Disease relevance of stigmatellin

• The substitutions M1401, F144S and L, G152S, T163A and V333A in cytochrome b of the ubiquinol-cytochrome c oxidoreductase (bc1 complex) from Rhodobacter capsulatus provide resistance to the quinol oxidation (Qo) inhibitors myxothiazol, mucidin and stigmatellin [1].
• Stigmatellin A (1) isolated from the myxobacterium Stigmatella aurantiaca is a powerful inhibitor of electron transport in mitochondria and chloroplasts [2].

High impact information on stigmatellin

• Effects of mutation at this residue suggest that this group is involved in ligation of stigmatellin and quinol, but not quinone, and that the carboxylate function is essential for rapid turnover [3].
• The site of mitochondrial ROS production was determined to be mitochondrial respiratory complex III (cytochrome bc1), because 1). stigmatellin, a Qo site inhibitor, blocked ROS production and prevented the MPT and cell death and 2). cytochrome bc1 activity was abolished in cells protected from the redox-dependent MPT by stigmatellin [4].
• Deductions from the molecular analysis of the 65,000-bp stigmatellin biosynthetic gene cluster are reported [5].
• The biosynthesis of the aromatic myxobacterial electron transport inhibitor stigmatellin is directed by a novel type of modular polyketide synthase [5].
• In addition, inactivation of a cytochrome P450 monooxygenase-encoding gene involved in post-PKS hydroxylation of the aromatic ring leads to the formation of two novel stigmatellin derivatives [5].

Biological context of stigmatellin

• It was deduced from these results that the QP center is a spacious pocket formed by domains of cytochrome b, bearing the E-beta-methoxcyacrylate binding site, and the iron-sulfur protein, bearing the stigmatellin binding site [6].
• The inhibitors 2-n-heptyl-4-hydroxyquinoline-N-oxide and stigmatellin both have significant effects on the reduction kinetics of NarGHI(H56R) and NarGHI(H205Y) [7].
• In order to identify regulatory elements, we submitted the argyrin and stigmatellin producer Cystobacter fuscus to a random transposon mutagenesis strategy and screened 1,000 mutants for the occurrence of strains showing remarkably increased or decreased production of these compounds [8].
• Membrane potential was collapsed (<60 mV) by cyanide and stigmatellin [9].
• 5. Correlations have been drawn between the natural resistance of the protozoan mitochondria to antimycin, stigmatellin and myxothiazol and peculiar features in the structure of their apocytochrome b, on the basis of an accurate alignment of the sequences of this protein [10].

Anatomical context of stigmatellin

• 9. The Qo-site inhibitor stigmatellin induced spectral changes analogous to those reported for Rieske centers from mitochondria and chloroplasts [11].
• Both stigmatellin and 2-n-heptyl-4-hydroxyquinoline-N-oxide (HOQNO) inhibit menadiol:nitrate oxidoreductase activity with I50 values of 0.25 and 6 microM, respectively, and prevent the generation of a NarGHI-dependent proton electrochemical potential across the cytoplasmic membrane [12].
• Studies on the effect of stigmatellin derivatives on cytochrome b and the Rieske iron-sulfur cluster of cytochrome c reductase from bovine heart mitochondria [13].
• The rereduction of the oxidized cytochrome c was suppressed by the addition of stigmatellin both in the whole cells and isolated membranes [14].

Associations of stigmatellin with other chemical compounds

• Superoxide formation, determined by EPR and acetylated cytochrome c reduction in mitochondria was stimulated by antimycin A, and partially inhibited by myxothiazol and stigmatellin [15].
• When mitochondria are inhibited with myxothiazol or stigmatellin, there is no detectable formation of superoxide [16].
• These mutants behaved like a wild type strain with respect to their Ps+ growth ability, inhibitor sensitivity, EPR spectra of their [2Fe-2S] cluster, and response to stigmatellin or to the Qpool redox state [17].
• Direct evidence for the interaction of stigmatellin with a protonated acidic group in the bc(1) complex from Saccharomyces cerevisiae as monitored by FTIR difference spectroscopy and 13C specific labeling [18].
• The electron paramagnetic resonance spectrum of the cyt bH heme is altered by antimycin, consistent with a change in the dihedral angle between the ligating histidine imidazoles, while the spectrum of the cyt bL heme is broadened by stigmatellin [19].

Gene context of stigmatellin

• Perhaps the common action of MPP(+) and stigmatellin on the functional coupling of the PSST and ND1 subunits is initiated by binding at a semiquinone binding site in complex I [20].
• Rates of cytochrome f photooxidation in all strains were similar (t1/2 approximately = 300 microsec), whereas the rate of re-reduction sensitive to stigmatellin (at Eh = 0 mV, (where Eh is the ambient redox potential) for wild-type, Y1W, Y1F, Y1S, P2V, and V3P had a tl/2 of 3, 4, 5, 9, 40, and 2 ms, respectively [21].
• The orientation of the g-tensors of the Rieske iron-sulfur protein subunit was determined in a single crystal of the bovine mitochondrial cytochrome bc1 complex with stigmatellin in the Qo quinol binding site [22].
• Interaction of stigmatellin and DNP-INT with the Rieske iron-sulfur center of the chloroplast cytochrome b6-f complex [23].
• This stigmatellin mutant also shows an altered circular-dichroic spectrum of the low-potential haem of cytochrome b [24].

Analytical, diagnostic and therapeutic context of stigmatellin

• Optical and EPR spectroscopies performed in the presence of stigmatellin or HOQNO provide further evidence that these inhibitors bind at a heme bL-associated QP site [12].
• To see whether similar changes occur in the related photosynthetic b(6)f complex, we have studied the effect of the binding of stigmatellin to the eukaryotic b(6)f complex by electron crystallography [25].
• Involvement of the PKS gene cluster in stigmatellin biosynthesis is shown using site-directed mutagenesis [5].
• Natural stigmatellin A induced clear shifts in the redox-induced FTIR difference spectra [18].
• The inhibitory function of E-beta-methoxyacrylate-stilbene and myxothiazol may result from the increase of mobility in ISP, whereas the function of stigmatellin and 5-undecyl-6-hydroxy-4,7-dioxobenzothiazole may result from the immobilization of ISP [26].

References