Jason Micklefield Explained

Jason Micklefield
Birth Name:Jason Micklefield
Fields:Organic Chemistry, Biochemistry and Molecular Biology
Workplaces:University of WashingtonBirkbeck College, University of LondonUniversity of Manchester
Alma Mater:Hull University (BSc)University of Cambridge (PhD)
Doctoral Advisor:Prof. Sir Alan Battersby
Known For:Discovery, characterisation and engineering of enzymes and biosynthetic pathways. Biocatalysis and integrated catalysis. Modified nucleic acids and orthogonal riboswitches.
Website:https://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

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

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.[7] They have discovered and characterised hybrid NRPS-PKS assembly lines producing the structurally unique antibiotic K16. 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.[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. 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 and developed methods for selective derivatisation of tyrosine residues in peptides/proteins using methyltransferases and SAM analogues for labelling etc. 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

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]

Notes and References

  1. Thong . Wei Li . Zhang . Yingxin . Zhuo . Ying . Robins . Katherine J. . Fyans . Joanna K. . Herbert . Abigail J. . Law . Brian J. C. . Micklefield . Jason . 2021-11-25 . Gene editing enables rapid engineering of complex antibiotic assembly lines . Nature Communications . en . 12 . 1 . 6872 . 10.1038/s41467-021-27139-1 . 2041-1723 . 8616955 . 34824225.
  2. 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 . en . 593 . 7859 . 391–398 . 10.1038/s41586-021-03447-w . 1476-4687. free .
  3. 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 . en . 1 . 12 . 977–984 . 10.1038/s41929-018-0178-2 . 2520-1158.
  4. 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 . en . 4 . 5 . 385–394 . 10.1038/s41929-021-00603-3 . 2520-1158.
  5. Bering . Luis . Craven . Elliott J. . Sowerby Thomas . Stanley A. . Shepherd . Sarah A. . Micklefield . Jason . 2022-01-19 . Merging enzymes with chemocatalysis for amide bond synthesis . Nature Communications . en . 13 . 1 . 380 . 10.1038/s41467-022-28005-4 . 2041-1723 . 8770729 . 35046426.
  6. Latham . Jonathan . Henry . Jean-Marc . Sharif . Humera H. . Menon . Binuraj R. K. . Shepherd . Sarah A. . Greaney . Michael F. . Micklefield . Jason . 2016-06-10 . Integrated catalysis opens new arylation pathways via regiodivergent enzymatic C–H activation . Nature Communications . en . 7 . 1 . 11873 . 10.1038/ncomms11873 . 2041-1723 . 4906404 . 27283121.
  7. Thirlway . Jenny . Lewis . Richard . Nunns . Laura . Al Nakeeb . Majid . Styles . Matthew . Struck . Anna-Winona . Smith . Colin P. . Micklefield . Jason . 2012-07-16 . Introduction of a Non-Natural Amino Acid into a Nonribosomal Peptide Antibiotic by Modification of Adenylation Domain Specificity . Angewandte Chemie International Edition . en . 51 . 29 . 7181–7184 . 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 . 2024-07-01 . Cryptic enzymatic assembly of peptides armed with β-lactone warheads . Nature Chemical Biology . en . 1–9 . 10.1038/s41589-024-01657-7 . 1552-4469. free .
  9. Winn . Michael . Francis . Daniel . Micklefield . Jason . 2018-06-04 . De novo Biosynthesis of "Non-Natural" Thaxtomin Phytotoxins . Angewandte Chemie International Edition . en . 57 . 23 . 6830–6833 . 10.1002/anie.201801525 . 6001691 . 29603527.
  10. Menon . Binuraj R. K. . Brandenburger . Eileen . Sharif . Humera H. . Klemstein . Ulrike . Shepherd . Sarah A. . Greaney . Michael F. . Micklefield . Jason . 2017-09-18 . RadH: A Versatile Halogenase for Integration into Synthetic Pathways . Angewandte Chemie International Edition . en . 56 . 39 . 11841–11845 . 10.1002/anie.201706342 . 5637929 . 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 . 2015-05-18 . Extending the biocatalytic scope of regiocomplementary flavin-dependent halogenase enzymes . Chemical Science . en . 6 . 6 . 3454–3460 . 10.1039/C5SC00913H . 2041-6539 . 5659210 . 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 . 2018-08-13 . Structure and Biocatalytic Scope of Coclaurine N ‐Methyltransferase . Angewandte Chemie International Edition . en . 57 . 33 . 10600–10604 . 10.1002/anie.201805060 . 1433-7851 . 6099451 . 29791083.
