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Sam P De Visser - One of the best experts on this subject based on the ideXlab platform.

  • differences and comparisons of the properties and reactivities of iron iii hydroperoxo complexes with saturated coordination sphere
    Chemistry: A European Journal, 2015
    Co-Authors: Abayomi S Faponle, Matthew G Quesne, Chivukula V Sastri, Frederic Banse, Sam P De Visser
    Abstract:

    Heme and nonheme monoxygenases and dioxygenases catalyze important oxygen atom transfer reactions to substrates in the body. It is now well established that the cytochrome P450 enzymes react through the formation of a high-valent iron(IV)–oxo heme cation radical. Its precursor in the catalytic cycle, the iron(III)–hydroperoxo complex, was tested for catalytic activity and found to be a sluggish oxidant of Hydroxylation, epoxidation and sulfoxidation reactions. In a recent twist of events, evidence has emerged of several nonheme iron(III)–hydroperoxo complexes that appear to react with substrates via oxygen atom transfer processes. Although it was not clear from these studies whether the iron(III)–hydroperoxo reacted directly with substrates or that an initial O–O bond cleavage preceded the reaction. Clearly, the catalytic activity of heme and nonheme iron(III)–hydroperoxo complexes is substantially different, but the origins of this are still poorly understood and warrant a detailed analysis. In this work, an extensive computational analysis of Aromatic Hydroxylation by biomimetic nonheme and heme iron systems is presented, starting from an iron(III)–hydroperoxo complex with pentadentate ligand system (L52). Direct C–O bond formation by an iron(III)–hydroperoxo complex is investigated, as well as the initial heterolytic and homolytic bond cleavage of the hydroperoxo group. The calculations show that [(L52)FeIII(OOH)]2+ should be able to initiate an Aromatic Hydroxylation process, although a low-energy homolytic cleavage pathway is only slightly higher in energy. A detailed valence bond and thermochemical analysis rationalizes the differences in chemical reactivity of heme and nonheme iron(III)–hydroperoxo and show that the main reason for this particular nonheme complex to be reactive comes from the fact that they homolytically split the O–O bond, whereas a heterolytic O–O bond breaking in heme iron(III)–hydroperoxo is found.

  • axial ligand effect on the rate constant of Aromatic Hydroxylation by iron iv oxo complexes mimicking cytochrome p450 enzymes
    Journal of Physical Chemistry B, 2012
    Co-Authors: Narahari G Sastry, Devesh Kumar, Sam P De Visser
    Abstract:

    The cytochromes P450 are important iron-heme based monoxygenases that catalyze a range of different oxygen atom transfer reactions in nature. One of the key bioprocesses catalyzed by these enzymes is the Aromatic Hydroxylation of unactivated arenes. To gain insight into axial ligand effects and, in particular, how it affects Aromatic Hydroxylation processes by P450 model complexes, we studied the effects of the axial ligand on spectroscopic parameters (trans-influence) as well as on Aromatic Hydroxylation kinetics (trans-effect) using a range of [FeIV(O)(Por+•)X] oxidants with X = SH–, Cl–, F–, OH–, acetonitrile, GlyGlyCys–, CH3COO–, and CF3COO–. These systems give red-shifted Fe–O vibrations that are dependent on the strength of the axial ligand. Despite structural changes, however, the electron affinities of these oxidants are very close in energy, but sharp differences in pKa values are found. The Aromatic Hydroxylation of the para-position of ethylbenzene was tested with these oxidants, and they all s...

  • predictive studies of oxygen atom transfer reactions by compound i of cytochrome p450 aliphatic and Aromatic Hydroxylation epoxidation and sulfoxidation
    Advances in Inorganic Chemistry, 2012
    Co-Authors: Sam P De Visser
    Abstract:

    Abstract This review overviews recent density functional theory studies accompanied by valence bond (VB) modeling of the reactivity patterns of Compound I of cytochrome P450 and taurine/α-ketoglutarate dioxygenase. These two enzymes both have a high-valent iron(IV)–oxo species as their active intermediate and are involved in oxygen atom transfer reactions to substrates including aliphatic Hydroxylation, double-bond epoxidation, heteroatom oxidation (sulfoxidation), and Aromatic Hydroxylation. In recent years, a number of systematic studies on these four reaction mechanisms have been performed, and the barrier heights of the rate-determining steps in these reactions have been analyzed with VB models via curve-crossing diagrams. Those diagrams predict the overall mechanisms and explain the nature of the rate-determining step in the reaction through electron transfer processes. The computational models have gained insight into the fundamental factors that drive the reaction mechanisms and explain the differences between the various reaction processes.

