylation is a classic uncoupler.

    • The substance transports protons across mitochondrial membranes.

    • This uncoupler prevents mitochondria from forming ATP when electrons are transported from NADH to O2. The protons in the inner mitochondrial membrane are dissipated, resulting in the production of ATP.

    • In metabolic studies, DNA or other uncouplers are extremely useful because of their specific effect on phosphorylation outside the cell.

  2. Dicoumarol (Vitamin K analogue)

    • Inhibits the formation of blood clots.

  3. Calcium

    • Uncoupling can be caused by Ca+2 ions being transported into mitochondria.

    • Oxidative phosphorylation is tightly coupled to mitochondrial Ca+2 transport.

    • Uptake of pi is also involved.

    • Electron transport can occur in mitochondria when calcium is transported there, but energy is required to pump Ca+2 into the mitochondria. ATP cannot be stored as a result.

  4. CCCP (Chloro Carbonyl Cyanide Phenylhydrazone)

    • Uncoupler with the most activity.

    • Protons can cross the inner mitochondrial membrane with the help of these lipid-soluble substances.

  5. Physiological uncouplers

    • Thyroxine hormone is produced in excess

    • Brown adipose tissue contains long-chain FA

    • The unconjugated form of hyperbilirubinemia

  6. Valinomycin

    • It is produced by the streptomyces.

    • There are four types of residues in this repeating macrocyclic molecule (L-lactate, L-Valine, D-hydroxyisovalerate, and D-Valine).

    • Reduces the proton gradient by transporting K+ from cytosol to matrix and H+ from matrix to the cytosol.

Commonly Asked Questions:

  1. Define and explain Inhibitors of ETC and oxidative phosphorylation.

  2. What are Uncouplers? Give some examples.
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