Chromanols and Cytochrome bc1 Complex
Chem. Res. Toxicol., Vol. 23, No. 1, 2010 201
and to a lesser extent of other bands as seen in the presence of
Stig (Figure 8C) is related to the H-bond strength between the
His-161 of the ISP and the inhibitor molecule or UQH2 in the
cyt bc1 complex (54). Because of analysis of crystal structures,
Glu-272 (Glu-271 in 2A06) as another interacting residue for
H-bond formation with substrate and inhibitors was proposed
(54). Our experiment reproduced the inhibitor influence by the
observation of shifts of the gx to higher and gz bands to lower
g-factors upon addition of Stig (Figure 8C vs A). In view of
the fact that Stig is a highly potent inhibitor, it was surprising
that although higher concentrations of TMC2O were required,
the latter compound did produce a spectral shift of the EPR
lines of the FeS in the ISP (Figure 8B). For TMC2O, the
sensitivity order of g-factors was gx . gz > gy ≈ 0 (Table 2).
This suggests that TMC2O, although with lower affinity,
interacts with the ISP but possesses binding sites in the Qo
pocket similar but not identical to Stig.
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By docking experiments, we intended to explore the effects
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Conclusions
The 6-hydroxy chroman structures of Toc-related and the
para-benzoquinone structure of TQ-related molecules can
modulate the function of the mitochondrial cyt bc1 complex.
For both Toc and TQ, an incomplete methyl substitution
(ꢀ-, γ-, and δ-congeners) increases the inhibitory potential in
comparison with fully substituted R-congeners. This affinity can
be further enhanced by the introduction of keto groups into the
chroman ring, thus leading to chromanones. For TMC2O, it was
shown that it binds to the Qo pocket of the cyt bc1 complex and
delays the electron transfer from dUQH2 to cyt c1 in the
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an unspecific effect but is based on their pattern of polar vs
apolar structural motifs.
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¨
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Acknowledgment. The generous help of Dr. Massimiliano
D’Arienzo (University of Milano), Dr. Michael Elser and Prof.
Oliver Diwald (Technical University of Vienna) in setting up
the helium cryostat for low temperature EPR measurements is
gratefully acknowledged.