  • how does the axial ligand of cytochrome p450 biomimetics influence the regioselectivity of aliphatic versus Aromatic Hydroxylation
    Chemistry: A European Journal, 2009
    Co-Authors: Sam P De Visser, Laleh Tahsini
    Abstract:

    The catalytic activity of high- valent iron-oxo active species of heme enzymes is known to be dependent on the nature of the axial ligand trans to the iron-oxo group. In a similar fash- ion, experimental studies on iron-oxo porphyrin biomimetic systems have shown a significant axial ligand effect on ethylbenzene Hydroxylation, with an axial acetonitrile ligand leading to phenyl Hydroxylation products and an axial chloride anion giving predomi- nantly benzyl Hydroxylation products. To elucidate the fundamental factors that distinguish this regioselectivity re- versal in iron-oxo porphyrin catalysis, we have performed a series of density functional theory calculations on the Hydroxylation of ethylbenzene by (Fe IV =OA + C)L) (Por = porphyrin; L = NCCH3 or Cl ), which affords 1-phe- nylethanol and p-ethylphenol products. The calculations confirm the experi- mentally determined product distribu- tions. Furthermore, a detailed analysis of the electronic differences between the two oxidants shows that their re- versed regioselectivity is a result of dif- ferences in orbital interactions between the axial ligand and iron-oxo porphy- rin system. In particular, three high- lying orbitals (p*xz, p*yz and a2u), which are singly occupied in the reactant complex, are stabilised with an anionic ligand such as Cl, which leads to en- hanced HOMO-LUMO energy gaps. As a consequence, reactions leading to cationic intermediates through the two- electron reduction of the metal centre are disfavoured. The aliphatic hydrox- ylation mechanism, in contrast, is a radical process in which only one elec- tron is transferred in the rate-determin- ing transition state, which means that the effect of the axial ligand on this mechanism is much smaller.

Laleh Tahsini - One of the best experts on this subject based on the ideXlab platform.

  • how does the axial ligand of cytochrome p450 biomimetics influence the regioselectivity of aliphatic versus Aromatic Hydroxylation
    Chemistry: A European Journal, 2009
    Co-Authors: Sam P De Visser, Laleh Tahsini
    Abstract:

    The catalytic activity of high- valent iron-oxo active species of heme enzymes is known to be dependent on the nature of the axial ligand trans to the iron-oxo group. In a similar fash- ion, experimental studies on iron-oxo porphyrin biomimetic systems have shown a significant axial ligand effect on ethylbenzene Hydroxylation, with an axial acetonitrile ligand leading to phenyl Hydroxylation products and an axial chloride anion giving predomi- nantly benzyl Hydroxylation products. To elucidate the fundamental factors that distinguish this regioselectivity re- versal in iron-oxo porphyrin catalysis, we have performed a series of density functional theory calculations on the Hydroxylation of ethylbenzene by (Fe IV =OA + C)L) (Por = porphyrin; L = NCCH3 or Cl ), which affords 1-phe- nylethanol and p-ethylphenol products. The calculations confirm the experi- mentally determined product distribu- tions. Furthermore, a detailed analysis of the electronic differences between the two oxidants shows that their re- versed regioselectivity is a result of dif- ferences in orbital interactions between the axial ligand and iron-oxo porphy- rin system. In particular, three high- lying orbitals (p*xz, p*yz and a2u), which are singly occupied in the reactant complex, are stabilised with an anionic ligand such as Cl, which leads to en- hanced HOMO-LUMO energy gaps. As a consequence, reactions leading to cationic intermediates through the two- electron reduction of the metal centre are disfavoured. The aliphatic hydrox- ylation mechanism, in contrast, is a radical process in which only one elec- tron is transferred in the rate-determin- ing transition state, which means that the effect of the axial ligand on this mechanism is much smaller.

