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Critical Reviews in Oncology/hematology Oct 2021Herbs, food and dietary supplements (HFDS), can interact significantly with anticancer drug treatments via cytochrome p450 isoforms (CYP) CYP3A4, CYP2D6, CYP1A2, and... (Review)
Review
Herbs, food and dietary supplements (HFDS), can interact significantly with anticancer drug treatments via cytochrome p450 isoforms (CYP) CYP3A4, CYP2D6, CYP1A2, and CYP2C8. The objective of this review was to assess the influence of HFDS compounds on these cytochromes. Interactions with CYP activities were searched for 189 herbs and food products, 72 dietary supplements in Web of Knowledge® databases. Analyses were made from 140 of 3125 clinical trials and 236 of 3374 in vitro, animal model studies or case reports. 18 trials were found to report direct interactions between 9 HFDS with 8 anticancer drugs. 21 HFDS were found to interact with CYP3A4, a major metabolic pathway for many anticancer drugs. All 261 HFDS were classified for their interaction with the main cytochromes P450 involved in the metabolism of anticancer drugs. We provided an easy-to-use colour-coded table to easily match potential interactions between 261 HFDS and 117 anticancer drugs.
Topics: Animals; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Dietary Supplements; Humans; Inactivation, Metabolic; Neoplasms
PubMed: 33930533
DOI: 10.1016/j.critrevonc.2021.103342 -
Molecular Biology and Evolution Jul 2022Multiheme cytochromes play key roles in diverse biogeochemical cycles, but understanding the origin and evolution of these proteins is a challenge due to their ancient...
Multiheme cytochromes play key roles in diverse biogeochemical cycles, but understanding the origin and evolution of these proteins is a challenge due to their ancient origin and complex structure. Up until now, the evolution of multiheme cytochromes composed by multiple redox modules in a single polypeptide chain was proposed to occur by gene fusion events. In this context, the pentaheme nitrite reductase NrfA and the tetraheme cytochrome c554 were previously proposed to be at the origin of the extant octa- and nonaheme cytochrome c involved in metabolic pathways that contribute to the nitrogen, sulfur, and iron biogeochemical cycles by a gene fusion event. Here, we combine structural and character-based phylogenetic analysis with an unbiased root placement method to refine the evolutionary relationships between these multiheme cytochromes. The evidence show that NrfA and cytochrome c554 belong to different clades, which suggests that these two multiheme cytochromes are products of truncation of ancestral octaheme cytochromes related to extant octaheme nitrite reductase and MccA, respectively. From our phylogenetic analysis, the last common ancestor is predicted to be an octaheme cytochrome with nitrite reduction ability. Evolution from this octaheme framework led to the great diversity of extant multiheme cytochromes analyzed here by pruning and grafting of protein modules and hemes. By shedding light into the evolution of multiheme cytochromes that intervene in different biogeochemical cycles, this work contributes to our understanding about the interplay between biology and geochemistry across large time scales in the history of Earth.
Topics: Cytochromes; Heme; Nitrite Reductases; Oxidation-Reduction; Phylogeny
PubMed: 35714268
DOI: 10.1093/molbev/msac139 -
Scientific Reports 2013Microsomal monoxygenase enzymes of the cytochrome-P450 family are found in all biological kingdoms, and play a central role in the breakdown of metabolic as well as...
Microsomal monoxygenase enzymes of the cytochrome-P450 family are found in all biological kingdoms, and play a central role in the breakdown of metabolic as well as xenobiotic, toxic and 70% of the drugs in clinical use. Full-length cytochrome-b5 has been shown to be important for the catalytic activity of cytochrome-P450. Despite the significance in understanding the interactions between these two membrane-associated proteins, only limited high-resolution structural information on the full-length cytochrome-P450 and the cytochromes-b5-P450 complex is available. Here, we report a structural study on a functional ~72-kDa cytochromes-b5-P450 complex embedded in magnetically-aligned bicelles without having to freeze the sample. Functional and solid-state NMR (Nuclear Magnetic Resonance) data reveal interactions between the proteins in fluid lamellar phase bilayers. In addition, our data infer that the backbone structure and geometry of the transmembrane domain of cytochrome-b5 is not significantly altered due to its interaction with cytochrome-P450, whereas the mobility of cytochrome-b5 is considerably reduced.
