Professional Education


  • Doctor of Philosophy, University of Oxford (2017)
  • Master of Science, University of Bristol (2012)

All Publications


  • The Jumonji-C oxygenase JMJD7 catalyzes (3S)-lysyl hydroxylation of TRAFAC GTPases (vol 14, pg 688, 2018) NATURE CHEMICAL BIOLOGY Markolovic, S., Zhuang, Q., Wilkins, S. E., Eaton, C. D., Abboud, M. I., Katz, M. J., McNeil, H. E., Lesniak, R. K., Hall, C., Struwe, W. B., Konietzny, R., Davis, S., Yang, M., Ge, W., Benesch, J. P., Kessler, B. M., Ratcliffe, P. J., Cockman, M. E., Fischer, R., Wappner, P., Chowdhury, R., Coleman, M. L., Schofield, C. J. 2018; 14 (10): 988

    Abstract

    In the version of this article initially published, authors Sarah E. Wilkins, Charlotte D. Eaton, Martine I. Abboud and Maximiliano J. Katz were incorrectly included in the equal contributions footnote in the affiliations list. Footnote number seven linking to the equal contributions statement should be present only for Suzana Markolovic and Qinqin Zhuang, and the statement should read "These authors contributed equally: Suzana Markolovic, Qinqin Zhuang." The error has been corrected in the HTML and PDF versions of the article.

    View details for PubMedID 29950663

  • The Jumonji-C oxygenase JMJD7 catalyzes (3S)-lysyl hydroxylation of TRAFAC GTPases NATURE CHEMICAL BIOLOGY Markolovic, S., Zhuang, Q., Wilkins, S. E., Eaton, C. D., Abboud, M. I., Katz, M. J., McNeil, H. E., Lesniak, R. K., Hall, C., Struwe, W. B., Konietzny, R., Davis, S., Yang, M., Ge, W., Benesch, J. P., Kessler, B. M., Ratcliffe, P. J., Cockman, M. E., Fischer, R., Wappner, P., Chowdhury, R., Coleman, M. L., Schofield, C. J. 2018; 14 (7): 688-+

    Abstract

    Biochemical, structural and cellular studies reveal Jumonji-C (JmjC) domain-containing 7 (JMJD7) to be a 2-oxoglutarate (2OG)-dependent oxygenase that catalyzes (3S)-lysyl hydroxylation. Crystallographic analyses reveal JMJD7 to be more closely related to the JmjC hydroxylases than to the JmjC demethylases. Biophysical and mutation studies show that JMJD7 has a unique dimerization mode, with interactions between monomers involving both N- and C-terminal regions and disulfide bond formation. A proteomic approach identifies two related members of the translation factor (TRAFAC) family of GTPases, developmentally regulated GTP-binding proteins 1 and 2 (DRG1/2), as activity-dependent JMJD7 interactors. Mass spectrometric analyses demonstrate that JMJD7 catalyzes Fe(II)- and 2OG-dependent hydroxylation of a highly conserved lysine residue in DRG1/2; amino-acid analyses reveal that JMJD7 catalyzes (3S)-lysyl hydroxylation. The functional assignment of JMJD7 will enable future studies to define the role of DRG hydroxylation in cell growth and disease.

    View details for PubMedID 29915238

    View details for PubMedCentralID PMC6027965

  • Crystallographic analyses of isoquinoline complexes reveal a new mode of metallo-beta-lactamase inhibition CHEMICAL COMMUNICATIONS Li, G., Brem, J., Lesniak, R., Abboud, M. I., Lohans, C. T., Clifton, I. J., Yang, S., Jimenez-Castellanos, J., Avison, M. B., Spencer, J., McDonough, M. A., Schofield, C. J. 2017; 53 (43): 5806–9

    Abstract

    Crystallographic analyses of the VIM-5 metallo-β-lactamase (MBL) with isoquinoline inhibitors reveal non zinc ion binding modes. Comparison with other MBL-inhibitor structures directed addition of a zinc-binding thiol enabling identification of potent B1 MBL inhibitors. The inhibitors potentiate meropenem activity against clinical isolates harboring MBLs.

    View details for DOI 10.1039/c7cc02394d

    View details for Web of Science ID 000402296200003

    View details for PubMedID 28470248

    View details for PubMedCentralID PMC5516270

  • Human carnitine biosynthesis proceeds via (2S, 3S)-3-hydroxy-N-epsilon-trimethyllysine CHEMICAL COMMUNICATIONS Lesniak, R. K., Markolovic, S., Tars, K., Schofield, C. J. 2017; 53 (2): 440–42

    Abstract

    Nε-Trimethyllysine hydroxylase (TMLH) catalyses the first step in mammalian biosynthesis of carnitine, which plays a crucial role in fatty acid metabolism. The stereochemistry of the 3-hydroxy-Nε-trimethyllysine product of TMLH has not been defined. We report enzymatic and asymmetric synthetic studies, which define the product of TMLH catalysis as (2S,3S)-3-hydroxy-Nε-trimethyllysine.