Kendall N. Houk - One of the best experts on this subject based on the ideXlab platform.

  • Phenalenone Polyketide Cyclization Catalyzed by Fungal Polyketide Synthase and Flavin-Dependent Monooxygenase.
    Journal of the American Chemical Society, 2016
    Co-Authors: Abing Duan, Wei Xu, Peiyuan Yu, Leibniz Hang, Kendall N. Houk
    Abstract:

    Phenalenones are polyketide natural products that display diverse structures and biological activities. The core of phenalenones is a peri-fused tricyclic ring system cyclized from a linear polyketide precursor via an unresolved mechanism. Toward understanding the unusual cyclization steps, the phn biosynthetic gene cluster responsible for herqueinone biosynthesis was identified from the genome of Penicillium herquei. A nonreducing polyketide synthase (NR-PKS) PhnA was shown to synthesize the heptaketide backbone and cyclize it into the angular, hemiketal-containing naphtho-γ-pyrone prephenalenone. The product template (PT) domain of PhnA catalyzes only the C4–C9 aldol condensation, which is unprecedented among known PT domains. The transformation of prephenalenone to phenalenone requires an FAD-dependent monooxygenase (FMO) PhnB, which catalyzes the C2 Aromatic Hydroxylation of prephenalenone and ring opening of the γ-pyrone ring simultaneously. Density functional theory calculations provide insights int...

  • Phenalenone Polyketide Cyclization Catalyzed by Fungal Polyketide Synthase and Flavin-Dependent Monooxygenase
    2016
    Co-Authors: Shu-shan Gao, Abing Duan, Leibniz Hang, Kendall N. Houk, Yi Tang
    Abstract:

    Phenalenones are polyketide natural products that display diverse structures and biological activities. The core of phenalenones is a peri-fused tricyclic ring system cyclized from a linear polyketide precursor via an unresolved mechanism. Toward understanding the unusual cyclization steps, the phn biosynthetic gene cluster responsible for herqueinone biosynthesis was identified from the genome of Penicillium herquei. A nonreducing polyketide synthase (NR-PKS) PhnA was shown to synthesize the heptaketide backbone and cyclize it into the angular, hemiketal-containing naphtho-γ-pyrone prephenalenone. The product template (PT) domain of PhnA catalyzes only the C4–C9 aldol condensation, which is unprecedented among known PT domains. The transformation of prephenalenone to phenalenone requires an FAD-dependent monooxygenase (FMO) PhnB, which catalyzes the C2 Aromatic Hydroxylation of prephenalenone and ring opening of the γ-pyrone ring simultaneously. Density functional theory calculations provide insights into why the hydroxylated intermediate undergoes an aldol-like phenoxide–ketone cyclization to yield the phenalenone core. This study therefore unveiled new routes and biocatalysts for polyketide cyclization

Barry Halliwell - One of the best experts on this subject based on the ideXlab platform.

  • peroxynitrite dependent Aromatic Hydroxylation and nitration of salicylate and phenylalanine is hydroxyl radical involved
    Free Radical Research, 1997
    Co-Authors: Harparkash Kaur, Matthew Whiteman, Barry Halliwell
    Abstract:

    There is considerable dispute about whether the hydroxylating ability of peroxynitrite (ONOO-)-derived species involves hydroxyl radicals (OH*). This was investigated by using salicylate and phenylalanine, attack of OH* upon which leads to the formation of 2, 3– and 2, 5-dihydroxybenzoates, and o-, m- and p-tyrosines respectively. On addition of ONOO- to salicylate, characteristic products of Hydroxylation (and nitration) were observed in decreasing amounts with rise in pH, although added products of Hydroxylation of salicylate were not recovered quantitatively at pH 8.5, suggesting further oxidation of these products and underestimation of Hydroxylation at alkaline pH. Hydroxylation products decreased in the presence of several OH* scavengers, especially formate, to extents similar to those obtained when Hydroxylation was achieved by a mixture of iron salts, H2O2 and ascorbate. However, OH* scavengers also inhibited formation of salicylate nitration products. Ortho, p- and m-tyrosines as well as nitratio...

