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The FEBS Journal

Cover image for Vol. 279 Issue 9

Special Issue: Cytochrome P450 Structure and Function

May 2012

Volume 279, Issue 9

Pages 1515–1707

  1. Special Issue

    1. Top of page
    2. Special Issue
    3. Author index
    1. Review Articles

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      Special Issue: Cytochrome P450 structure and function : Introduction (page 1515)

      Andrew W. Munro and David Leys

      Version of Record online: 5 APR 2012 | DOI: 10.1111/j.1742-4658.2012.08578.x

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      Accompanied by a podcast, listen now. Or listen in iTunes The 17th International Conference on Cytochrome P450 Biochemistry, Biophysics and Structure was held in Manchester, UK from 26–30 June 2011. This issue of FEBS J. contains review and primary research articles reflecting the breadth of science covered at this conference, and reflecting the impact of P450-related research in fields as diverse as steroid metabolism, plant biochemistry, structural biology and biotechnology.

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      Cytochrome P450s in the synthesis of cholesterol and bile acids – from mouse models to human diseases (pages 1516–1533)

      Gregor Lorbek, Monika Lewinska and Damjana Rozman

      Version of Record online: 22 DEC 2011 | DOI: 10.1111/j.1742-4658.2011.08432.x

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      This review describes the transgenic mouse models designed to evaluate the functions of cytochromes P450 of cholesterol synthesis (CYP51) and bile acid synthesis (CYPs of families 7,8,27,39,46), and their link to disease. Despite important physiological differences between humans and mice, mouse models prove to be invaluable tools in understanding the multifactorial facets of cholesterol and bile acid related disorders.

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      Kinetic and spectroscopic probes of motions and catalysis in the cytochrome P450 reductase family of enzymes (pages 1534–1544)

      Christopher R. Pudney, Derren J. Heyes, Basile Khara, Sam Hay, Stephen E. J. Rigby and Nigel S. Scrutton

      Version of Record online: 9 JAN 2012 | DOI: 10.1111/j.1742-4658.2011.08442.x

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      The diflavin oxidoreductase family of flavoproteins are electron transferases that transfer electrons to a variety of downstream redox partner proteins. The mechanism of electron transfer is linked to domain motion. We review here the biophysical and structural studies that have revealed major insight into these conformationally coupled electron transfer reactions.

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      Possible evolution of alliarinoside biosynthesis from the glucosinolate pathway in Alliaria petiolata (pages 1545–1562)

      Tina Frisch and Birger L. Møller

      Version of Record online: 1 FEB 2012 | DOI: 10.1111/j.1742-4658.2011.08469.x

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      Hydroxynitrile glucosides are natural products widespread among plants but generally do not occur in glucosinolate producing species. The biosynthesis of alliarinoside may be the first known case of a hydroxynitrile glucoside pathway having evolved from the glucosinolate pathway. Homomethionine and the corresponding oxime are suggested as shared intermediates in the biosynthesis of alliarinoside and 2-propenyl glucosinolate.

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      Autocatalysed oxidative modifications to 2-oxoglutarate dependent oxygenases (pages 1563–1575)

      Monica Mantri, Zhihong Zhang, Michael A. McDonough and Christopher J. Schofield

      Version of Record online: 20 FEB 2012 | DOI: 10.1111/j.1742-4658.2012.08496.x

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      Iron and 2-oxoglutarate dependent oxygenases catalyse a range of oxidative reactions. Their catalytic flexibility is proposed to be related to their nonhaem iron binding site which employs two or three protein ligands. A possible penalty for this flexibility is that they may be more prone to oxidative damage. Here we review the evidence for auto-catalysed oxidative modifications to 2-oxoglutarate-dependent oxygenases.

    6. Original Articles

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      A novel method for monitoring the localization of cytochromes P450 and other endoplasmic reticulum membrane associated proteins: a tool for investigating the formation of metabolons (pages 1576–1583)

      Jean-Etienne Bassard, Jérôme Mutterer, Frédéric Duval and Danièle Werck-Reichhart

      Version of Record online: 15 SEP 2011 | DOI: 10.1111/j.1742-4658.2011.08312.x

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      A novel tool for investigating the formation of metabolons from the information captured by confocal microscopy. The method is designed to evaluate protein distribution and distance around the ER tubules (ER-FWHM). It is suitable for investigating the dynamics of protein-membrane association, and for detection of loose association of soluble proteins.

