Stigmatellin

Enders and coworkers developed a synthesis stigmatellin A (281) using al-dol reactions to set two of the four chiral centers [88]. Stigmatellin A is a natural product isolated from bacterium Stigmatdla aurantica and is one 

---

A 6 positional state that is stabilized by the interaction of His 161 with a molecule of the inhibitor stigmatellin bound in the quinone binding pocket (41), which is supposed to mimic the hydrogen bonding pattern of the reaction intermediate, semiqui-none (43)... 

When the fully conserved residue Thr 140, which is packed against the Pro loop, was substituted by Gly, His, or Arg in Rhodobacter capsulatus, the midpoint potential of the Rieske cluster was decreased by 50-100 mV, the cluster interacted with the quinone pool and the bci complex had 10-24% residual activity but the Rieske cluster was rapidly destroyed upon exposure to oxygen (49). In contrast, the residual activity was <5%, the cluster showed no interaction with the quinone pool, and the interaction with the inhibitor stigmatellin... 

Fig. 15. EPR spectra of the Rieske cluster in membranes of Paracoccus denitrificans in different redox states of the quinone pool and with inhibitors added. Q x, ascorbate reduced Qred) reduced with trimethylhydroquinone dissolved in dimethyl sulfoxide +EtOH, reduced with trimethylhydroquinone dissolved in 90% ethanol +Myxo, ascorbate reduced with myxothiazol added + Stigma, ascorbate reduced with stigmatellin added. Only the gy and signals are shown. The dotted line has been drawn at...

Treatment of bovine heart bci complex with ethoxyformic anhydride (EFA), which is known to modify amino acid residues covalently (preferentially histidine residues), inhibits electron transfer and has an effect on the EPR spectra of the Rieske cluster comparable to that observed upon addition of stigmatellin, that is, a decrease in rhombicity (80). This further supports the suggestion that quinones as well as quinonoid inhibitors interact directly with the histidine ligands of the Rieske cluster. 

Figure 13.12 The protonmotive Q cycle. Electron transfer reactions are numbered and circled. Dashed arrows designate movement of ubiquinol or ubiquinone between centres N and P and of the ISP between cytochrome b and cytochrome c,. Solid black bars indicate sites of inhibition by antimycin, UHDTB and stigmatellin. (From Hunte et al., 2003. Copyright 2003, with permission from Elsevier.)...

Only a few of the many known cytochrome bci complex inhibitors will be mentioned in this chapter. Cytochrome bci inhibitors that bind at the Qo site (p side, near the intermembrane space) include myxothiazol (MYX) and stigmatellin (SMA) (see Figure 7.29). MYX and SMA inhibit electron transfer from ubiquinol (QH2) to cytochrome c (outside the bci complex) or to other domains of the bci complex. Antimycin A (see Figure 7.29), a fungicide, binds... 

In 2005, the E. A. Berry group published X-ray crystallographic studies of cytochrome bci with bound inhibitors. The structure of PDB 1PP9, resolution 2.23 A, includes stigmatellin A (SMA) in the Qo site and substrate ubiquinone (UQ) in the Qi site, while PDB IPPJ, resolution 2.28 A, includes stigmatellin A in the Qo site and antimycin Ai (ANY) in the Qi site. These... 

PDB 1PP9 cytochrome bcj with inhibitor stigmatellin Note [2Fe-2S] centers interact with hemes in the other monomer. 

Figure 7.30 Comparison of cytochrome bci structures (A) PDB 1PP9 with inhibitor stigmatellin and (B) PDB IPPJ with inhibitors stigmatellin and antimycin A. Visualized using The PyMOL Molecular Graphics System and ChemDraw Ultra, version 10.0. (Printed with permission of Delano Scientific, LLC and CambridgeSoft Corporation.) (See color plate)...

---