Micklefield Lab

Professor of Chemical Biology

Solvitur ambulando

 

Imperial College London 
Department of Chemistry
Molecular Sciences Research Hub
White City Campus, 82 Wood Lane, London W12 0BZ

Email: j.micklefield@imperial.ac.uk

Twitter: @Micklefield_Lab

 

 

 

Marie Sklodowska-Curie Actions (MSCA) Postdoctoral Fellowships

Our lab hosted several successful Marie Curie Fellows in the last few years. Email us if you are interested in research at the chemistry-biology interface & want to apply for a MCSA Fellowship

 

Biography

The Micklefield Lab develop more sustainable bio-inspired ways to build molecules. Our lab has an eclectic philosophy and is highly interdisciplinary, engaged in Chemical and Synthetic Biology research tackling diverse challenges at the Chemistry-Biology interface. We exploit techniques and knowledge from organic chemistry and enzymology through to molecular microbiology and genetics to develop sustainable routes to target molecules for therapeutic and other applications. The main research themes include: 1) Biosynthesis and biosynthetic pathway engineering providing novel bioactive natural products particularly new antibiotics to combat antimicrobial resistance (AMR) and treat neglected diseases; 2) Biocatalysis & integrated catalysis – Enzyme discovery, characterisation & engineering for enzymatic synthesis. Merging chemo- and biocatalysis for telescoping more sustainable routes to pharmaceuticals and other valuable products; 3) Nucleic acids chemistry and biology, including developing new routes to nucleic acid therapeutics (NAT) and functional tools such as riboswitches and aptamers.

To learn more about our research and lab culture watch this video produced by the RSC in recognition of our lab’s recent RSC Horizon Prize – The Rita and John Cornforth Award (2023).

Want to see what a typical day in our lab looks like. Meet members of our group having fun, planning, executing and presenting their exciting research!