  13. Herbert . Abigail J. . Shepherd . Sarah A. . Cronin . Victoria A. . Bennett . Matthew R. . Sung . Rehana . Micklefield . Jason . 2020-08-24 . Engineering Orthogonal Methyltransferases to Create Alternative Bioalkylation Pathways . Angewandte Chemie International Edition . en . 59 . 35 . 14950–14956 . 10.1002/anie.202004963 . 1433-7851 . 7496830 . 32402113.
  14. Law . Brian J. C. . Struck . Anna-Winona . Bennett . Matthew R. . Wilkinson . Barrie . Micklefield . Jason . 2015-04-20 . Site-specific bioalkylation of rapamycin by the RapM 16-O-methyltransferase . Chemical Science . en . 6 . 5 . 2885–2892 . 10.1039/C5SC00164A . 2041-6539 . 5729408 . 29403635.
  15. Law . Brian J. C. . Bennett . Matthew R. . Thompson . Mark L. . Levy . Colin . Shepherd . Sarah A. . Leys . David . Micklefield . Jason . 2016-02-18 . Effects of Active-Site Modification and Quaternary Structure on the Regioselectivity of Catechol- O -Methyltransferase . Angewandte Chemie International Edition . en . 55 . 8 . 2683–2687 . 10.1002/anie.201508287 . 4770447 . 26797714.
  16. Struck . Anna-Winona . Bennett . Matthew R. . Shepherd . Sarah A. . Law . Brian J. C. . Zhuo . Ying . Wong . Lu Shin . Micklefield . Jason . 2016-03-09 . An Enzyme Cascade for Selective Modification of Tyrosine Residues in Structurally Diverse Peptides and Proteins . Journal of the American Chemical Society . en . 138 . 9 . 3038–3045 . 10.1021/jacs.5b10928 . 0002-7863. free .
  17. Okrasa . Krzysztof . Levy . Colin . Wilding . Matthew . Goodall . Mark . Baudendistel . Nina . Hauer . Bernhard . Leys . David . Micklefield . Jason . 2009-09-28 . Structure-Guided Directed Evolution of Alkenyl and Arylmalonate Decarboxylases . Angewandte Chemie International Edition . en . 48 . 41 . 7691–7694 . 10.1002/anie.200904112.
  18. Chesters . Christopher . Wilding . Matthew . Goodall . Mark . Micklefield . Jason . 2012-04-27 . Thermal Bifunctionality of Bacterial Phenylalanine Aminomutase and Ammonia Lyase Enzymes . Angewandte Chemie International Edition . en . 51 . 18 . 4344–4348 . 10.1002/anie.201200669.
  19. Francis . Daniel . Winn . Michael . Latham . Jonathan . Greaney . Michael F. . Micklefield . Jason . 2017-02-16 . An Engineered Tryptophan Synthase Opens New Enzymatic Pathways to β-Methyltryptophan and Derivatives . ChemBioChem . en . 18 . 4 . 382–386 . 10.1002/cbic.201600471.
  20. Dixon . Neil . Duncan . John N. . Geerlings . Torsten . Dunstan . Mark S. . McCarthy . John E. G. . Leys . David . Micklefield . Jason . 2010-02-16 . Reengineering orthogonally selective riboswitches . Proceedings of the National Academy of Sciences . en . 107 . 7 . 2830–2835 . 10.1073/pnas.0911209107 . 0027-8424 . 2840279 . 20133756.
  21. Wu . Ming-Cheng . Lowe . Phillip T. . Robinson . Christopher J. . Vincent . Helen A. . Dixon . Neil . Leigh . James . Micklefield . Jason . 2015-07-22 . Rational Re-engineering of a Transcriptional Silencing PreQ 1 Riboswitch . Journal of the American Chemical Society . en . 137 . 28 . 9015–9021 . 10.1021/jacs.5b03405 . 0002-7863. 10023/7200 . free .
  22. Robinson . Christopher J. . Vincent . Helen A. . Wu . Ming-Cheng . Lowe . Phillip T. . Dunstan . Mark S. . Leys . David . Micklefield . Jason . 2014-07-30 . Modular Riboswitch Toolsets for Synthetic Genetic Control in Diverse Bacterial Species . Journal of the American Chemical Society . en . 136 . 30 . 10615–10624 . 10.1021/ja502873j . 0002-7863. free .
  23. Web site: Enzyme discovery - 2023 Chemistry Biology Interface Horizon Prize: Rita and John Cornforth Award winner . 2023-07-24 . Royal Society of Chemistry . en-GB.
  24. Web site: Professor Jason Micklefield - 2022 Interdisciplinary Prize winner . 2023-07-24 . Royal Society of Chemistry . en-GB.
  25. Web site: Bader Prize - previous winners . 2023-07-24 . Royal Society of Chemistry . en-GB.

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