Jason Micklefield

Jason Micklefield
Professor Jason Micklefield at the Manchester Institute of Biotechnology
Born
Jason Micklefield
Alma materHull University (BSc) University of Cambridge (PhD)
Known forDiscovery, characterisation and engineering of enzymes and biosynthetic pathways. Biocatalysis and integrated catalysis. Modified nucleic acids and orthogonal riboswitches.
Scientific career
FieldsOrganic Chemistry, Biochemistry and Molecular Biology
InstitutionsUniversity of Washington

Birkbeck College, University of London

University of Manchester
Doctoral advisorProf. Sir Alan Battersby
Websitehttps://www.micklefieldlab.chemistry.manchester.ac.uk/

Jason Micklefield is a British Biochemist and a professor in the Department of Chemistry at The University of Manchester. His research involves the discovery, characterisation and engineering of biosynthetic pathways to new bioactive natural products, particularly antibiotics.[1][2][3] He is also interested in the discovery, structure, mechanism and engineering of enzymes for synthetic applications, including the integration of enzymes with chemocatalysis for telescoping routes to pharmaceuticals and other valuable products.[4][5][6]

Education

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Micklefield attended Royds Comprehensive School in Leeds. He received his BSc. Degree in Chemistry from Hull University in 1989 and earned a Ph.D. from the University of Cambridge in 1993 working with Professor Sir Alan Battersby to complete the first total synthesis of haem d1, a coenzyme in bacteria.

Career and research

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Following his PhD, Micklefield was awarded a NATO fellowship to work on enzyme mechanisms and biosynthesis with Professor Heinz G. Floss at the University of Washington, Seattle USA. In 1995, Micklefield was appointed Lecturer in Organic Chemistry at Birkbeck College, University of London, before moving to Manchester in 1998. He was promoted to Professor of Chemical Biology at the University of Manchester in 2008 where his research group is based in the Manchester Institute of Biotechnology (MIB). Micklefield is also visiting professor at the East China University of Science and Technology (ECUST) in Shanghai. He is co-director of the EPSRC Centre for Doctoral Training in Integrated Catalysis (iCAT) and served as Director of the BBSRC Natural Product Discovery and Bioengineering Network (NPRONET). Micklefield was the recipient of the RSC Interdisciplinary Prize (2022), Bader Award (2019), Natural Product Reports (NPR) Lecture Award (2008). He also received a European Research Council (ERC) Advanced grant and his lab also won the RSC Horizon Prize & Rita and John Cornforth Award (2023).

Micklefield's research focuses on natural product biosynthesis, pathway engineering and biocatalysis. His lab developed new methods for engineering complex NRPS enzymes that deliver new lipopeptide antibiotics.[1][7] They have discovered and characterised hybrid NRPS-PKS assembly lines producing the structurally unique antibiotic K16.[3] Micklefield's team also discovered and determined structures of novel ATP-dependent ligase enzymes, from PKS-NRPS pathways, which were engineered to produce agrochemicals and pharmaceuticals including drugs in clinical trials for COVID-19.[2][8] New synthetic biology approaches were also used to create a de novo pathway to thaxtomin phytotoxin derivatives, with improved herbicidal properties for crop protection.[9] In addition to biosynthesis, Micklefield is widely recognised for his research in biocatalysis. His lab employed structure-guided mutagenesis and directed evolution to improve activity, expand the substrate scope and switch the regioselectivities of halogenase enzymes.[10][11] They showed how engineered halogenases can be integrated with Pd-catalysed cross-coupling chemistry, in one-pot reactions, to affect the direct regioselective arylation, alkenylation, cyanation and further functionalisation of C-H positions in diverse scaffolds.[4][6] Micklefield's lab also characterised various methyltransferases, demonstrating how these can be used in the regioselective alkyl-diversification of tetrahydroisoquinolines, rapamycin immunosuppressive agents and other bioactive natural and non-natural products.[12][13][14][15][16] His lab succeeded in engineering orthogonal methyltransferases creating alternative bioalkylation pathways[13] and developed methods for selective derivatisation of tyrosine residues in peptides/proteins using methyltransferases and SAM analogues for labelling etc.[16] His team also characterised, engineered and developed many other important biocatalysts.[17][18][19] The Micklefield lab is also engaged in nucleic acids research, re-engineering the first orthogonal riboswitches (genetic tools and biosensors).[20][21][22]

Awards and honours

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Royal Society of Chemistry, Chemistry Biology Interface Horizon Prize: Rita and John Cornforth Award (2023)[23] Also see RSC Video: Horizon Prize 2023

Royal Society of Chemistry, Interdisciplinary Prize (2022)[24]

Royal Society of Chemistry, Bader Award (2019)[25]