  • Aromatic Hydroxylation and nitration of phenylalanine and tyrosine by peroxynitrite evidence for hydroxyl radical production from peroxynitrite
    FEBS Letters, 1994
    Co-Authors: Albert Van Der Vliet, Barry Halliwell, C A Oneill, Carroll E Cross, Harparkash Kaur
    Abstract:

    Peroxynitrite is a highly reactive species, generated from Superoxide and nitric oxide. Some effects of peroxynitrite are ascribed to the molecule itself, but decomposition products of the protonated form, peroxynitrous acid, may account for much of its reactivity in biological systems. Suggested products include highly-reactive hydroxyl radicals, but thermodynamic calculations have been used to claim that free hydroxyl radicals cannot be formed from peroxynitrite. We utilized Aromatic Hydroxylation of phenylalanine as a specific detector of hydroxyl radicals, and found that incubation of phenylalanine with peroxynitrite leads to a small amount of p-, m- and o-tyrosine, specific products of attack by this radical. Products of nitration of phenylalanine and tyrosine were also detected, as was dityrosine. Peroxynitrite decomposition generates several reactive species, including some that can nitrate Aromatic rings. Formation of nitro-Aromatic compounds may be a useful marker of peroxynitrite generation in biological systems.

  • use of Aromatic Hydroxylation of phenylalanine to measure production of hydroxyl radicals after myocardial ischemia in vivo direct evidence for a pathogenetic role of the hydroxyl radical in myocardial stunning
    Circulation Research, 1993
    Co-Authors: Jian Zhong Sun, Barry Halliwell, Harparkash Kaur, Roberto Bolli
    Abstract:

    A pathogenetic role of .OH in myocardial stunning has been inferred from the protective effects of .OH scavengers and iron chelators. However, conclusive demonstration of the .OH radical hypothesis of myocardial stunning requires direct verification of three major, but still unproven, assumptions: (1) .OH is produced in the stunned myocardium in vivo; (2) antioxidant therapy inhibits .OH production; and (3) such inhibition results in enhanced recovery of contractility (ie, .OH is necessary for the development of myocardial stunning). Since phenylalanine (Phe) reacts with .OH to form the hydroxylated products ortho-, meta-, and para-tyrosines (o-, m-, and p-tyr), we used Aromatic Hydroxylation of Phe to detect .OH formation in the stunned myocardium. Open-chest dogs undergoing a 15-minute coronary occlusion followed by reperfusion received an intravenous infusion of Phe (54.3 mg/kg for 11.5 minutes beginning 90 seconds before reperfusion); these animals were given either no antioxidant therapy (group I, n = 15), N-2-mercaptopropionyl glycine (MPG) (group II, n = 11), or MPG combined with superoxide dismutase, catalase, and desferrioxamine (group III, n = 12). In addition, group IV (nonischemic control group, n = 6) received Phe but did not undergo coronary occlusion, whereas group V (ischemic control group, n = 16) underwent a 15-minute occlusion but did not receive Phe or antioxidants. The plasma concentrations of tyrosines in the local venous effluent and in the arterial blood were measured with high-performance liquid chromatography. In group I, production of o- and m-tyr, which are specific markers of .OH formation, began during coronary occlusion but increased dramatically immediately after reperfusion, peaking at 1 minute and continuing up to 10 minutes of reperfusion. In group II, the production of o- and m-tyr was markedly decreased throughout the first 10 minutes of reperfusion. In group III, the production of m-tyr was decreased to levels similar to those in group II, whereas the production of o-tyr was almost completely abolished. There was no appreciable production of o- or m-tyr in group IV. Recovery of contractile function (assessed as systolic wall thickening) was increased in group I vs group V. Recovery of function was further enhanced in group II, with only a slight additional improvement in group III.(ABSTRACT TRUNCATED AT 400 WORDS)