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      Circadian expression of steroidogenic cytochromes P450 in the mouse adrenal gland – involvement of cAMP-responsive element modulator in epigenetic regulation of Cyp17a1 (pages 1584–1593)

      Rok Košir, Ursula Prosenc Zmrzljak, Tanja Bele, Jure Acimovic, Martina Perse, Gregor Majdic, Cornelia Prehn, Jerzy Adamski and Damjana Rozman

      Version of Record online: 26 SEP 2011 | DOI: 10.1111/j.1742-4658.2011.08317.x

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      By applying cAMP responsive element modulator (Crem) knockout mice we evaluated how CREM isoforms contribute to circadian expression of steroidogenic Cyp51, 11a1, 17a1, 11b1, 11b2 and 21a1 in mouse adrenal glands. Most striking is the CREM dependent hypo-methylation of Cyp17a1 promoter at zeitgeber time 12 that resulted in higher Cyp17a1 mRNA and protein expression in the knockout adrenals.

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      Linoleic acid positioning in psi factor producing oxygenase A, a fusion protein with an atypical cytochrome P450 activity (pages 1594–1606)

      Christian Koch, Alistair J. Fielding, Florian Brodhun, Marina Bennati and Ivo Feussner

      Version of Record online: 7 OCT 2011 | DOI: 10.1111/j.1742-4658.2011.08352.x

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      In PpoA, the prototype-enzyme of the CYP6001-family, two different heme-domains sequentially oxidize a fatty acid to yield a signal molecule that is supposed to play a fundamental role in pathogenicity. Based on predicted structures, we could identify residues that are responsible for substrate positioning and an atypical shortcut of the reaction catalyzed by the P450-domain of the enzyme.

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      Investigation by site-directed mutagenesis of the role of cytochrome P450 2B4 non-active-site residues in protein–ligand interactions based on crystal structures of the ligand-bound enzyme (pages 1607–1620)

      P. Ross Wilderman, Sean C. Gay, Hyun-Hee Jang, Qinghai Zhang, C. David Stout and James R. Halpert

      Version of Record online: 25 NOV 2011 | DOI: 10.1111/j.1742-4658.2011.08411.x

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      A systematic investigation was undertaken by site-directed mutagenesis of unique residue-residue interactions predicted from crystal structures of a closed conformation of cytochrome P450 2B4 in complex with 4-(4-chlorophenyl)imidazole or an expanded conformation in complex with bifonazole. Several mutants far from the active site exhibited profound changes in susceptibility to inhibition by the two compounds and/or catalytic efficiency with several substrates.

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      Structural comparison of cytochromes P450 2A6, 2A13, and 2E1 with pilocarpine (pages 1621–1631)

      Natasha M. DeVore, Kathleen M. Meneely, Aaron G. Bart, Eva S. Stephens, Kevin P. Battaile and Emily E. Scott

      Version of Record online: 25 NOV 2011 | DOI: 10.1111/j.1742-4658.2011.08412.x

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      Human xenobiotic-metabolizing cytochrome P450 enzymes each bind and monooxygenate a diverse sets of drug substrates, but protein structural similarities and differences controlling overlapping selectivity are not well understood. Structures for three human cytochrome P450 enzymes (CYP2A6, CYP2A13, and CYP2A13) binding the common inhibitor pilocarpine, a muscarinic receptor agonist, reveal how individual amino acids result in different binding orientations.

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      Crystal structure of guaiacol and phenol bound to a heme peroxidase (pages 1632–1639)

      Emma J. Murphy, Clive L. Metcalfe, Chukwudi Nnamchi, Peter C. E. Moody and Emma L. Raven

      Version of Record online: 5 DEC 2011 | DOI: 10.1111/j.1742-4658.2011.08425.x

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      Guaiacol is a universal substrate for all peroxidases and its use in a simple colorimetric assay has wide applications. However its exact binding location has never been defined. Here we report the crystal structures of guaiacol bound to cytochrome c peroxidase (CcP). A related structure, with phenol bound, is also presented.

