David Leys

Summary

Affiliation: University of Leicester
Country: UK

Publications

  1. doi Probing the dynamic interface between trimethylamine dehydrogenase (TMADH) and electron transferring flavoprotein (ETF) in the TMADH-2ETF complex: role of the Arg-alpha237 (ETF) and Tyr-442 (TMADH) residue pair
    Selena G Burgess
    Department of Biochemistry, University of Leicester, Leicester LE1 9HN, UK
    Biochemistry 47:5168-81. 2008
  2. pmc Channelling and formation of 'active' formaldehyde in dimethylglycine oxidase
    David Leys
    University of Leicester, Department of Biochemistry, University Road, Leicester LE1 7RH, UK
    EMBO J 22:4038-48. 2003
  3. ncbi Crystal structures at atomic resolution reveal the novel concept of "electron-harvesting" as a role for the small tetraheme cytochrome c
    David Leys
    Laboratory of Protein Biochemistry and Protein Engineering, Department of Biochemistry, Physiology, and Microbiology, K L Ledeganckstraat 35, 9000 Gent, Belgium
    J Biol Chem 277:35703-11. 2002
  4. ncbi Extensive conformational sampling in a ternary electron transfer complex
    David Leys
    Department of Biochemistry, University of Leicester, University Road, Leicester LE1 7RH, UK
    Nat Struct Biol 10:219-25. 2003
  5. ncbi Atomic structure of Mycobacterium tuberculosis CYP121 to 1.06 A reveals novel features of cytochrome P450
    David Leys
    Department of Biochemistry, University of Leicester, The Adrian Building, University Road, Leicester LE1 7RH, United Kingdom
    J Biol Chem 278:5141-7. 2003
  6. ncbi Crystal structure of the Mycobacterium tuberculosis P450 CYP121-fluconazole complex reveals new azole drug-P450 binding mode
    Harriet E Seward
    Department of Biochemistry, University of Leicester, Henry Wellcome Building, Lancaster Road, Leicester LE6 0HQ, United Kingdom
    J Biol Chem 281:39437-43. 2006
  7. ncbi Stabilization of non-productive conformations underpins rapid electron transfer to electron-transferring flavoprotein
    Helen S Toogood
    Department of Biochemistry, University of Leicester, Henry Wellcome Building, Lancaster Road, LE1 7RH, Leicester United Kingdom
    J Biol Chem 280:30361-6. 2005
  8. ncbi Flavocytochrome P450 BM3 mutant A264E undergoes substrate-dependent formation of a novel heme iron ligand set
    Hazel M Girvan
    Department of Biochemistry, University of Leicester, Leicester LE1 7RH, United Kingdom
    J Biol Chem 279:23274-86. 2004
  9. ncbi Mechanism of FAD reduction and role of active site residues His-225 and Tyr-259 in Arthrobacter globiformis dimethylglycine oxidase: analysis of mutant structure and catalytic function
    Jaswir Basran
    Department of Biochemistry, University of Leicester, UK
    Biochemistry 45:11151-61. 2006
  10. ncbi Thermodynamic and biophysical characterization of cytochrome P450 BioI from Bacillus subtilis
    Rachel J Lawson
    Department of Biochemistry, University of Leicester, UK
    Biochemistry 43:12410-26. 2004

Collaborators

Detail Information

Publications46

  1. doi Probing the dynamic interface between trimethylamine dehydrogenase (TMADH) and electron transferring flavoprotein (ETF) in the TMADH-2ETF complex: role of the Arg-alpha237 (ETF) and Tyr-442 (TMADH) residue pair
    Selena G Burgess
    Department of Biochemistry, University of Leicester, Leicester LE1 9HN, UK
    Biochemistry 47:5168-81. 2008
    ..Our work also points to the importance of Arg-alpha237 in controlling the thermodynamics of electron transfer, the dynamics of ETF, and the protection of reducing equivalents following disassembly of the TMADH-2ETF complex...