    View details for DOI 10.1039/c6cc08381a

    View details for Web of Science ID 000391736100035

    View details for PubMedID 27965989

    View details for PubMedCentralID PMC5644716

  • Discovery and Characterization of GSK2801, a Selective Chemical Probe for the Bromodomains BAZ2A and BAZ2B JOURNAL OF MEDICINAL CHEMISTRY Chen, P., Chaikuad, A., Bamborough, P., Bantscheff, M., Bountra, C., Chung, C., Fedorov, O., Grandi, P., Jung, D., Lesniak, R., Lindon, M., Mueller, S., Philpott, M., Prinjha, R., Rogers, C., Selenski, C., Tallant, C., Werner, T., Willson, T. M., Knapp, S., Drewry, D. H. 2016; 59 (4): 1410–24

    Abstract

    Bromodomains are acetyl-lysine specific protein interaction domains that have recently emerged as a new target class for the development of inhibitors that modulate gene transcription. The two closely related bromodomain containing proteins BAZ2A and BAZ2B constitute the central scaffolding protein of the nucleolar remodeling complex (NoRC) that regulates the expression of noncoding RNAs. However, BAZ2 bromodomains have low predicted druggability and so far no selective inhibitors have been published. Here we report the development of GSK2801, a potent, selective and cell active acetyl-lysine competitive inhibitor of BAZ2A and BAZ2B bromodomains as well as the inactive control compound GSK8573. GSK2801 binds to BAZ2 bromodomains with dissociation constants (KD) of 136 and 257 nM for BAZ2B and BAZ2A, respectively. Crystal structures demonstrated a canonical acetyl-lysine competitive binding mode. Cellular activity was demonstrated using fluorescent recovery after photobleaching (FRAP) monitoring displacement of GFP-BAZ2A from acetylated chromatin. A pharmacokinetic study in mice showed that GSK2801 had reasonable in vivo exposure after oral dosing, with modest clearance and reasonable plasma stability. Thus, GSK2801 represents a versatile tool compound for cellular and in vivo studies to understand the role of BAZ2 bromodomains in chromatin biology.

    View details for DOI 10.1021/acs.jmedchem.5b00209

    View details for Web of Science ID 000371103600012

    View details for PubMedID 25799074

    View details for PubMedCentralID PMC4770311

  • Cation-pi Interactions Contribute to Substrate Recognition in gamma-Butyrobetaine Hydroxylase Catalysis CHEMISTRY-A EUROPEAN JOURNAL Kamps, J. G., Khan, A., Choi, H., Lesniak, R. K., Brem, J., Rydzik, A. M., McDonough, M. A., Schofield, C. J., Claridge, T. W., Mecinovic, J. 2016; 22 (4): 1270–76

    Abstract

    γ-Butyrobetaine hydroxylase (BBOX) is a non-heme Fe(II) - and 2-oxoglutarate-dependent oxygenase that catalyzes the stereoselective hydroxylation of an unactivated C-H bond of γ-butyrobetaine (γBB) in the final step of carnitine biosynthesis. BBOX contains an aromatic cage for the recognition of the positively charged trimethylammonium group of the γBB substrate. Enzyme binding and kinetic analyses on substrate analogues with P and As substituting for N in the trimethylammonium group show that the analogues are good BBOX substrates, which follow the efficiency trend N(+) >P(+) >As(+). The results reveal that an uncharged carbon analogue of γBB is not a BBOX substrate, thus highlighting the importance of the energetically favorable cation-π interactions in productive substrate recognition.

    View details for DOI 10.1002/chem.201503761

    View details for Web of Science ID 000368922500013

    View details for PubMedID 26660433

    View details for PubMedCentralID PMC4736438

  • Development and application of ligand-based NMR screening assays for gamma-butyrobetaine hydroxylase MEDCHEMCOMM Khan, A., Lesniak, R. K., Brem, J., Rydzik, A. M., Choi, H., Leung, I. H., McDonough, M. A., Schofield, C. J., Claridge, T. W. 2016; 7 (5): 873–80

    View details for DOI 10.1039/c6md00004e

    View details for Web of Science ID 000377139400015