  • biologically relevant metal ion dependent hydroxyl radical generation an update
    FEBS Letters, 1992
    Co-Authors: Barry Halliwell, John M.c. Gutteridge
    Abstract:

    Transition metal ions, especially iron, appear to be important mediators of oxidative damage in vivo. Iron(II) reacts with H2O2 to give more-reactive radicals. On the basis of ESR spin-trapping data with DMPO, supported by Aromatic Hydroxylation studies and patterns of DNA base modification, it is concluded that hydroxyl radical (OH.) is likely to be the major damaging species formed in Fenton Systems under biologically-relevant conditions (which include iron concentrations no higher than the micromolar range). Although reactive oxo-iron species (such as ferryl and perferryl) may also be important, direct chemical evidence for their formation and identity in biologically relevant Fenton systems is currently lacking. Studies at alkaline pH values show that iron(IV) and iron(V) species are highly oxidizing under those reaction conditions, with a pattern of reactivity different from that of OH..

Manfred Metzler - One of the best experts on this subject based on the ideXlab platform.

  • Aromatic Hydroxylation and catechol formation a novel metabolic pathway of the growth promotor zeranol
    Toxicology Letters, 2010
    Co-Authors: Andreas A Hildebrand, Erika Pfeiffer, Manfred Metzler
    Abstract:

    α-Zearalanol (α-ZAL, zeranol) is a macrocyclic resorcylic acid lactone, which is highly estrogenic and used as a growth promotor for cattle in various countries. Little is known about the phase I metabolism of α-ZAL. We now report that α-ZAL and its major metabolite zearalanone (ZAN) are extensively monohydroxylated at the Aromatic ring by microsomes from human liver in vitro. This novel pathway leads to catechols, the chemical structures of which were unambiguously established by the use of deuterium-labeled α-ZAL and ZAN, and by the synthesis of authentic standards. The Aromatic Hydroxylation of α-ZAL is almost exclusively mediated by the human cytochrome P450 (hCYP) 1A2 isoform. The catechol metabolites of α-ZAL and ZAN are unstable and readily oxidized to quinones, which could be detected among the metabolites of α-ZAL and ZAN generated by human hepatic microsomes and hCYP1A2. Furthermore, the quinone metabolites are able to form covalent adducts with N-acetylcysteine (NAC), as several of such adducts were found in microsomal incubations fortified with NAC. Aromatic Hydroxylation of α-ZAL was also observed with bovine, porcine and rat hepatic microsomes. Further studies are needed to demonstrate the catechol pathway of α-ZAL in vivo and to assess its toxicological significance.

  • novel oxidative in vitro metabolites of the mycotoxins alternariol and alternariol methyl ether
    Molecular Nutrition & Food Research, 2007
    Co-Authors: Erika Pfeiffer, Joachim Podlech, Nils Helge Schebb, Manfred Metzler
    Abstract:

    The Alternaria toxins alternariol (AOH; 3,7,9-trihydroxy-1-methyl-6H-benzo[c]chromen-6-one) and alternariol methyl ether (AME, 3,7-dihydroxy-9-methoxy-1-methyl-6H-benzo[c]chromen-6-one) are common contaminants of food and feed, but their oxidative metabolism in mammals is as yet unknown. We have therefore incubated AME and AOH with microsomes from rat, human, and porcine liver and analyzed the microsomal metabolites with HPLC and GC-MS/MS. Seven oxidative metabolites of AME and five of AOH were detected. Their chemical structures were derived from their mass spectra using deuterated trimethylsilyl (TMS) derivatives, and from the information obtained from enzymatic methylation. Several of the metabolites were identified by comparison with synthetic reference compounds. AME as well as AOH were monohydroxylated at each of the four possible Aromatic carbon atoms and also at the methyl group. In addition, AME was demethylated to AOH and dihydroxylated to a small extent. As the four metabolites arising through Aromatic Hydroxylation of AME and AOH are either catechols or hydroquinones, the oxidative metabolism of these mycotoxins may be of toxicological significance.