  2. pmc Channelling and formation of 'active' formaldehyde in dimethylglycine oxidase
    David Leys
    University of Leicester, Department of Biochemistry, University Road, Leicester LE1 7RH, UK
    EMBO J 22:4038-48. 2003
    ..This mode of channelling in DMGO is distinct from other channelling mechanisms...
  3. ncbi Crystal structures at atomic resolution reveal the novel concept of "electron-harvesting" as a role for the small tetraheme cytochrome c
    David Leys
    Laboratory of Protein Biochemistry and Protein Engineering, Department of Biochemistry, Physiology, and Microbiology, K L Ledeganckstraat 35, 9000 Gent, Belgium
    J Biol Chem 277:35703-11. 2002
    ..quot; This optimizes the efficiency of intermolecular electron transfer by maximizing chances of productive collision with redox partners...
  4. ncbi Extensive conformational sampling in a ternary electron transfer complex
    David Leys
    Department of Biochemistry, University of Leicester, University Road, Leicester LE1 7RH, UK
    Nat Struct Biol 10:219-25. 2003
    ..This study establishes the role of conformational sampling in multi-domain redox systems, providing insight into electron transfer between ETFs and structurally distinct redox partners...
  5. ncbi Atomic structure of Mycobacterium tuberculosis CYP121 to 1.06 A reveals novel features of cytochrome P450
    David Leys
    Department of Biochemistry, University of Leicester, The Adrian Building, University Road, Leicester LE1 7RH, United Kingdom
    J Biol Chem 278:5141-7. 2003
    ..Most interestingly, the electron density indicates weak binding of a dioxygen molecule to the P450. This structure provides a basis for rational design of putative antimycobacterial agents...
  6. ncbi Crystal structure of the Mycobacterium tuberculosis P450 CYP121-fluconazole complex reveals new azole drug-P450 binding mode
    Harriet E Seward
    Department of Biochemistry, University of Leicester, Henry Wellcome Building, Lancaster Road, Leicester LE6 0HQ, United Kingdom
    J Biol Chem 281:39437-43. 2006
    ....
  7. ncbi Stabilization of non-productive conformations underpins rapid electron transfer to electron-transferring flavoprotein
    Helen S Toogood
    Department of Biochemistry, University of Leicester, Henry Wellcome Building, Lancaster Road, LE1 7RH, Leicester United Kingdom
    J Biol Chem 280:30361-6. 2005
    ..ETF Glu-165beta plays a key role in stabilizing positions incompatible with fast interprotein electron transfer, thus ensuring high rates of complex dissociation...
  8. ncbi Flavocytochrome P450 BM3 mutant A264E undergoes substrate-dependent formation of a novel heme iron ligand set
    Hazel M Girvan
    Department of Biochemistry, University of Leicester, Leicester LE1 7RH, United Kingdom
    J Biol Chem 279:23274-86. 2004
    ..Glutamate coordination of the heme iron is confirmed by structural studies of the A264E mutant (Joyce, M. G., Girvan, H. M., Munro, A. W., and Leys, D. (2004) J. Biol. Chem. 279, 23287-23293)...
  9. ncbi Mechanism of FAD reduction and role of active site residues His-225 and Tyr-259 in Arthrobacter globiformis dimethylglycine oxidase: analysis of mutant structure and catalytic function
    Jaswir Basran
    Department of Biochemistry, University of Leicester, UK
    Biochemistry 45:11151-61. 2006
    ..Our data are discussed in the context of the crystallographic data for DMGO and also in relation to contemporary mechanisms for flavoprotein-catalyzed oxidation of amine substrates...
  10. ncbi Thermodynamic and biophysical characterization of cytochrome P450 BioI from Bacillus subtilis
    Rachel J Lawson
    Department of Biochemistry, University of Leicester, UK
    Biochemistry 43:12410-26. 2004
    ..Calorimetry shows that structural stability of the protein was altered by addition of the reductant dithiothreitol, suggesting that the disulfide is important to integrity of BioI structure...
