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PubMed2002

The metal reductase activity of some multiheme cytochromes c: NMR structural characterization of the reduction of chromium(VI) to chromium(III) by cytochrome c(7).

The redox reaction between CrO(4)(2-) and the fully reduced three-heme cytochrome c(7) from Desulfuromonas acetoxidans to give chromium(III) and the fully oxidized protein has been followed by NMR spectroscopy. The hyperfine coupling between the oxidized protein protons and chromium(III), which remains bound to the protein, gives rise to line-broadening effects on the NMR resonances that can be transformed into proton-metal distance restraints. Structure calculations based on these unconventional constraints allowed us to demonstrate that chromium(III) binds at a unique site and to locate it on the protein surface. The metal ion is located 7.9 +/- 0.4 A from the iron of heme IV, 16.3 +/- 0.7 A from the iron of heme III, and 22.5 +/- 0.5 A from the iron of heme I. Shift changes caused by the presence of unreactive MoO(4)(2-), a CrO(4)(2-) analogue, indicate the involvement of the same protein area in the anion binding. The titration of the oxidation of cytochrome c(7) shows a detailed mechanism of action. The presence of a specific binding site supports the hypothesis of the biological role of this cytochrome as a metal reductase.

Binding Sites↗
PubMed2002

Functional coadaptation between cytochrome c and cytochrome c oxidase within allopatric populations of a marine copepod.

Geographically isolated populations may accumulate alleles that function well on their own genetic backgrounds but poorly on the genetic backgrounds of other populations. Consequently, interpopulation hybridization may produce offspring of low fitness as a result of incompatibilities arising in allopatry. Genes participating in these epistatic incompatibility systems remain largely unknown. In fact, despite the widely recognized importance of epistatic interactions among gene products, few data directly address the functional consequences of such interactions among natural genetic variants. In the marine copepod, Tigriopus californicus, we found that the cytochrome c variants isolated from two different populations each had significantly higher activity with the cytochrome c oxidase derived from their respective source population. Three amino acid substitutions in the cytochrome c protein appear to be sufficient to confer population specificity. These results suggest that electron transport system (ETS) proteins form coadapted sets of alleles within populations and that disruption of the coadapted ETS gene complex leads to functional incompatibilities that may lower hybrid fitness.

Analysis of Variance↗
PubMed1982

Primary structure of a cytochrome P-450: coding nucleotide sequence of phenobarbital-inducible cytochrome P-450 cDNA from rat liver.

We determined the coding nucleotide sequence of phenobarbital-inducible cytochrome P-450 mRNA of the rat by analysis of three cloned cDNAs and by primer extension methods. The deduced amino acid sequence of the cytochrome is composed of 491 amino acids, and its predicted molecular weight and amino acid composition concur with those determined with the purified protein. The sequence of one of the three cloned cDNAs is not identical with that of the other two. In their 922 overlapping nucleotides, 14 nucleotide substitutions occur, and 7 of them result in 6 amino acid changes, therefore indicating the presence of at least two similar but distinct mRNAs for phenobarbital-inducible cytochrome P-450. These substitutions occur in a limited portion of the sequence, apparently forming some sort of a "variable region."

Amino Acid Sequence↗
PubMed1996

Peroxo-iron and oxenoid-iron species as alternative oxygenating agents in cytochrome P450-catalyzed reactions: switching by threonine-302 to alanine mutagenesis of cytochrome P450 2B4.

