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Biomedical subjects

A Ghelli

Publications and source records attributed to A Ghelli.

28 records · Page 2Linked to original sources
PubMed1994

Thienylvinylindoles as inhibitors of mitochondrial NADH dehydrogenase.

In connection with a previous study, new phenylindoles bearing a 2- or 3-thienyl group were synthesized and tested as specific inhibitors of mitochondrial NADH dehydrogenase. The position of the phenyl ring and the geometrical configuration play an important role in the activity and specificity of these derivatives. In order to study the mechanism of action of these thienylvinylindoles, their activity was compared with that of known inhibitors in a new test employing exogenous quinones.

Animals↗
PubMed1993

Mitochondrial cytochrome b: evolution and structure of the protein.

Cytochrome b is the central redox catalytic subunit of the quinol: cytochrome c or plastocyanin oxidoreductases. It is involved in the binding of the quinone substrate and it is responsible for the transmembrane electron transfer by which redox energy is converted into a protonmotive force. Cytochrome b also contains the sites to which various inhibitors and quinone antagonists bind and, consequently, inhibit the oxidoreductase. Ten partial primary sequences of cytochrome b are presented here and they are compared with sequence data from over 800 species for a detailed analysis of the natural variation in the protein. This sequence information has been used to predict some aspects of the structure of the protein, in particular the folding of the transmembrane helices and the location of the quinone- and heme-binding pockets. We have observed that inhibitor sensitivity varies greatly among species. The comparison of inhibition titrations in combination with the analysis of the primary structures has enabled us to identify amino acid residues in cytochrome b that may be involved in the binding of the inhibitors and, by extrapolation, quinone/quinol. The information on the quinone-binding sites obtained in this way is expected to be both complementary and supplementary to that which will be obtained in the future by mutagenesis and X-ray crystallography.

Amino Acid Sequence↗
PubMed1993

Complex I and complex III of mitochondria have common inhibitors acting as ubiquinone antagonists.

Mitochondrial complex I and complex III have common inhibitors with ubiquinone-like structure. The tridecyl analog of stigmatellin, which inhibits mitochondrial complex III at nanomolar concentrations, also inhibits the NADH:ubiquinone reductase activity of complex I at micromolar concentrations. The inhibitor titer depends upon the concentration of the mitochondrial particles and extrapolates to 0.2 microM at zero particle concentration. The stigmatellin analog is more powerful than its parent compound and is noncompetitive with exogenous ubiquinones, rotenone and piericidin. Myxothiazol, which is another potent inhibitor of complex III, is also found to inhibit the activity of complex I with a titer comparable to that of the tridecyl analog of stigmatellin. Additionally, piericidin, which is the most powerful inhibitor of complex I, inhibits the ubiquinol:cytochrome c reductase activity of complex III at micromolar concentrations in mitochondrial particles and at submicromolar concentrations in the isolated enzyme complex.

Animals↗
PubMed1992

Cytochrome b of fish mitochondria is strongly resistant to funiculosin, a powerful inhibitor of respiration.

We report here some unusual properties of ubiquinol: cytochrome c reductase of eel and other fish mitochondria. The turnover rate of the reductase is clearly higher than in mammalian mitochondria and the binding constant for ubiquinone seems to be larger than in other vertebrates. Additionally, the reductase activity of fish mitochondria is resistant to some powerful inhibitors that bind to cytochrome b, in particular to funiculosin. After sequencing most of the gene of eel cytochrome b and comparing the deduced amino acid sequence with that of other fish and animals, we hypothesize that the decreased binding of funiculosin could be due to a few amino acid replacements in the third and fourth transmembrane helix of the protein. In particular, the presence of methionine instead of alanine at position 125 seems to be largely responsible for the strong resistance to funiculosin and also to the partial resistance to myxothiazol in all fish mitochondria. Correlations between some residue substitutions in cytochrome b and the different effects of funiculosin in different species are also considered.

Amino Acid Sequence↗
PubMed1992

Cytochrome b of protozoan mitochondria: relationships between function and structure.

1. The sensitivity of ubiquinol:cytochrome c reductase to its most powerful inhibitors has been characterized in mitochondria from three ciliate and two trypanosome protozoans and compared with that in mitochondria of animals and plants. 2. Mitochondria of ciliates, particularly those of Tetrahymena pyriformis, are resistant to antimycin. 3. Mitochondria of trypanosomes are quite resistant to stigmatellin, as they exhibit a 40-fold higher titer than that in ciliate or animals mitochondria. 4. Both ciliates and trypanosomes are highly resistant to myxothiazol. 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.

Amino Acid Sequence↗
PubMed1990

The cytochrome b of the sea urchin Paracentrotus lividus is naturally resistant to myxothiazol and mucidin.

The ubiquinol:cytochrome c reductase activity of Paracentrotus lividus mitochondria is relatively insensitive to the specific inhibitors myxothiazol and mucidin. The I50 of myxothiazol and mucidin are three and two orders of magnitude higher, respectively, in P. lividus than in bovine heart mitochondria. The natural resistance of the P. lividus reductase to these inhibitors can be correlated with a single amino replacement, an alanine for a glycine at position 143, in the sequence of cytochrome b. This position is located in a conserved region of the molecule, believed to be important in the oxidation of ubiquinol by the reductase.

Alkenes↗
PubMedDate not supplied

New approaches to the prediction of the folding of membrane proteins with redox function.

A new method is elaborated for determining the hydropathy profile of membrane haemoproteins. The method is called membrane propensity for haemoproteins (MPH) and is based on the statistical analysis of the amino acid composition of the predicted transmembrane regions of cytochrome b from the bc1 and the b6f complexes. The accuracy of the MPH method in predicting the ends of the known transmembrane segments of the reaction center of Rhodopseudomonas viridis is higher than that obtained by hydropathy methods based on physico-chemical parameters. The MPH method is able to clearly exclude from the membrane polypeptides that are not consistently predicted to be transmembrane by other methods or techniques, for instance the region corresponding to helix IV of mitochondrial cytochrome b. A correlation has been found between the shape of the hydropathy profile of the transmembrane segments predicted by this new method and the known structure of the membrane-spanning helices of Rhodobacter reaction centers. From the above correlation it is proposed that the haem-coordinating domain of mitochondrial cytochrome b is folded in a novel structure, called "clepsydra domain", which is formed by distorted transmembrane helices packed in a waisted antiparallel bundle.

Amino Acids↗