  • microsomal Hydroxylation and glucuronidation of 6 gingerol
    Journal of Agricultural and Food Chemistry, 2006
    Co-Authors: Erika Pfeiffer, Franziska F Heuschmid, Stefan Kranz, Manfred Metzler
    Abstract:

    [6]-Gingerol is the major pungent principle of ginger and frequently is ingested with various condiments and nutritional supplements. We report here that incubation of [6]-gingerol with NADPH-fortified rat hepatic microsomes gave rise to eight metabolites, which were tentatively identified by GC-MS analysis as two products of Aromatic Hydroxylation as well as the diastereomers of two aliphatic Hydroxylation products and the diastereomers of [6]-gingerdiol. Hepatic microsomes from rats and humans fortified with UDPGA glucuronidated [6]-gingerol predominantly at the phenolic hydroxyl group, but small amounts of a second monoglucuronide involving the aliphatic hydroxyl group were also identified by LC-MS/MS analysis. Human intestinal microsomes formed the phenolic glucuronide only. Supersomes containing human UGT1A1 and 1A3 exclusively generated the phenolic glucuronide, albeit with very low activities, whereas UGT1A9 catalyzed the specific formation of the alcoholic glucuronide and UGT2B7 the predominant formation of the phenolic glucuronide with high activities. Our study indicates a rather complex metabolism of [6]-gingerol, which should be taken into consideration for the multiple biological activities of this compound.

  • studies on the metabolism of the plant lignans secoisolariciresinol and matairesinol
    Journal of Agricultural and Food Chemistry, 2003
    Co-Authors: Heike B Niemeyer, Doris M Honig, Sabine E Kulling, Manfred Metzler
    Abstract:

    The plant lignans secoisolariciresinol and matairesinol occur in numerous foods such as oilseeds, whole grains, vegetables, and fruits. We have studied the hitherto unknown oxidative metabolism of secoisolariciresinol and matairesinol in hepatic microsomes from untreated and Aroclor 1254-induced Wistar rats and from humans. Five oxidative metabolites of secoisolariciresinol and 10 oxidative metabolites of matairesinol were detected in rat liver microsomes, and their chemical structures were elucidated. The pathways in the metabolism of both secoisolariciresinol and matairesinol included aliphatic and Aromatic Hydroxylation, whereas oxidative demethylation was only observed for matairesinol. Human hepatic microsomes were able to metabolize secoisolariciresinol whereas matairesinol was only poorly metabolized. This study clearly shows that secoisolariciresinol and matairesinol are substrates of cytochrome P450-mediated metabolism. However, from preliminary experiments with rats dosed orally with secoisolariciresinol and matairesinol, it appears that the intestinal absorption and subsequent oxidative metabolism of these plant lignans occur only to a very small extent due to the highly efficient conversion of secoisolariciresinol and matairesinol to the mammalian lignans enterodiol and enterolactone by the gut microflora.

  • oxidative metabolism of the mammalian lignans enterolactone and enterodiol by rat pig and human liver microsomes
    Journal of Agricultural and Food Chemistry, 1999
    Co-Authors: Eric Jacobs, Manfred Metzler
    Abstract:

    Hepatic microsomes from aroclor-treated male Wistar rats biotransform enterolactone to 12 metabolites, six of which carry an additional hydroxy group at the Aromatic and six at the aliphatic moiety according to HPLC/MS and GC/MS analysis. The Aromatic Hydroxylation products were identified with the help of synthesized reference compounds as enterolactone monohydroxylated in the para position and in both ortho positions of the original phenolic hydroxy group of either Aromatic ring. The synthesis of the reference compounds and their spectroscopic characterization is described. Enterodiol is metabolized by hepatic microsomes from aroclor-treated male rats to three Aromatic and four aliphatic monohydroxylated metabolites. Aromatic Hydroxylation occurs in the para position and the two ortho positions of the original phenolic hydroxy group. Most of the metabolites of enterolactone and enterodiol were also formed with microsomes from uninduced rat, pig, and human liver, suggesting that oxidative metabolism is a common feature in the disposition of these lignans in the mammalian organism.