Biology Reference
In-Depth Information
trans-membrane electrochemical gradients causing tremendous metabolic upheaval in many
organisms including microorganisms. It is for this reason that valinomycin was recognized as
an antibiotic long before it was identified as an ionophore. Currently several ionophores are
added to animal feed as antibiotics and growth enhancing additives
[33]
. Recently valinomy-
cin has been reported to be the most potent agent against SARS-CoV (severe acute respiratory
syndrome-coronavirus), a severe form of pneumonia first identified in 2003
[34]
.
2,4-Dinitrophenol (DNP)
2,4-Dinitrophenol (DNP) is considered to be the classic uncoupler of oxidative phosphor-
ylation. It is a synthetic lipid-soluble proton ionophore that dissipates proton gradients
across bioenergetic membranes (mitochondrial inner, thylakoid, bacterial plasma). An
uncoupler is therefore an H
þ
facilitated diffusion carrier. Elucidating the role of DNP in
uncoupling oxidative phosphorylation was an essential component in support of Peter
Mitchell's Chemiosmotic Hypothesis
[25]
. Electron movement from NADH or FARH
2
to
O
2
via the mitochondrial electron transport system generates a considerable amount of elec-
trical energy that is partially captured as a trans-membrane pH gradient. The movement of
H
þ
s back across the membrane, driven by the electrochemical gradient, is through a channel
in the F
1
ATPase (an F-type primary active transport system, see above) that is coupled to ATP
synthesis. DNP short-circuits the H
þ
gradient before it can pass through the F
1
ATPase, thus
uncoupling electron transport, the energy source for generating the H
þ
gradient, from ATP
synthesis. Therefore, in the presence of DNP, electron transport continues, even at an accel-
erated rate, but ATP production is diminished. The energy that should have been converted
to chemical energy as ATP is then released as excess heat.
This combination of properties led to the medical application of DNP to treat obesity from
1933 to 1938
[35]
. Upon addition of DNP:
The patient became weak due to low ATP levels.
Breathing increased due to increased electron transport to rescue ATP production.
Metabolic rate increased.
Body temperature increased due to inability to trap electrical energy as chemical energy in
the form of ATP.
Body weight decreased due to increased respiration burning more stored fat.
DNP was indeed a successful weight loss drug. Two of the early proponents of the use of
DNP as a diet drug, Cutting and Tainter at Stanford University, estimated that more than
100,000 people in the United States had tested the weight-loss drug during its first year in
use
[35]
. DNP, however, did have one disturbing side effect
death! Fatality was not caused
by a lack of ATP, but rather by a dangerous increase in body temperature (hyperthermia). In
humans, 20
e
e
50 mg/kg of DNP can be lethal. Although general use of DNP in the United
States was discontinued in 1938, it is still employed in other countries and by bodybuilders
to eliminate fat before competitions.
Crown Ethers
Crown ethers are a family of synthetic ionophores that are generally similar in function to the
natural product valinomycin
[36]
. The first crown ether was synthesized by Charles Pederson