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      Investigating conservation of the albaflavenone biosynthetic pathway and CYP170 bifunctionality in streptomycetes (pages 1640–1649)

      Suzy C. Moody, Bin Zhao, Li Lei, David R. Nelson, Jonathan G. L. Mullins, Michael R. Waterman, Steven L. Kelly and David C. Lamb

      Version of Record online: 27 JAN 2012 | DOI: 10.1111/j.1742-4658.2011.08447.x

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      The characterization of S. albus CYP170B1 validated this enzyme as an albaflaveone synthase. However, in contrast to the bifunctional CYP170A1 from S. coelicolor A3(2), CYP170B1 was unable to catalyze the conversion of FPP to farnesene. We propose that absence of key amino acid residues in binding the essential terpene synthase cofactor Mg2+ is the explanation for loss of CYP170B1 bifunctionality.

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      Cloning, expression and characterization of CYP102D1, a self-sufficient P450 monooxygenase from Streptomyces avermitilis (pages 1650–1662)

      Kwon-Young Choi, EunOk Jung, Da-Hye Jung, Bishnu Prasad Pandey, Hyungdon Yun, Hyung-yun Park, Romas J. Kazlauskas and Byung-Gee Kim

      Version of Record online: 23 JAN 2012 | DOI: 10.1111/j.1742-4658.2011.08462.x

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      CYP102D1 from S. avermitilis is a naturally self-sufficient CYP. Codon-optimized synthetic CYP102D1 was functionally active and catalyzed long chain fatty acid hydroxylation similar to other CYP102 family. We constructed a homology model of CYP102D1 in order to alter substrate specificity to aromatic compounds revealing that replacement of F96V/M246I increased catalytic activity 15 times higher for daidzein.

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      Hydroxylation of the triterpenoid dipterocarpol with CYP106A2 from Bacillus megaterium (pages 1663–1674)

      Daniela Schmitz, Josef Zapp and Rita Bernhardt

      Version of Record online: 24 FEB 2012 | DOI: 10.1111/j.1742-4658.2012.08503.x

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      The present work deals with the bacterial steroid-hydroxylase CYP106A2, from Bacillus megaterium ATCC 13368. The difference spectroscopy method was used to screen a natural product library of 502 compounds for new substrates. One hit, the triterpene dipterocarpol, was converted using B. megaterium into 7β-hyroxy- and 7β,11α-dihydroxydipterocarpol. The 7β-hydroxydipterocarpol turned out to be cytotoxic to two mammalian cell lines.

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      Characterization of Cupriavidus metallidurans CYP116B1 – A thiocarbamate herbicide oxygenating P450–phthalate dioxygenase reductase fusion protein (pages 1675–1693)

      Ashley J. Warman, Jacob W. Robinson, Dominika Luciakova, Andrew D. Lawrence, Ker R. Marshall, Martin J. Warren, Myles R. Cheesman, Stephen E. J. Rigby, Andrew W. Munro and Kirsty J. McLean

      Version of Record online: 21 MAR 2012 | DOI: 10.1111/j.1742-4658.2012.08543.x

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      The novel P450-phthalate dioxygenase reductase fusion enzyme CYP116B1 from Cupriavidus metallidurans was expressed/purified and shown to bind heme, FMN and 2Fe-2S cofactors. CYP116B1 is a monomeric protein that uses NAD(P)H to provide electrons for P450 catalysis. NADPH is preferred, reducing the CYP116B1 reductase at > 70 s−1. CYP116B1 catalyses hydroxylation and N-dealkylation reactions, to break down the thiocarbamate herbicides vernolate/EPTC.

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      The crystal structure of the FAD/NADPH-binding domain of flavocytochrome P450 BM3 (pages 1694–1706)

      Michael G Joyce, Idorenyin S. Ekanem, Olivier Roitel, Adrian J. Dunford, Rajasekhar Neeli, Hazel M. Girvan, George J. Baker, Robin A. Curtis, Andrew W. Munro and David Leys

      Version of Record online: 16 MAR 2012 | DOI: 10.1111/j.1742-4658.2012.08544.x

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      P450 BM3 is a model enzyme in the P450 superfamily. The structure of its FAD/NADPH-binding domain represents the final piece of the structural jigsaw for this biotechnologically important enzyme. Wild-type FAD domain is predominantly dimeric, but a variant containing the C773A mutation prevented disulfide bond formation, produced monomeric protein and enabled crystallization/structural elucidation of ligand-free and NADP+-bound FAD domain forms.

  2. Author index

    1. Top of page
    2. Special Issue
    3. Author index
    1. You have free access to this content
      Author index (page 1707)

      Version of Record online: 19 APR 2012 | DOI: 10.1111/j.1742-4658.2012.08329.x