Among biological catalysts, cytochrome P450 is unmatched in its multiplicity of isoforms, inducers, substrates, and types of chemical reactions catalyzed. In the present study, evidence is given that this versatility extends to the nature of the active oxidant. Although mechanistic evidence from several laboratories points to a hypervalent iron-oxenoid species in P450-catalyzed oxygenation reactions, Akhtar and colleagues [Akhtar, M., Calder, M. R., Corina, D. L. & Wright, J. N. (1982) Biochem. J. 201, 569-580] proposed that in steroid deformylation effected by P450 aromatase an iron-peroxo species is involved. We have shown more recently that purified liver microsomal P450 cytochromes, including phenobarbital-induced P450 2B4, catalyze the analogous deformylation of a series of xenobiotic aldehydes with olefin formation. The investigation presented here on the effect of site-directed mutagenesis of threonine-302 to alanine on the activities of recombinant P450 2B4 with N-terminal amino acids 2-27 deleted [2B4 (delta2-27)] makes use of evidence from other laboratories that the corresponding mutation in bacterial P450s interferes with the activation of dioxygen to the oxenoid species by blocking proton delivery to the active site. The rates of NADPH oxidation, hydrogen peroxide production, and product formation from four substrates, including formaldehyde from benzphetamine N-demethylation, acetophenone from 1-phenylethanol oxidation, cyclohexanol from cyclohexane hydroxylation, and cyclohexene from cyclohexane carboxaldehyde deformylation, were determined with P450s 2B4, 2B4 (delta2-27), and 2B4 (delta2-27) T302A. Replacement of the threonine residue in the truncated cytochrome gave a 1.6- to 2.5-fold increase in peroxide formation in the presence of a substrate, but resulted in decreased product formation from benzphetamine (9-fold), cyclohexane (4-fold), and 1-phenylethanol (2-fold). In sharp contrast, the deformylation of cyclohexane carboxaldehyde by the T302A mutant was increased about 10-fold. On the basis of these findings and our previous evidence that aldehyde deformylation is supported by added H202, but not by artificial oxidants, we conclude that the iron-peroxy species is the direct oxygen donor. It remains to be established which of the many other oxidative reactions involving P450 utilize this species and the extent to which peroxo-iron and oxenoid-iron function as alternative oxygenating agents with the numerous isoforms of this versatile catalyst.

Animals↗
PubMed2004

Two sites of interaction of anions with cytochrome a in oxidized bovine cytochrome c oxidase.

An interaction between cytochrome a in oxidized cytochrome c oxidase (CcO) and anions has been characterized by EPR spectroscopy. Those anions that affect the EPR g = 3 signal of cytochrome a can be divided into two groups. One group consists of halides (Cl-, Br-, and I-) and induces an upfield shift of the g = 3 signal. Nitrogen-containing anions (CN-, NO2-, N3-, NO3-) are in the second group and shift the g = 3 signal downfield. The shifts in the EPR spectrum of CcO are unrelated to ligand binding to the binuclear center. The binding properties of one representative from each group, azide and chloride, were characterized in detail. The dependence of the shift on chloride concentration is consistent with a single binding site in the isolated oxidized enzyme with a Kd of approximately 3 mm. In mitochondria, the apparent Kd was found to be about four times larger than that of the isolated enzyme. The data indicate it is the chloride anion that is bound to CcO, and there is a hydrophilic size-selective access channel to this site from the cytosolic side of the mitochondrial membrane. An observed competition between azide and chloride is interpreted by azide binding to three sites: two that are apparent in the x-ray structure plus the chloride-binding site. It is suggested that either Mg2+ or Arg-438/Arg-439 is the chloride-binding site, and a mechanism for the ligand-induced shift of the g = 3 signal is proposed.

Animals↗
PubMed1998

Baculovirus-mediated expression of cytochrome P4502C8 and human NADPH-cytochrome P450 reductase: optimization of protein expression.

1. High expression levels of cytochrome P450 (CYP) 2C8 and NADPH-cytochrome P450 oxidoreductase (OxR) in Spodoptera frugiperda (Sf21) cells have been achieved using the baculovirus expression system. 2. The baculovirus dual expression plasmid, pAcUW31, was used to insert CYP2C8 and OxR cDNAs downstream of the polyhedrin (polh) or p10 promoters, either separately or together, generating four recombinant baculoviruses; two expressing single proteins (CYP2C8 driven by the p10 promoter, bVp10.2C8 or OxR driven by the polh promoter, bVpolh.OxR) with another two coexpressing both CYP2C8 and OxR under reciprocal control of the polh and p10 promoters (bVpolh.OxR-p10.2C8 and bVpolh.2C8-p10.OxR). 3. High levels of singly expressed CYP2C8 and OxR were achieved from bVp10.2C8 and bVpolh.OxR, with levels of 0.7-1.2 nmol CYP/mg protein and 400-500 nmol cytochrome c reduced/min/mg protein respectively. 4. The two dual gene clones (bVpolh.OxR-p10.2C8 and bVpolh.2C8-p10.OxR) showed, in general, greater variation in CYP content and OxR activity than single gene clones. Screening was therefore necessary for the selection of dual gene clones expressing both proteins optimally. 5. Sf21 microsomes infected by selected dual gene clones were, on average, 14 times more active in tolbutamide hydroxylase activity than those expressing CYP2C8 alone, with a mean spectral CYP content of 79 pmol/mg cell lysate protein and a mean OxR level of 600 nmol/min/mg cell lysate protein.