References

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  1. ^ a b Thong, Wei Li; Zhang, Yingxin; Zhuo, Ying; Robins, Katherine J.; Fyans, Joanna K.; Herbert, Abigail J.; Law, Brian J. C.; Micklefield, Jason (25 November 2021). "Gene editing enables rapid engineering of complex antibiotic assembly lines". Nature Communications. 12 (1): 6872. doi:10.1038/s41467-021-27139-1. ISSN 2041-1723. PMC 8616955. PMID 34824225.
  2. ^ a b Winn, Michael; Rowlinson, Michael; Wang, Fanghua; Bering, Luis; Francis, Daniel; Levy, Colin; Micklefield, Jason (May 2021). "Discovery, characterization and engineering of ligases for amide synthesis". Nature. 593 (7859): 391–398. doi:10.1038/s41586-021-03447-w. ISSN 1476-4687.
  3. ^ a b Law, Brian J. C.; Zhuo, Ying; Winn, Michael; Francis, Daniel; Zhang, Yingxin; Samborskyy, Markiyan; Murphy, Annabel; Ren, Lujing; Leadlay, Peter F.; Micklefield, Jason (December 2018). "A vitamin K-dependent carboxylase orthologue is involved in antibiotic biosynthesis". Nature Catalysis. 1 (12): 977–984. doi:10.1038/s41929-018-0178-2. ISSN 2520-1158.
  4. ^ a b Craven, Elliott J.; Latham, Jonathan; Shepherd, Sarah A.; Khan, Imtiaz; Diaz-Rodriguez, Alba; Greaney, Michael F.; Micklefield, Jason (May 2021). "Programmable late-stage C−H bond functionalization enabled by integration of enzymes with chemocatalysis". Nature Catalysis. 4 (5): 385–394. doi:10.1038/s41929-021-00603-3. ISSN 2520-1158.
  5. ^ Bering, Luis; Craven, Elliott J.; Sowerby Thomas, Stanley A.; Shepherd, Sarah A.; Micklefield, Jason (19 January 2022). "Merging enzymes with chemocatalysis for amide bond synthesis". Nature Communications. 13 (1): 380. doi:10.1038/s41467-022-28005-4. ISSN 2041-1723. PMC 8770729. PMID 35046426.
  6. ^ a b Latham, Jonathan; Henry, Jean-Marc; Sharif, Humera H.; Menon, Binuraj R. K.; Shepherd, Sarah A.; Greaney, Michael F.; Micklefield, Jason (10 June 2016). "Integrated catalysis opens new arylation pathways via regiodivergent enzymatic C–H activation". Nature Communications. 7 (1): 11873. doi:10.1038/ncomms11873. ISSN 2041-1723. PMC 4906404. PMID 27283121.
  7. ^ Thirlway, Jenny; Lewis, Richard; Nunns, Laura; Al Nakeeb, Majid; Styles, Matthew; Struck, Anna-Winona; Smith, Colin P.; Micklefield, Jason (16 July 2012). "Introduction of a Non-Natural Amino Acid into a Nonribosomal Peptide Antibiotic by Modification of Adenylation Domain Specificity". Angewandte Chemie International Edition. 51 (29): 7181–7184. doi:10.1002/anie.201202043.
  8. ^ Xu, Guangcai; Torri, Daniele; Cuesta-Hoyos, Sebastian; Panda, Deepanjan; Yates, Luke R. L.; Zallot, Rémi; Bian, Kehan; Jia, Dongxu; Iorgu, Andreea I.; Levy, Colin; Shepherd, Sarah A.; Micklefield, Jason (1 July 2024). "Cryptic enzymatic assembly of peptides armed with β-lactone warheads". Nature Chemical Biology: 1–9. doi:10.1038/s41589-024-01657-7. ISSN 1552-4469.
  9. ^ Winn, Michael; Francis, Daniel; Micklefield, Jason (4 June 2018). "De novo Biosynthesis of "Non-Natural" Thaxtomin Phytotoxins". Angewandte Chemie International Edition. 57 (23): 6830–6833. doi:10.1002/anie.201801525. PMC 6001691. PMID 29603527.
  10. ^ Menon, Binuraj R. K.; Brandenburger, Eileen; Sharif, Humera H.; Klemstein, Ulrike; Shepherd, Sarah A.; Greaney, Michael F.; Micklefield, Jason (18 September 2017). "RadH: A Versatile Halogenase for Integration into Synthetic Pathways". Angewandte Chemie International Edition. 56 (39): 11841–11845. doi:10.1002/anie.201706342. PMC 5637929. PMID 28722773.
  11. ^ Shepherd, Sarah A.; Karthikeyan, Chinnan; Latham, Jonathan; Struck, Anna-Winona; Thompson, Mark L.; Menon, Binuraj R. K.; Styles, Matthew Q.; Levy, Colin; Leys, David; Micklefield, Jason (18 May 2015). "Extending the biocatalytic scope of regiocomplementary flavin-dependent halogenase enzymes". Chemical Science. 6 (6): 3454–3460. doi:10.1039/C5SC00913H. ISSN 2041-6539. PMC 5659210. PMID 29511510.
