Prof Jason Micklefield PhD

Biography

Jason Micklefield is Professor of Chemical Biology within the School of Chemistry and the Manchester Institute of Biotechnology. He graduated from the University of Cambridge in 1993 with a PhD in Chemistry, working with Prof Sir Alan R. Battersby FRS to complete the first total synthesis of haem d1. He then moved to the University of Washington, USA, as a NATO postdoctoral fellow investigating various biosynthetic pathways and enzyme mechanisms with Prof Heinz G. Floss. In 1995 he began his independent research career as a Lecturer in Organic Chemistry at Birkbeck College, University of London before moving to Manchester in 1998.

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.

Selected Publications

• 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 higlights: Chemical & Engineering News (C&EN), “Enzyme and copper combo builds amide bonds,” Nature Chemical Biology "Greener amide bonds," Nature Reviews Chemistry "Collaborative Catalysis," & see 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).
• 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
• Extending the biocatalytic scope of regiocomplementary flavin-dependent halogenase enzymes. SA Shepherd, C Karthikeyan, J Latham, AW Struck, ML Thompson, B Menon, C Levy, D Leys, J Micklefield Chemical Science 2015, 6, 3454–3460
• Site-specific Bioalkylation of Rapamycin by the RapM 16-O-Methyltransferase. BJC Law, AW Struck, MR Bennett, B Wilkinson, J Micklefield Chemical Science 2015, 6, 2885–2892
• 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.