Topics: Cytochrome P-450 Enzyme System; Cytochromes b5; Membrane Proteins; Nuclear Magnetic Resonance, Biomolecular; Protein Binding
PubMed: 23985776
DOI: 10.1038/srep02538 -
Journal of Bacteriology Dec 2022Reduction of extracellular acceptors requires electron transfer across the periplasm. In Geobacter sulfurreducens, three separate cytoplasmic membrane cytochromes are...
Reduction of extracellular acceptors requires electron transfer across the periplasm. In Geobacter sulfurreducens, three separate cytoplasmic membrane cytochromes are utilized depending on redox potential, and at least five cytochrome conduits span the outer membrane. Because G. sulfurreducens produces 5 structurally similar triheme periplasmic cytochromes (PpcABCDE) that differ in expression level, midpoint potential, and heme biochemistry, many hypotheses propose distinct periplasmic carriers could be used for specific redox potentials, terminal acceptors, or growth conditions. Using a panel of marker-free single, quadruple, and quintuple mutants, little support for these models could be found. Three quadruple mutants containing only one paralog (PpcA, PpcB, and PpcD) reduced Fe(III) citrate and Fe(III) oxide at the same rate and extent, even though PpcB and PpcD were at much lower periplasmic levels than PpcA. Mutants containing only PpcC and PpcE showed defects, but these cytochromes were nearly undetectable in the periplasm. When expressed sufficiently, PpcC and PpcE supported wild-type Fe(III) reduction. PpcA and PpcE from similarly restored metal respiration in G. sulfurreducens. PgcA, an unrelated extracellular triheme -type cytochrome, also participated in periplasmic electron transfer. While triheme cytochromes were important for metal reduction, sextuple Δ Δ mutants grew near wild-type rates with normal cyclic voltammetry profiles when using anodes as electron acceptors. These results reveal broad promiscuity in the periplasmic electron transfer network of metal-reducing and suggest that an as-yet-undiscovered periplasmic mechanism supports electron transfer to electrodes. Many inner and outer membrane cytochromes used by for electron transfer to extracellular acceptors have specific functions. How these are connected by periplasmic carriers remains poorly understood. G. sulfurreducens contains multiple triheme periplasmic cytochromes with unique biochemical properties and expression profiles. It is hypothesized that each could be involved in a different respiratory pathway, depending on redox potential or energy needs. Here, we show that periplasmic cytochromes instead show evidence of being highly promiscuous. Any of 6 triheme cytochromes supported similar growth with soluble or insoluble metals, but none were required when cells utilized electrodes. These findings fail to support many models of electron transfer, and question why these organisms produce such an array of periplasmic cytochromes.
Topics: Geobacter; Periplasm; Ferric Compounds; Electrons; Electron Transport; Cytochromes; Oxidation-Reduction
PubMed: 36383007
DOI: 10.1128/jb.00322-22 -
Redox Biology 2014Autoimmune reactions involving cytochrome P4502E1 (CYP2E1) are a feature of idiosyncratic liver injury induced by halogenated hydrocarbons and isoniazid, but are also... (Review)
Review
Autoimmune reactions involving cytochrome P4502E1 (CYP2E1) are a feature of idiosyncratic liver injury induced by halogenated hydrocarbons and isoniazid, but are also detectable in about one third of the patients with advanced alcoholic liver disease (ALD) and chronic hepatitis C (CHC). In these latter the presence of anti-CYP2E1 auto-antibodies is an independent predictor of extensive necro-inflammation and fibrosis and worsens the recurrence of hepatitis following liver transplantation, indicating that CYP2E1-directed autoimmunity can contribute to hepatic injury. The molecular characterization of the antigens recognized by anti-CYP2E1 auto-antibodies in ALD and CHC has shown that the targeted conformational epitopes are located in close proximity on the molecular surface. Furthermore, these epitopes can be recognized on CYP2E1 expressed on hepatocyte plasma membranes where they can trigger antibody-mediated cytotoxicity. This does not exclude that T cell-mediated responses against CYP2E1 might also be involved in causing hepatocyte damage. CYP2E1 structural modifications by reactive metabolites and molecular mimicry represent important factors in the breaking of self-tolerance against CYP2E1 in, respectively, ALD and CHC. However, genetic or acquired interferences with the mechanisms controlling the homeostasis of the immune system are also likely to contribute. More studies are needed to better characterize the impact of anti-CYP2E1 autoimmunity in liver diseases particularly in relation to the fact that common metabolic alterations such as obesity and diabetes stimulates hepatic CYP2E1 expression.