Animals↗
PubMed1991

A tobacco smoke-derived nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, is activated by multiple human cytochrome P450s including the polymorphic human cytochrome P4502D6.

We have developed a human B-lymphoblastoid cell line, designated 2D6/Hol, which stably expresses human cytochrome P450 CYP2D6 cDNA. This cell line exhibits bufuralol 1'-hydroxylase activity and immunologically detectable CYP2D6 protein. The specific activity of (+)-bufuralol 1'-hydroxylase in microsomes from 2D6/Hol cells was comparable to that observed in human liver microsomes. This cell line was used to examine the mutagenicity activation of three tobacco smoke-derived nitrosamines, N-nitrosonornicotine (NNN), 1-(N-methyl-N-nitrosamino)-1-(3-pyridinyl)-4-butanal) (NNA) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), by CYP2D6. Exposure of 2D6/Hol cells to NNK concentrations of 30-90 micrograms/ml induced a concentration-dependent decrease in relative survival and increase in mutant fraction at the hypoxanthine guanine phosphoribosyl transferase (hprt) locus. In contrast, NNK was non-mutagenic and non-cytotoxic to control cells at exposure concentrations up to 150 micrograms/ml. NNK mutagenicity in 2D6/Hol cells was compared to the responses observed in isogenic cell lines expressing human CYP1A2 (1A2/Hol), human CYP2A3 (2A3/Hol) and human CYP2E1 (2E1/Hol). These three additional human cytochrome P450-expressing cell lines were also found to be sensitive to NNK-induced mutagenicity and cytotoxicity. We found no evidence for CYP2D6-mediated activation of NNN or NNA. NNN was non-cytotoxic and non-mutagenic to both control and 2D6/Hol cells. NNA was equally cytotoxic and mutagenic to control cells and 2D6/Hol cells. The activation of NNA to a mutagen may have been carried out by P450 native to the AHH-1 TK +/- cell line. The 2D6/Hol cell line, in conjunction with the control cell line and other isogenic cell lines expressing other human cytochrome P450 cDNAs provides a useful system for the examination of the role of the polymorphic CYP2D6 in human procarcinogen activation and drug metabolism.

Biotransformation↗
PubMed1985

Regulation and expression of four cytochrome P-450 isoenzymes, NADPH-cytochrome P-450 reductase, the glutathione transferases B and C and microsomal epoxide hydrolase in preneoplastic and neoplastic lesions in rat liver.

Nitrosamine-induced hepatocarcinogenesis has been used to investigate the regulation and expression of different drug-metabolizing enzymes in preneoplastic and neoplastic lesions in the female Wistar rat. The enzymes investigated were two phenobarbital-inducible cytochrome P-450 (cyt. P-450) isoenzymes (PB1 and PB2, mol. wt. 52 000 and 53 500, respectively), two 3-methylcholanthrene-inducible forms (MC1 and MC2, mol. wt. 54 500 and 57 000, respectively), NADPH-cytochrome P-450 reductase, the cytosolic glutathione transferases (GSTs) B and C and the microsomal epoxide hydrolase with broad substrate specificity (mEHb). Carcinogen-induced lesions were identified by use of the known markers of hepatocarcinogenesis adenosinetriphosphatase and gamma-glutamyl transpeptidase. While the GSTs and mEHb were increased in all preneoplastic and neoplastic lesions, the levels of the individual cyt. P-450 isoenzymes were characteristically different from each other. In many of the early ATPase deficient islets PB1 was elevated, whereas the content of the other cyt. P-450 forms and NADPH-cytochrome P-450 reductase was either unchanged or slightly lowered. At later stages of hepatocarcinogenesis PB1 returned to the levels of the surrounding tissue, while the other cyt. P-450 isoenzymes were decreased, the most prominent reduction being found in MC1. In neoplastic nodules all the cyt. P-450s and NADPH-cyt. P-450 reductase were diminished, some of them dramatically. These findings indicate that in spite of a common response of groups of P-450s to inducing agents, individual P-450 isoenzymes are also regulated separately. Moreover, the constant elevation of mEHb and GSTs in all lesions investigated in this study demonstrates that these enzymes, which are largely involved in deactivation, are regulated in a different fashion from the predominantly carcinogen-activating monooxygenases. The observed differences in enzyme pattern may provide a useful method for subdividing and categorizing preneoplastic and neoplastic lesions.