  11. ncbi Proton transfer in the oxidative half-reaction of pentaerythritol tetranitrate reductase. Structure of the reduced enzyme-progesterone complex and the roles of residues Tyr186, His181, His184
    Huma Khan
    Department of Biochemistry, University of Leicester, UK
    FEBS J 272:4660-71. 2005
    ..Our data highlight mechanistic differences between Old Yellow Enzyme and PETN reductase and indicate that catalysis requires a metastable enzyme-steroid complex and not the most stable complex observed in crystallographic studies...
  12. ncbi Extensive domain motion and electron transfer in the human electron transferring flavoprotein.medium chain Acyl-CoA dehydrogenase complex
    Helen S Toogood
    Department of Biochemistry, University of Leicester, Leicester LE1 7RH, United Kingdom
    J Biol Chem 279:32904-12. 2004
    ....
  13. ncbi Expression, purification and spectroscopic characterization of the cytochrome P450 CYP121 from Mycobacterium tuberculosis
    Kirsty J McLean
    Department of Biochemistry, The Adrian Building, University of Leicester, UK
    J Inorg Biochem 91:527-41. 2002
    ..CYP121 binds very tightly to a range of azole antifungal drugs (e.g. clotrimazole, miconazole), suggesting that it may represent a novel target for these antibiotics in the M. tuberculosis pathogen...
  14. ncbi The 1.25 A resolution structure of the diheme NapB subunit of soluble nitrate reductase reveals a novel cytochrome c fold with a stacked heme arrangement
    Ann Brigé
    Laboratory of Protein Biochemistry and Protein Engineering, State University of Gent, Ledeganckstraat 35, B 9000 Gent, Belgium
    Biochemistry 41:4827-36. 2002
    ....
  15. ncbi A single mutation in cytochrome P450 BM3 induces the conformational rearrangement seen upon substrate binding in the wild-type enzyme
    M Gordon Joyce
    Department of Biochemistry, University of Leicester, Leicester LE1 7RH, United Kingdom
    J Biol Chem 279:23287-93. 2004
    ....
  16. doi The crystal structure of the FAD/NADPH-binding domain of flavocytochrome P450 BM3
    Michael G Joyce
    Department of Biochemistry, University of Leicester, Leicester, UK
    FEBS J 279:1694-706. 2012
    ..The FAD domain crystal structure enables molecular modelling of its interactions with its cognate FMN (flavodoxin-like) domain within the BM3 reductase module...
  17. ncbi Electrical circuitry in biology: emerging principles from protein structure
    David Leys
    Department of Biochemistry, University of Leicester, University Road, Leicester LE1 7RH, UK
    Curr Opin Struct Biol 14:642-7. 2004
    ..The use of an array of solvent-exposed, closely spaced redox centres can maximise productive collisions. Also, the use of conformational sampling via domain motion within the electron transfer complex optimises tunnelling probability...
  18. pmc Crystallization and preliminary X-ray diffraction analysis of a flavoenzyme amine dehydrogenase/oxidase from Pyrococcus furiosus DSM 3638
    Phillip J Monaghan
    Department of Biochemistry, University of Leicester, Leicester LE1 7RH, England
    Acta Crystallogr Sect F Struct Biol Cryst Commun 61:756-8. 2005
    ..3, b = 136.3, c = 203.8 A, alpha = 94.5, beta = 99.4, gamma = 102.7 degrees and a = 93.7, b = 116.3, c = 126.9 A, alpha = 97.3, beta = 99.9, gamma = 104.6 degrees...
  19. ncbi Crystallization and preliminary X-ray diffraction analysis of cytochrome c peroxidase from the purple phototrophic bacterium Rhodobacter capsulatus
    Lina De Smet
    Department of Biochemistry, Physiology and Microbiology, Laboratory for Protein Biochemistry and Protein Engineering, University of Gent, 9000 Gent, Belgium
    Acta Crystallogr D Biol Crystallogr 58:522-3. 2002
    ..2, b = 134.4, c = 167.9 A. These crystals diffracted to 2.7 A resolution and contained four peroxidase molecules per crystallographic asymmetric unit...