Topics: Animals; Autoantibodies; Autoimmune Diseases; Autoimmunity; Cytochrome P-450 CYP2E1; Cytochromes; Epitopes; Humans; Immune Tolerance; Liver Diseases
PubMed: 25462068
DOI: 10.1016/j.redox.2014.11.004 -
Genome Biology and Evolution Aug 2021During photosynthesis, electrons are transferred between the cytochrome b6f complex and photosystem I. This is carried out by the protein plastocyanin in plant...
During photosynthesis, electrons are transferred between the cytochrome b6f complex and photosystem I. This is carried out by the protein plastocyanin in plant chloroplasts, or by either plastocyanin or cytochrome c6 in many cyanobacteria and eukaryotic algal species. There are three further cytochrome c6 homologs: cytochrome c6A in plants and green algae, and cytochromes c6B and c6C in cyanobacteria. The function of these proteins is unknown. Here, we present a comprehensive analysis of the evolutionary relationship between the members of the cytochrome c6 family in photosynthetic organisms. Our phylogenetic analyses show that cytochromes c6B and c6C are likely to be orthologs that arose from a duplication of cytochrome c6, but that there is no evidence for separate origins for cytochromes c6B and c6C. We therefore propose renaming cytochrome c6C as cytochrome c6B. We show that cytochrome c6A is likely to have arisen from cytochrome c6B rather than by an independent duplication of cytochrome c6, and present evidence for an independent origin of a protein with some of the features of cytochrome c6A in peridinin dinoflagellates. We conclude with a new comprehensive model of the evolution of the cytochrome c6 family which is an integral part of understanding the function of the enigmatic cytochrome c6 homologs.
Topics: Cytochromes; Cytochromes c6; Electron Transport; Electrons; Photosynthesis; Phylogeny
PubMed: 34165554
DOI: 10.1093/gbe/evab146 -
Biochimica Et Biophysica Acta.... Dec 2020In oxidative phosphorylation, the transfer of electrons from reduced cofactors to molecular oxygen via the electron transport chain (ETC) sustains the electrochemical...
In oxidative phosphorylation, the transfer of electrons from reduced cofactors to molecular oxygen via the electron transport chain (ETC) sustains the electrochemical transmembrane potential needed for ATP synthesis. A key component of the ETC is complex III (CIII, cytochrome bc), which transfers electrons from reduced ubiquinone to soluble cytochrome c (Cc) coupled to proton translocation into the mitochondrial intermembrane space. One electron from every two donated by hydroquinone at site P is transferred to Cc via the Rieske-cytochrome c (Cc) pathway. According to recent structural analyses of CIII and its transitory complex with Cc, the interaction between the Rieske subunit and Cc switches intermittently during CIII activity. However, the electrochemical properties of Cc and their function as a wire between Rieske and Cc are rather unexplored. Here, temperature variable cyclic voltammetry provides novel data on the thermodynamics and kinetics of interfacial electron transfer of immobilized Cc. Findings reveal that Cc displays two channels for electron exchange, with a remarkably fast heterogeneous electron transfer rate. Furthermore, the electrochemical properties are strongly modulated by the binding mode of the protein. Additionally, we show that electron transfer from Cc to Cc is thermodynamically favored in the immobilized Cc-Cc complex. Nuclear Magnetic Resonance, HADDOCK, and Surface Plasmon Resonance experiments provide further structural and functional data of the Cc-Cc complex. Our data supports the Rieske-Cc-Cc pathway acting as a unilateral switch thyristor in which redox potential modulation through protein-protein contacts are complemented with the relay-like Rieske behavior.