Selected Publications

• Cryptic enzymatic assembly of peptides armed with β-lactone warheads. G. Xu, D. Torri, S. Cuesta-Hoyos, D. Panda, L. R. L. Yates, R. Zallot, K. Bian, D. Jia, A. I. Iorgu, C. Levy, S. A. Shepherd & Jason Micklefield* Nature Chem Biol 2024. Also see research briefing (https://doi.org/10.1038/s41589-024-01658-6) & behind the paper blog (https://go.nature.com/3LrIXUx).
• Merging Enzymes with Chemocatalysis for Sustainable Amide Bond Synthesis. L. Bering, E. J. Craven, S. A. Sowerby Thomas, S. A. Shepherd & J. Micklefield* Nature Commun. 2022, 13, 380. Also see news highlights: Chemical & Engineering News (C&EN) “Enzyme and copper combo builds amide bonds,” Nature Chemical Biology “Greener amide bonds,” Nature Reviews Chemistry “Collaborative Catalysis,” &  behind the paper (https://go.nature.com/3FCmSxf)
• Discovery, Characterisation and Engineering of Ligases for Amide Synthesis. M. Winn, F. Wang, M. Rowlinson, L. Bering, D. Francis, C. Levy & 
  J Micklefield Nature 2021, 593, 391–398. Shareable link (https://rdcu.be/cmdd4). Also see behind the paper (https://go.nature.com/3uQTAqp).
• Gene editing enables rapid engineering of complex antibiotic assembly lines. W. L. Thong, Y. Zhang, Y. Zhuo, K. J. Robins, J. K. Fyans, A. J. Herbert, B. J. C. Law & J. Micklefield Nature Commun 2021, 12, 6872. Shareable link (https://rdcu.be/cB1FR). Behind the paper (https://go.nature.com/3uQTAqp).
• Programmable late-stage C−H bond functionalization enabled by integration of enzymes with chemocatalysis. E.  J. Craven, J. Latham, S. A. Shepherd, I. Khan, A. Diaz-Rodriguez, M. F. Greaney & J.  Micklefield Nature Catalysis 2021, 4, 385–394. Shareable link (https://rdcu.be/cmdf6). Also see behind the paper (https://go.nature.com/3apWdqC).
• Engineering orthogonal methyltransferases to create alternative bioalkylation pathways. A.  J. Herbert, S. A. Shepherd, V. A. Cronin, M. R. Bennett, R. Sung & J Micklefield Angew. Chem. Int. Ed. 2020, 59, 2–9. Also see Nature Chemistry News & Views (https://rdcu.be/cmde1)
• A vitamin K-dependent carboxylase is involved in antibiotic biosynthesis. B. J. C. Law, Y. Zhuo, D. Francis, M. Winn, Y. Zhang, M. Samborskyy, A. Murphy, L. Ren, P. F. Leadlay & J. Micklefield. Nature Catalysis 2018, 1, 977-984. Also see Nature Catalysis News & Views (https://rdcu.be/bdd6j) and Nature Research Community News (https://go.nature.com/2r4Smbu)
• De novo Biosynthesis of ‘Non-Natural’ Thaxtomin Phytotoxins. M Winn, D Francis & J Micklefield Angew. Chem. Int. Ed. 2018, 57, 6830–6833.
• Structure and Biocatalytic Scope of Coclaurine N-Methyltransferase. MR Bennett, ML Thompson, SA Shepherd, MS Dunstan, AJ Herbert, DRM Smith, VA Cronin, BRK Menon, C Levy  & J Micklefield Angew. Chem. Int. Ed. 2018, 57, 10600-10604.
• RadH: A Versatile Halogenase for Integration into Synthetic Pathways. BRK Menon, E Brandenburger, HH Sharif, U Klemstein, MF Greaney & J. Micklefield Angew. Chem. Int. Ed. 2017, 56, 11841–11845.
• Integrated Catalysis Opens New Arylation Pathways via Regiodivergent Enzymatic C-H Activation. J Latham, HH Sharif, JM Henry, BRK Menon, SA Shepherd, MF Greaney, J.Micklefield Nature Commun. 2016, 7, 11873
• An Enzyme Cascade for Selective Modification of Tyrosine Residues in Structurally Diverse Peptides and Proteins. AW Struck, MR Bennett, SA Shepherd, BJC Law, Y Zhou & L S Wong, J Micklefield J. Am. Chem. Soc. 2016, 138, 3038–3045
• Effects of Active Site Modification and Quaternary Structure on the Regioselectivity of Catechol-O-Methyltransferase. BJC Law, MR Bennett, ML Thompson, C Levy, SA Shepherd, D Leys, J Micklefield Angew. Chem. Int. Ed. 2016, 55, 2683–2687
• A flavin-dependent decarboxylase-dehydrogenase-monooxygenase assembles the warhead of α, β-epoxyketone proteasome inhibitors. D Zabala, J Cartwright, D Roberts, BJC Law, L Song, M Samborskyy, PF Leadlay, J Micklefield, GL Challis J. Am. Chem. Soc. 2016, 138, 4342–4345
• Rational Re-engineering of the Transcriptional Silencing PreQ1 Riboswitch. MC Wu, PT Lowe, CJ Robinson, HA Vincent, N Dixon, J Leigh, J Micklefield J. Am. Chem. Soc. 2015, 137, 9015–9021
• Modular Riboswitch Toolsets for Synthetic Genetic Control in Diverse Bacterial Species. CJ Robinson, HA. Vincent, M-C Wu, PT. Lowe, MS. Dunstan, D Leys, J Micklefield J Am Chem Soc 2014, 136, 10615–10624
• Introduction of a non-natural amino acid into a nonribosomal peptide by modification of adenylation domain specificity. J Thirlway, R Lewis, L Nunns, M Al Nakeeb, M Styles, A-W Struck, CP Smith, J Micklefield Angew Chem Int Ed 2012, 51, 7181–7184
• Thermal Bifunctionality of Bacterial MIO-Dependent Mutase and Lyase Enzymes. C Chesters, M Wilding, M Goodall, J. Micklefield Angew Chem Int Ed 2012, 51, 4344–4348
• Orthogonal Riboswitches for Tuneable Co-expression in Bacteria. N Dixon, C Robinson, JN Duncan, T Geerlings, SP Drummond, J. Micklefield Angew Chem Int Ed 2012, 51, 3620–3624
• Protein micro- and nano-patterning using aminosilanes with protein-resistant photolabile protecting groups. SA Alang Ahmad, LS Wong, E ul-Haq, JK Hobbs, GJ Leggett, J. Micklefield J Am Chem Soc 2011, 133, 2749–2759
• Reengineering orthogonally selective riboswitches. N Dixon, J Duncan, T Geerlings, MS Dunstan, D Leys, J. Micklefield Proc Natl Acad Sci USA 2010, 107, 2830-2835.
• Structure guided directed evolution of alkenyl and arylmalonate decarboxylases. K Okrasa, C Levy, M Wilding, M Goodall, N Baudendistel, B Hauer, D Leys, J Micklefield Angew Chem Int Ed 2009, 48, 7691-7694
• Direct site-selective covalent protein immobilization catalyzed by a phosphopantetheinyl transferase. LS Wong, J Thirlway, J. Micklefield J Am Chem Soc 2008, 130, 12456-12464
• Engineered biosynthesis of nonribosomal lipopeptide antibiotics with modified fatty acid side chains. A Powell, M Borg, B Amir-Heidari, JM Neary, J Thirlway, B Wilkinson, CP Smith, J Micklefield J Am Chem Soc 2007, 129, 15182-15191
• Mining and engineering natural-product biosynthetic pathways. B. Wilkinson & J. Micklefield Nature Chem. Biol. 2007, 3, 379–386.