  20. doi Trp(359) regulates flavin thermodynamics and coenzyme selectivity in Mycobacterium tuberculosis FprA
    Rajasekhar Neeli
    Manchester Interdisciplinary Biocentre, The University of Manchester, Faculty of Life Sciences, 131 Princess Street, Manchester M1 7DN, UK
    Biochem J 411:563-70. 2008
    ..The results demonstrate that the conserved Trp(359) is critical in regulating FprA FAD binding, thermodynamic properties, catalytic efficiency and coenzyme selectivity...
  21. ncbi Dynamics driving function: new insights from electron transferring flavoproteins and partner complexes
    Helen S Toogood
    Manchester Interdisciplinary Biocentre, Faculty of Life Sciences, University of Manchester, Manchester, UK
    FEBS J 274:5481-504. 2007
    ..ETF complexes point to mechanisms of electron transfer in which 'dynamics drive function', a feature that is probably widespread in biology given the modular assembly and flexible nature of biological electron transfer systems...
  22. ncbi Mechanism of coenzyme binding to human methionine synthase reductase revealed through the crystal structure of the FNR-like module and isothermal titration calorimetry
    Kirsten R Wolthers
    Faculty of Life Sciences, University of Manchester, Manchester Interdisciplinary Biocentre, 131 Princess Street, Manchester M1 7DN, United Kingdom
    Biochemistry 46:11833-44. 2007
    ..The biological implications of an attenuated mechanism of MS reactivation by MSR on methionine and folate metabolism are discussed...
  23. ncbi Structural and spectroscopic characterization of P450 BM3 mutants with unprecedented P450 heme iron ligand sets. New heme ligation states influence conformational equilibria in P450 BM3
    Hazel M Girvan
    School of Chemical Engineering and Analytical Science, Manchester Interdisciplinary Biocentre, University of Manchester, Manchester M1 7DN, UK
    J Biol Chem 282:564-72. 2007
    ....
  24. ncbi Crystal structure and solution characterization of the activation domain of human methionine synthase
    Kirsten R Wolthers
    Faculty of Life Sciences, University of Manchester, UK
    FEBS J 274:738-50. 2007
    ..The reported structure is a component of the multidomain hMS : MSR complex, and represents an important step in understanding the impact of clinical mutations and polymorphisms in this key electron transfer complex...
  25. ncbi New insights into the reductive half-reaction mechanism of aromatic amine dehydrogenase revealed by reaction with carbinolamine substrates
    Anna Roujeinikova
    Manchester Interdisciplinary Biocenter, University of Manchester, Manchester M17DN, United Kingdom
    J Biol Chem 282:23766-77. 2007
    ..Slow hydrolysis of the amide occurs after, rather than prior to, TTQ oxidation and leads ultimately to a carboxylic acid product...
  26. ncbi Structural and functional studies on DHC, the diheme cytochrome c from Rhodobacter sphaeroides, and its interaction with SHP, the sphaeroides heme protein
    Helen R Gibson
    School of Chemistry, University of Edinburgh, UK
    Biochemistry 45:6363-71. 2006
    ..These potentials are unaltered upon complex formation...
  27. ncbi Crystallization and preliminary crystallographic analysis of a novel cytochrome P450 from Mycobacterium tuberculosis
    Christopher G Mowat
    Institute of Cell and Molecular Biology, University of Edinburgh, Mayfield Road, Edinburgh EH9 3JR, Scotland
    Acta Crystallogr D Biol Crystallogr 58:704-5. 2002
    ..3, c = 265.6 A. Native data have been collected to 1.6 A resolution and Hg-derivative data to 2.5 A resolution using a synchrotron-radiation source...
  28. ncbi Role of His505 in the soluble fumarate reductase from Shewanella frigidimarina
    Katherine L Pankhurst
    Department of Chemistry, University of Edinburgh, West Mains Road, Edinburgh EH9 3JJ, United Kingdom
    Biochemistry 41:8551-6. 2002
    ..The combined crystallographic and kinetic results suggest that His505 is not essential for sodium binding but does affect catalytic activity perhaps by influencing the pK(a) of the adjacent His504...