  12. ^ Bennett, Matthew R.; Thompson, Mark L.; Shepherd, Sarah A.; Dunstan, Mark S.; Herbert, Abigail J.; Smith, Duncan R. M.; Cronin, Victoria A.; Menon, Binuraj R. K.; Levy, Colin; Micklefield, Jason (13 August 2018). "Structure and Biocatalytic Scope of Coclaurine N ‐Methyltransferase". Angewandte Chemie International Edition. 57 (33): 10600–10604. doi:10.1002/anie.201805060. ISSN 1433-7851. PMC 6099451. PMID 29791083.
  13. ^ a b Herbert, Abigail J.; Shepherd, Sarah A.; Cronin, Victoria A.; Bennett, Matthew R.; Sung, Rehana; Micklefield, Jason (24 August 2020). "Engineering Orthogonal Methyltransferases to Create Alternative Bioalkylation Pathways". Angewandte Chemie International Edition. 59 (35): 14950–14956. doi:10.1002/anie.202004963. ISSN 1433-7851. PMC 7496830. PMID 32402113.
  14. ^ Law, Brian J. C.; Struck, Anna-Winona; Bennett, Matthew R.; Wilkinson, Barrie; Micklefield, Jason (20 April 2015). "Site-specific bioalkylation of rapamycin by the RapM 16-O-methyltransferase". Chemical Science. 6 (5): 2885–2892. doi:10.1039/C5SC00164A. ISSN 2041-6539. PMC 5729408. PMID 29403635.
  15. ^ Law, Brian J. C.; Bennett, Matthew R.; Thompson, Mark L.; Levy, Colin; Shepherd, Sarah A.; Leys, David; Micklefield, Jason (18 February 2016). "Effects of Active-Site Modification and Quaternary Structure on the Regioselectivity of Catechol- O -Methyltransferase". Angewandte Chemie International Edition. 55 (8): 2683–2687. doi:10.1002/anie.201508287. PMC 4770447. PMID 26797714.
  16. ^ a b Struck, Anna-Winona; Bennett, Matthew R.; Shepherd, Sarah A.; Law, Brian J. C.; Zhuo, Ying; Wong, Lu Shin; Micklefield, Jason (9 March 2016). "An Enzyme Cascade for Selective Modification of Tyrosine Residues in Structurally Diverse Peptides and Proteins". Journal of the American Chemical Society. 138 (9): 3038–3045. doi:10.1021/jacs.5b10928. ISSN 0002-7863.
  17. ^ Okrasa, Krzysztof; Levy, Colin; Wilding, Matthew; Goodall, Mark; Baudendistel, Nina; Hauer, Bernhard; Leys, David; Micklefield, Jason (28 September 2009). "Structure-Guided Directed Evolution of Alkenyl and Arylmalonate Decarboxylases". Angewandte Chemie International Edition. 48 (41): 7691–7694. doi:10.1002/anie.200904112.
  18. ^ Chesters, Christopher; Wilding, Matthew; Goodall, Mark; Micklefield, Jason (27 April 2012). "Thermal Bifunctionality of Bacterial Phenylalanine Aminomutase and Ammonia Lyase Enzymes". Angewandte Chemie International Edition. 51 (18): 4344–4348. doi:10.1002/anie.201200669.
  19. ^ Francis, Daniel; Winn, Michael; Latham, Jonathan; Greaney, Michael F.; Micklefield, Jason (16 February 2017). "An Engineered Tryptophan Synthase Opens New Enzymatic Pathways to β-Methyltryptophan and Derivatives". ChemBioChem. 18 (4): 382–386. doi:10.1002/cbic.201600471.
  20. ^ Dixon, Neil; Duncan, John N.; Geerlings, Torsten; Dunstan, Mark S.; McCarthy, John E. G.; Leys, David; Micklefield, Jason (16 February 2010). "Reengineering orthogonally selective riboswitches". Proceedings of the National Academy of Sciences. 107 (7): 2830–2835. doi:10.1073/pnas.0911209107. ISSN 0027-8424. PMC 2840279. PMID 20133756.
  21. ^ Wu, Ming-Cheng; Lowe, Phillip T.; Robinson, Christopher J.; Vincent, Helen A.; Dixon, Neil; Leigh, James; Micklefield, Jason (22 July 2015). "Rational Re-engineering of a Transcriptional Silencing PreQ 1 Riboswitch". Journal of the American Chemical Society. 137 (28): 9015–9021. doi:10.1021/jacs.5b03405. hdl:10023/7200. ISSN 0002-7863.
  22. ^ Robinson, Christopher J.; Vincent, Helen A.; Wu, Ming-Cheng; Lowe, Phillip T.; Dunstan, Mark S.; Leys, David; Micklefield, Jason (30 July 2014). "Modular Riboswitch Toolsets for Synthetic Genetic Control in Diverse Bacterial Species". Journal of the American Chemical Society. 136 (30): 10615–10624. doi:10.1021/ja502873j. ISSN 0002-7863.
  23. ^ "Enzyme discovery - 2023 Chemistry Biology Interface Horizon Prize: Rita and John Cornforth Award winner". Royal Society of Chemistry. Retrieved 24 July 2023.
  24. ^ "Professor Jason Micklefield - 2022 Interdisciplinary Prize winner". Royal Society of Chemistry. Retrieved 24 July 2023.
  25. ^ "Bader Prize - previous winners". Royal Society of Chemistry. Retrieved 24 July 2023.
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