Animals↗
PubMed1986

Characterization by EPR spectroscopy of cytochrome b-562 isolated from the cytochrome b-c1 complex of Rhodopseudomonas sphaeroides R-26.

The EPR spectra of cytochrome b-562 isolated from the cytochrome b-c1 complex of Rhodopseudomonas sphaeroides were measured at liquid helium temperature. The purified cytochrome b-562 gives a high spin signal at g = 6.0. Anaerobic titration of this signal confirmed the presence of two redox components with Em = 40 and -110 mV at pH 7.5. These values are consistent with the published ones, Em = 55 and -100 mV at pH 7.0, that were optically estimated for the same type of preparation (Iba et al. (1985) FEBS Lett. 183, 151-154). The power saturation behavior of the g = 6.0 signal at different redox potentials indicated a direct spin-spin interaction between these two redox centers.

Cytochrome b Group↗
PubMed1981

Studies on algal cytochromes. III. Amino acid sequence of cytochrome c-553 from a brown alga, Petalonia fascia.

The amino acid sequence of a photosynthetic cytochrome c-553 isolated from a brown alga, Petalonia fascia was determined by BrCN fragmentation and a solid phase Edman degradation. The cytochrome contains 85 amino acid residues, giving a molecular weight of 9,803. The complete amino acid sequence is as follows: Val-Asp-Ile-Asn-Asn-Gly-Glu-Ser-Val-Phe-Thr-Ala-Asn-Cys-Ser-Ala-Cys-His-Ala-Gly -Gly-Asn-Asn-Val-Ile-Met-Pro-Glu-Lys-Thr-Leu-Lys-Lys-Asp-Ala-Leu-Glu-Glu-Asn-Gl u-Met-Asn-Asn-Ile-Lys-Ser-Ile-Thr-Tyr-Gln-Val-Thr-Asn-Gly-Lys-Asn-Ala-Met-Pro-A la-Phe-Gly-Gly-Arg-Leu-Ser-Glu-Thr-Asp-Ile-Glu-Asp-Val-Ala-Asn-Phe-Val-Ile-Ser-Gln-Ser-Gln-Lys-Gly-Trp. The highest homology was found between the sequences of cytochromes c-553 of P. fascia and Alaria esculenta, the next between those of P. fascia and Porphyria tenera.

Amino Acid Sequence↗
PubMed1984

Studies on algal cytochromes. V. Purification and characterization of cytochrome c-552 from a red alga, Polysiphonia urceolata.

Cytochrome c-552 was extracted from a red alga, Polysiphonia urceolata, by immersion of the frozen trichomes in deionized water. Purification was carried out by acrinol treatment, ammonium sulfate fractionation, DEAE-Sephacel chromatography, hydroxyapatite column chromatography, and Bio-Gel P-10 gel filtration. The ferrocytochrome c-552 has absorption maxima at 551.5(alpha), 522.5(beta), 416.3(gamma), 318(delta), 292, and 270 nm; those of the ferricytochrome are at 525, 408.5(gamma), and 358 nm. The pyridine ferrohemochrome showed absorption maxima at 550(alpha), 520(beta), and 414 nm(gamma). The alpha-band of the ferrocytochrome is symmetric without any shoulder at room temperature, and does not split even at liquid nitrogen temperature. The ferricytochrome showed a weak absorption shoulder at 695 nm, suggesting a methionine sulfur to be the sixth ligand of heme c iron. The cytochrome is oxidized by ferricyanide and reduced by ferrocyanide, cysteine, ascorbate, and hydrosulfite. Autoxidation was not observed. The midpoint potential (Em) of the cytochrome was determined by equilibration with the ferro- and ferricyanide system to be 0.333 volt at pH 7.0 and 25 degrees C. The isoelectric points of the ferro- and ferricytochromes were determined to be at pH 3.85 and 4.02, respectively, by the isoelectric focusing method. The molecular weight was estimated to be about 12,000 from the results of gel filtration and SDS polyacrylamide gel electrophoresis.

