This document lists inhibitors that block the five complexes of oxidative phosphorylation as well as the ATP synthase and ATP-ADP translocase. It provides examples of specific inhibitors such as rotenone for complex I, antimycin A for complex III, and oligomycin for ATP synthase. The document also discusses uncouplers that dissipate the proton gradient across the inner mitochondrial membrane, preventing ATP synthesis but allowing the electron transport chain to continue producing heat. Hibernating animals use this mechanism to stay warm in winter without needing ATP.

1. Inhibitors of Oxidative Phosphorylation
• Complex I: Rotenone
• Complex II: Carboxin
• Complex III: Antimycin A
• Complex IV: Cyanide, Azide, Carbon monoxide
• ATP synthase: Oligomycin
• ATP-ADP translocase: Atractyloside (a plant
glycoside)

2. •
Rotenone inhibits Complex I - and helps natives of
the Amazon rain forest catch fish. Rotenone is a
common insecticide that strongly inhibits the
electron transport of complex I. Rotenone is a
natural product obtained from the roots of several
species of plants. Tribes in certain parts of the
world beat the roots of trees along riverbanks to
release rotenone into the water which paralyzes
fish and makes them easy prey.
•
Amytal is a barbiturate that inhibits the electron
transport of complex I.
•
Demerol is painkiller that also inhibits complex I.

3. 2-Thenoyltrifluoroacetone and carboxin specifically
block soluble ubiquinone-deficient succinate:
ubiquinone reductase transport in Complex II.
•
Antimycin A1is an antibiotic produced by
Streptomyces. Sp, that inhibits electron transfer in
complex III by blocking the transfer of electrons
between Cyt b and coenzyme Q bound at the Q site.
It is a most potent inhibitors of the mitochondrial
respiratory chain.
•
Cyanide, azide and CO inhibit Complex IV, binding
tightly to the ferric form (Fe3+
) of a3

4. Cyanide and azide are potent inhibitors at this site
which accounts for there acute toxicity
Inhibitors of ATP Synthase
•
DCCD, forms covalent bonds to a glutamate residue
of the c subunit of F0. When DCCD is covalently
attached it blocks the proton channel, which causes
the rotation and ATP synthesis to cease.
•
Oligomycin are macrolides created by Streptomyces
binds directly to ATP synthase F0 subunit and blocks
the flow of protons through the channel.

7. Uncouplers inhibit oxidative phosphorylation.
• They ‘uncouple’ the ETC from oxidative
phosphorylation. Uncouplers are hydrophobic
molecules with a dissociable proton
• The ETC remains intact and electrons are
transferred to O2 to generate H2O. All of the
uncouplers will collapse the pH gradient by binding
a proton on the acidic side of the membrane,
diffusing through the inner mitochondrial
membrane and releasing the proton on the
membrane’s alkaline side.
Uncouplers

9. The pH and electrical gradient is not generated and
ATP is not synthesized. In the presence of an
uncoupling agent, energy released via the ETC is
converted into heat.
• This mechanism is used by hibernating animals to
stay warm in the winter, since they don’t need ATP
for anabolic processes while they are resting. Eg
2,4-Dinitrophenol,dicumarol and carbonyl cyanide-p-
trifluorocarbonyl-cyanide methoxyphenyl
hydrazone (FCCP).

10. The pH and electrical gradient is not generated and
ATP is not synthesized. In the presence of an
uncoupling agent, energy released via the ETC is
converted into heat.
• This mechanism is used by hibernating animals to
stay warm in the winter, since they don’t need ATP
for anabolic processes while they are resting. Eg
2,4-Dinitrophenol,dicumarol and carbonyl cyanide-p-
trifluorocarbonyl-cyanide methoxyphenyl
hydrazone (FCCP).