396 IRON-CONTAINING PROTEINS AND ENZYMES
tions may result in mitochondrial myopathies, causing neuromuscular disease
symptoms. In the cytochrome b subunit of bc 1 complex, these myopathies
enhance superoxide production at the ubihydroquinone (ubiquinol) oxidation
site, thus causing harmful free - radical damage. The bypass reaction producing
superoxide appears to be an unavoidable part of the cytochrome bc 1 reaction
mechanism and results in cellular aging. Consequently, researchers in the fi eld
believe that an understanding of the mechanism of the bc 1 complex may be
central to our understanding of the aging process.
Another explanation of the Q - cycle mechanism is given by Iwata et al.^83
The central reaction of the Q cycle is a bifurcation that takes place at the Q p
site (called Q o by other researchers) that is in contact with the positive (inter-
membrane) side of the membrane. Here, during the hydroquinone (QH 2 )
oxidation reaction, one electron is transferred via the high potential [2Fe – 2S]
center of the ISP and cytochrome c 1 and thus to cytochrome c, while the second
electron is transferred to heme b L. From there, the second electron is trans-
ferred through the membrane dielectric to heme b H. Heme b H is part of the
quinone reduction site Q N (called Q i by other researchers) that is in contact
with the negative (matrix) side of the membrane. The Iwata group proposed
a “ three - state ” model to explain the electron transfer – proton translocation:
(1) With fully oxidized complex, before hydroquinone is bound, the ISP is in
an intermediate position (Fe II/III ions of [2Fe – 2S] ∼ 27 Å from cytochrome c 1
and∼ 31 Å from heme b L PDB: 1BGY; Table 7.6 , Iwata “ Int ” state); (2) hydro-
quinone binds in the Q p (Q o ) site, in a cavity formed near the end of helix C,
loop/helix cd1 and loop ef of cytochrome b (see Figure 7.28 ); (3) hydroquinone
is deprotonated to semiquinone status (QH − • ) at this site (the activation barrier
of hydroquinone oxidation), causing the ISP to move away to a position in
which the Fe II/III ions of [2Fe – 2S] are ∼ 31 – 32 Å from cytochrome c 1 and ∼ 26 –
27 Å from heme b L (PDB: 1QCR,^79 3BCC^84 ; Table 7.6 , the Iwata “ b ” state); (4)
the semiquinone is tightly bound to the reduced [2Fe – 2S] center; a second
electron is transferred from the semiquinone to heme b L ; (5) the interaction
between the resulting quinone and the [2Fe – 2S] center lessens, and the reduced
iron – sulfur center moves back toward heme c 1 for electron transfer in that
direction (Fe II/III ions of [2Fe – 2S] ∼ 15 – 21 Å from cytochrome c 1 and ∼ 34 – 35.5 Å
from heme b L (PDB: 1BE3,^83 1BCC^84 ; Table 7.6 , Iwata “ c 1 ” state); and (6)
electrons are transferred from cytochrome c 1 to cytochrome c and from heme
bL to heme b H and the system returns to step (1) of the cycle. The proposed
cycle is predicated on the facile movement of the iron – sulfur center in the
iron – sulfur protein (ISP) and is supported by X - ray crystallographic structures
showing the ISP in differing locations. However, it is important to remember
that the X - ray crystallographic studies represent a solid frozen in space and
not the dynamic, in solution, physiological state found in nature.
Another method used by researchers to indicate the mobility of the ISP
protein is to measure the anomalous peak heights of iron atoms belonging to
the various hemes and the [2Fe – 2S] cluster of the cytochrome bc 1 complex.
Considering the heme b H iron ion as the most stable position and giving it a