Cytochrome c Group↗
PubMed1995

A gene encoding a cytochrome c oxidase-like protein is located closely to the cytochrome c-553 gene in the anaerobic bacterium, Desulfovibrio vulgaris (Miyazaki F).

The gene encoding cytochrome c-553 from Desulfovibrio vulgaris (Miyazaki F) was cloned using a synthetic oligodeoxyribonucleotide probe. The nucleotide sequence indicated that cytochrome c-553 was synthesized as a precursor protein with an NH2-terminal signal sequence of 23 residues. In the cloned DNA fragment, there are three other open reading frames whose products have 191, 157, 541 amino acid residues, respectively. The putative ORF-4 product is highly homologous with the cytochrome c oxidase subunit I from various organisms.

Amino Acid Sequence↗
PubMed1988

The immunocytochemical localisation and distribution of cytochrome P-450 in normal human hepatic and extrahepatic tissues with a monoclonal antibody to human cytochrome P-450.

1. The localisation and distribution of cytochrome P-450 in human tissues has been studied by immunocytochemistry using a monoclonal antibody to a major form of human hepatic cytochrome P-450, P-450hA7, which is closely related to cytochromes P-450 HLp and P-450NF. 2. Strong immunoreactivity was identified in hepatocytes, columnar absorptive epithelial cells of the small intestine, polymorphonuclear leucocytes and their precursors in the bone marrow, and in mast cells. 3. Weak immunoreactivity was present in the proximal tubules of the kidney, pancreatic acini, gall bladder epithelium, squamous epithelium and sebaceous glands of the skin, interstitial cells of the testis and luteal cells of the ovary. 4. Immunoreactivity could not be demonstrated in the adrenal gland, placenta, colonic epithelium and alveolar type II cells and Clara cells of the lung.

Adult↗
PubMed1995

Cloning and sequence analysis of cycH gene from Paracoccus denitrificans: the cycH gene product is required for assembly of all c-type cytochromes, including cytochrome c1.

A transposon Tn5 mutant of Paracoccus denitrificans, DP108, was incapable of anaerobic or methylotrophic growth and scored negative in the Nadi cytochrome c oxidase test. P. denitrificans DP108 grown aerobically on succinate or choline was devoid of soluble c-type cytochromes and accumulated periplasmic apocytochrome c550, but the membrane-bound holocytochromes c1 and c552 were present at 5-10% of the levels observed in wild-type cells. DP108 genomic DNA flanking the site of Tn5 insertion was cloned by marker rescue and used to probe a P. denitrificans wild-type DNA library. A hybridizing 3.05 kb BamHI fragment capable of complementing the DP108 mutation was isolated and a 2.05 kb region of this was sequenced. One major open reading frame equivalent to 413 amino acids was identified, the predicted product of which was similar (33% identity, 55% similarity) to the predicted product of the cycH gene previously identified in Bradyrhizobium japonicum. Similarity of the two cycH gene products to the predicted products of two Escherichia coli genes, nrfG and yejP, was also detected. Significant differences between the phenotypes of P. denitrificans DP108 and the B. japonicum cycH mutant COX3, especially with respect to cytochrome c1 synthesis, suggest that the cycH gene product may be an assembly factor.

Amino Acid Sequence↗
PubMed1985

Cytochrome P-450 isozyme/isozyme functional interactions and NADPH-cytochrome P-450 reductase concentrations as factors in microsomal metabolism of warfarin.