  29. ncbi Engineering water to act as an active site acid catalyst in a soluble fumarate reductase
    Christopher G Mowat
    Department of Chemistry, University of Edinburgh, West Mains Road, Edinburgh EH9 3JJ, Scotland, U K
    Biochemistry 41:11990-6. 2002
    ..However, in this mutant enzyme Michaelis complex formation is impaired due to significant and unpredicted structural changes at the active site...
  30. ncbi The TB structural genomics consortium: providing a structural foundation for drug discovery
    Celia W Goulding
    Bioscience Division, Mail Stop M888, Los Alamos National Laboratory, Los Alamos, NM 87545, USA
    Curr Drug Targets Infect Disord 2:121-41. 2002
    ..The Consortium has determined structures of 28 proteins from TB to date. These protein structures are already providing a basis for drug discovery efforts...
  31. ncbi Mutagenesis of morphinone reductase induces multiple reactive configurations and identifies potential ambiguity in kinetic analysis of enzyme tunneling mechanisms
    Christopher R Pudney
    Manchester Interdisciplinary Biocentre, Faculty of Life Sciences, University of Manchester, 131 Princess Street, Manchester, M1 7DN, U K
    J Am Chem Soc 129:13949-56. 2007
    ..Implications for the interpretation from kinetic data of tunneling mechanisms in enzymes are discussed...
  32. pmc Molecular basis of halorespiration control by CprK, a CRP-FNR type transcriptional regulator
    Colin Levy
    Manchester Interdisciplinary Biocentre, The University of Manchester, Manchester M1 7DN, UK
    Mol Microbiol 70:151-67. 2008
    ..This suggests that, despite significant structural homology, distinct allosteric mechanisms are used, enabling this protein family to control a very wide range of processes...
  33. ncbi The preponderance of P450s in the Mycobacterium tuberculosis genome
    Kirsty J McLean
    Manchester Interdisciplinary Biocentre, School of Chemical Engineering and Analytical Science and School of Life Sciences, University of Manchester, Jackson s Mill, Sackville Street, Manchester, UK, M60 1QD
    Trends Microbiol 14:220-8. 2006
    ..Elucidation of structure, function and metabolic roles will be essential in targeting the P450s as an 'Achilles heel' in this major human pathogen...
  34. ncbi Atomic description of an enzyme reaction dominated by proton tunneling
    Laura Masgrau
    Manchester Interdisciplinary Biocentre, University of Manchester, Jackson s Mill, Post Office Box 88, Manchester M60 1QD, UK
    Science 312:237-41. 2006
    ..We show that, in this enzyme system, tunneling is promoted by a short-range motion modulating proton-acceptor distance and no long-range coupled motion is required...
  35. ncbi Catalysis by the isolated tryptophan tryptophylquinone-containing subunit of aromatic amine dehydrogenase is distinct from native enzyme and synthetic model compounds and allows further probing of TTQ mechanism
    Parvinder Hothi
    Manchester Interdisciplinary Biocentre, Faculty of Life Sciences, University of Manchester, UK
    Biochemistry 47:183-94. 2008
    ..This is attributed to the absence of structural rearrangement prior to H-transfer that limits the rate of TTQ reduction by para-substituted benzylamines in native enzyme...
  36. doi Atomistic insight into the origin of the temperature-dependence of kinetic isotope effects and H-tunnelling in enzyme systems is revealed through combined experimental studies and biomolecular simulation
    Sam Hay
    Manchester Interdisciplinary Biocentre and Faculty of Life Science, University of Manchester, 131 Princess Street, Manchester M1 7DN, U K
    Biochem Soc Trans 36:16-21. 2008
    ....
  37. doi Structure and mechanism of an unusual malonate decarboxylase and related racemases
    Krzysztof Okrasa
    School of Chemistry and Manchester Interdisciplinary Biocentre, The University of Manchester, 131 Princess Street, Manchester, UK
    Chemistry 14:6609-13. 2008
  38. ncbi Isotope effects reveal that para-substituted benzylamines are poor reactivity probes of the quinoprotein mechanism for aromatic amine dehydrogenase
    Parvinder Hothi
    Manchester Interdisciplinary Biocentre, Faculty of Life Sciences, University of Manchester, UK
    Biochemistry 46:9250-9. 2007
    ....
