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CASE FILES: BIOCHEMISTRY
cytochromes have a long isoprenoid [(CH2-CH=C(CH3)-CH2)n] tail bound at
one side-chain position.
Inhibition of the electron transport chain in coupled mitochondria can occur
at any of the three constituent functional processes; electron transport per se,
formation of ATP, or antiport translocation of ADP/ATP (Table 16-1). The
best known inhibitor of the ADP/ATP translocase is atractyloside in
the presence of which no ADP for phosphorylation is transported across
the inner membrane to the ATP synthase and no ATP is transported out.
In the absence of ADP phosphorylation the proton gradient is not reduced
allowing other protons to be extruded into the intermembrane space because
of the elevated [H+], and thus electron transfer is halted. Likewise the antibiotic
oligomycin directly inhibits the ATP synthase, causing a cessation of ATP for-
mation, buildup of protons in the intermembrane space, and a halt in electron
transfer. Similarly, a blockade of complex I, III, or IV that inhibits electron
flow down the chain to O2 would also stop both ATP formation and ADP/ATP
translocation across the inner mitochondrial membrane.
Cyanide ion (CN-) is a potent inhibitor of complex IV the cytochrome c oxi-
dase component of the electron transport system in the oxidized state of the heme
(Fe3+). It can be delivered to tissue electron transport systems as a dissolved gas
after breathing HCN or ingested as a salt such as KCN or as a medication lead-
ing to the formation of CN- such as nitroprusside. Cyanide ion competes effec-
tively with oxygen for binding to cytochrome c oxidase at the oxygen-binding
site. Cyanide binding and therefore cyanide poisoning is reversible if treated
properly and early. The treatment strategy depends on dissociation of cyanide
from cytochrome a/a3 (Fe3+). Increasing the percentage of oxygen breathed
will increase the competition of oxygen over cyanide for the cytochrome a/a3
(Fe3+). Two other medications foster this competition. Nitrite ion (NO2-) is
administered to convert some oxyhemoglobin [HbO2(Fe2+)] to methemoglobin
Table 16-1
RESPIRATORY CHAIN SITES AND INHIBITORS
RESPIRATORY CHAIN SITES
INHIBITOR
Complex I: NADH: CoQ reductase
Piericidin A
Amytal
Rotenone
Complex III: Cytochrome c reductase
Antimycin A
Complex IV: Cytochrome oxidase
Cyanide ion
Carbon monoxide
ATP synthase
Oligomycin
ADP/ATP translocase
Atractyloside, Bongkrekate
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