The basis for our previous observations [Kaminsky, L.S., Guengerich, F.P., Dannan, G.A. & Aust, S.D. (1983) Arch. Biochem. Biophys. 225, 398-404] that rates of microsomal metabolism of warfarin were markedly less than the sum of rates of the reconstituted constituent isozymes of cytochrome P-450 has been investigated. Metabolism of warfarin to 4'-, 6-, 7-, 8-, and 10-hydroxywarfarin and dehydrowarfarin by highly purified rat liver cytochrome P-450 (P-450) isozymes reconstituted with NADPH-cytochrome P-450 reductase and by hepatic microsomes from variously pretreated rats was used to probe functional consequences of P-450 isozyme/isozyme interactions and of the effect of microsomal reductase concentrations. Binary mixtures of P-450 isozymes were reconstituted and the regioselectivity and stereoselectivity were used to probe metabolism by each individual isozyme. The isozymes specifically inhibited each other to variable extents and the order of inhibitory potency was: P-450UT-F greater than P-450PB-D greater than or equal to P-450UT-A greater than or equal to P-450BNF/ISF-G greater than P-450PB/PCN-E greater than P-450PB-B greater than or equal to P-450PB-C greater than or equal to P-450BNF-B. The inhibition, possibly a consequence of aggregation, explains the low rate of microsomal metabolism relative to the metabolic potential of the component P-450 isozymes. When purified reductase was added to microsomes it appeared to bind to microsomes at different sites from endogenous reductase and it enhanced warfarin hydroxylase activity only to a minor extent, thus possibly precluding low reductase concentrations from being a major factor in the relatively low rates of microsomal metabolism. Antibody to the reductase differentially inhibited microsomal metabolism of warfarin by the various P-450 isozymes. The results suggest that the reductase and P-450 isozymes may be located differently relative to one another in the various microsomal preparations.

Animals↗
PubMed1985

Cytochrome b, the var 1 protein, and subunits I and III of cytochrome c oxidase are synthesized without transient presequences in Saccharomyces cerevisiae.

The N-termini of four mitochondrial translation products, the var 1 protein, cytochrome b, and subunits I and III of cytochrome c oxidase have been characterized in Saccharomyces cerevisiae and compared with the known DNA sequences of the respective structural genes. The four mature proteins correspond to the predicted primary translation products and retain the formylated methionine residue. Thus, subunit II of cytochrome c oxidase studied previously [Pratje et al. (1983) EMBO J.2, 1049-1054] is so far the only mitochondrial translation product carrying a N-terminal-extended transient presequence in S. cerevisiae.

Amino Acid Sequence↗
PubMed1987

The soluble c-type cytochromes from the bacterium Aquaspirillum itersonii. The complete amino acid sequence of the cytochrome c-550.

A complete amino acid sequence is proposed for the cytochrome c-550 isolated from the gram-negative chemo-organotrophic bacterium Aquaspirillum itersonii. The sequence, a single polypeptide chain of 111 residues, was deduced from the sequences of peptides obtained by tryptic, thermolytic or chymotryptic digestion. The cytochrome shows a high degree of sequence homology with the cytochrome c2 from the photosynthetic bacterium Rhodospirillum rubrum, and the evolutionary implications of this are considered.

Amino Acid Sequence↗
PubMed1988

EPR determination of interaction redox potentials in a multiheme cytochrome: cytochrome c3 from Desulfovibrio desulfuricans Norway.

In cytochromes c3 which contain four hemes per molecule, the redox properties of each heme may depend upon the redox state of the others. This effect can be described in terms of interaction redox potentials between the hemes and must be taken into account in the characterization of the redox properties of the molecule. We present here a method of measurement of these interactions based on the EPR study of the redox equilibria of the protein. The microscopic and macroscopic midpoint potentials and the interaction potentials are deduced from the analysis of the redox titration curves of the intensity and the amplitude of the EPR spectrum. This analysis includes a precise simulation of the spectrum of the protein in the oxidized state in order to determine the relative contribution of each heme to the spectral amplitude. Using our method on cytochrome c3 from D. desulfuricans Norway, we found evidence for the existence of weak interaction potentials between the hemes. The three interaction potentials which have been measured are characterized by absolute values lower than 20 mV in contrast with the values larger than 40-50 mV which have been reported for cytochrome c3 from D. gigas. Simulations of the spectra of samples poised at different potentials indicate a structural modification of the heme with the most negative potential during the first step of reduction. The correspondence between the redox sites as characterized by the EPR potentiometric titration and the hemes in the tridimensional structure is discussed.

Binding Sites↗