  39. ncbi Mechanistic aspects and redox properties of hyperthermophilic L-proline dehydrogenase from Pyrococcus furiosus related to dimethylglycine dehydrogenase/oxidase
    Phillip J Monaghan
    Manchester Interdisciplinary Biocentre and Faculty of Life Sciences, University of Manchester, UK
    FEBS J 274:2070-87. 2007
    ..These studies provide the first detailed account of the kinetic/redox properties of this hyperthermophilic L-proline dehydrogenase. Implications for its mechanism of action are discussed...
  40. ncbi Transcriptional activation by CprK1 is regulated by protein structural changes induced by effector binding and redox state
    Hortense Mazon
    Department of Biomolecular Mass Spectrometry, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Sorbonnelaan 16, 3584 CA Utrecht, The Netherlands
    J Biol Chem 282:11281-90. 2007
    ....
  41. ncbi Atomic level insight into the oxidative half-reaction of aromatic amine dehydrogenase
    Anna Roujeinikova
    Manchester Interdisciplinary Biocentre, University of Manchester, Manchester M1 7DN, United Kingdom
    J Biol Chem 281:40264-72. 2006
    ....
  42. pmc Hydrogen tunnelling in enzyme-catalysed H-transfer reactions: flavoprotein and quinoprotein systems
    Michael J Sutcliffe
    Manchester Interdisciplinary Biocentre, School of Chemical Engineering and Analytical Science, Faculty of Life Sciences, University of Manchester, UK
    Philos Trans R Soc Lond B Biol Sci 361:1375-86. 2006
    ..Furthermore, tunnelling mechanisms in enzymes are supported by atomistic computational studies performed within the framework of modern TST, which incorporates quantum nuclear effects...
  43. ncbi CprK crystal structures reveal mechanism for transcriptional control of halorespiration
    M Gordon Joyce
    Manchester Interdisciplinary Biocentre, P O Box 88, Manchester, M60 1QD, United Kingdom
    J Biol Chem 281:28318-25. 2006
    ..These structures provide a structural framework for further studies on transcriptional control by CRP-FNR homologs in general and of halorespiration regulation by CprK in particular...
  44. ncbi Lys-D48 is required for charge stabilization, rapid flavin reduction, and internal electron transfer in the catalytic cycle of dihydroorotate dehydrogenase B of Lactococcus lactis
    Jonathan P Combe
    Faculty of Life Sciences, Manchester Interdisciplinary Biocentre, University of Manchester, Jackson s Mill, Sackville Street, Manchester M60 1QD, United Kingdom
    J Biol Chem 281:17977-88. 2006
    ....
  45. ncbi Tryptophan tryptophylquinone cofactor biogenesis in the aromatic amine dehydrogenase of Alcaligenes faecalis. Cofactor assembly and catalytic properties of recombinant enzyme expressed in Paracoccus denitrificans
    Parvinder Hothi
    Manchester Interdisciplinary Biocentre and Faculty of Life Sciences, University of Manchester, UK
    FEBS J 272:5894-909. 2005
    ..1 and 9.3, again with the maximum value realized in the alkaline region. The potential origin of these kinetically influential ionizations is discussed...
  46. ncbi The dimeric form of flavocytochrome P450 BM3 is catalytically functional as a fatty acid hydroxylase
    Rajasekhar Neeli
    Manchester Interdisciplinary Biocentre, School of Chemical Engineering and Analytical Science, The University of Manchester, Jackson s Mill, UK
    FEBS Lett 579:5582-8. 2005
    ..Fatty acid oxidation is reconstituted by mixing inactive oxygenase (A264H) and FMN-depleted (G570D) mutants, demonstrating that inter-monomer (FMN(1)-to-heme(2)) electron transfer supports oxygenase activity in the BM3 dimer...