Topics: Adsorption; Biophysical Phenomena; Cytochromes c; Cytochromes c1; Electrochemistry; Electron Transport; Humans; Immobilized Proteins; Kinetics; Magnetic Resonance Spectroscopy; Models, Molecular; Oxidation-Reduction; Protein Domains; Recombinant Proteins; Solubility; Thermodynamics
PubMed: 32717223
DOI: 10.1016/j.bbabio.2020.148277 -
Microbiology and Molecular Biology... Sep 1997Biogenesis of respiratory cytochromes is defined as consisting of the posttranslational processes that are necessary to assemble apoprotein, heme, and sometimes... (Review)
Review
Biogenesis of respiratory cytochromes is defined as consisting of the posttranslational processes that are necessary to assemble apoprotein, heme, and sometimes additional cofactors into mature enzyme complexes with electron transfer functions. Different biochemical reactions take place during maturation: (i) targeting of the apoprotein to or through the cytoplasmic membrane to its subcellular destination; (ii) proteolytic processing of precursor forms; (iii) assembly of subunits in the membrane and oligomerization; (iv) translocation and/or modification of heme and covalent or noncovalent binding to the protein moiety; (v) transport, processing, and incorporation of other cofactors; and (vi) folding and stabilization of the protein. These steps are discussed for the maturation of different oxidoreductase complexes, and they are arranged in a linear pathway to best account for experimental findings from studies concerning cytochrome biogenesis. The example of the best-studied case, i.e., maturation of cytochrome c, appears to consist of a pathway that requires at least nine specific genes and more general cellular functions such as protein secretion or the control of the redox state in the periplasm. Covalent attachment of heme appears to be enzyme catalyzed and takes place in the periplasm after translocation of the precursor through the membrane. The genetic characterization and the putative biochemical functions of cytochrome c-specific maturation proteins suggest that they may be organized in a membrane-bound maturase complex. Formation of the multisubunit cytochrome bc, complex and several terminal oxidases of the bo3, bd, aa3, and cbb3 types is discussed in detail, and models for linear maturation pathways are proposed wherever possible.
Topics: Amino Acid Sequence; Bacteria; Cytochromes; Escherichia coli; Molecular Sequence Data; Oxygen; Sequence Alignment
PubMed: 9293186
DOI: 10.1128/mmbr.61.3.337-376.1997 -
Biological Chemistry May 2013Aerobic respiration, the energetically most favorable metabolic reaction, depends on the action of terminal oxidases that include cytochrome c oxidases. The latter forms... (Review)
Review
Aerobic respiration, the energetically most favorable metabolic reaction, depends on the action of terminal oxidases that include cytochrome c oxidases. The latter forms a part of the heme-copper oxidase superfamily and consists of three different families (A, B, and C types). The crystal structures of all families have now been determined, allowing a detailed structural comparison from evolutionary and functional perspectives. The A2-type oxidase, exemplified by the Thermus thermophilus caa(3) oxidase, contains the substrate cytochrome c covalently bound to the enzyme complex. In this article, we highlight the various features of caa(3) enzyme and provide a discussion of their importance, including the variations in the proton and electron transfer pathways.
Topics: Amino Acid Sequence; Cytochrome c Group; Cytochromes a; Cytochromes a3; Electron Transport Complex IV; Models, Chemical; Molecular Sequence Data; Molecular Structure; Substrate Specificity; Thermus thermophilus
PubMed: 23399637
DOI: 10.1515/hsz-2012-0343 -
Protein & Cell Jun 2012Cytochromes c covalently bind their heme prosthetic groups through thioether bonds between the vinyl groups of the heme and the thiols of a CXXCH motif within the... (Review)
Review
Cytochromes c covalently bind their heme prosthetic groups through thioether bonds between the vinyl groups of the heme and the thiols of a CXXCH motif within the protein. In Gram-negative bacteria, this process is catalyzed by the Ccm (cytochrome c maturation) proteins, also called System I. The Ccm proteins are found in the bacterial inner membrane, but some (CcmE, CcmG, CcmH, and CcmI) also have soluble functional domains on the periplasmic face of the membrane. Elucidation of the mechanisms involved in the transport and relay of heme and the apocytochrome from the bacterial cytosol into the periplasm, and their subsequent reaction, has proved challenging due to the fact that most of the proteins involved are membrane-associated, but recent progress in understanding some key components has thrown up some surprises. In this Review, we discuss advances in our understanding of this process arising from a substrate's point of view and from recent structural information about individual components.
Topics: Cytochromes c; Models, Biological
PubMed: 22723177
DOI: 10.1007/s13238-012-2912-x