Biography:Jason Micklefield

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Short description: British Biochemist
Jason Micklefield
Jasonmicklefield.jpg
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

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) and Natural Product Reports (NPR) Lecture Award (2008).

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] New synthetic biology approaches were also used to create a de novo pathway to thaxtomin phytotoxin derivatives, with improved herbicidal properties for crop protection.[8] 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.[9][10] 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.[11][12][13][14][15] His lab succeeded in engineering orthogonal methyltransferases creating alternative bioalkylation pathways[12] and developed methods for selective derivatisation of tyrosine residues in peptides/proteins using methyltransferases and SAM analogues for labelling etc.[15] His team also characterised, engineered and developed many other important biocatalysts.[16][17][18] The Micklefield lab is also engaged in nucleic acids research, re-engineering the first orthogonal riboswitches (genetic tools and biosensors).[19][20][21]

Awards and honours

Royal Society of Chemistry, Chemistry Biology Interface Horizon Prize: Rita and John Cornforth Award (2023)[22]

Royal Society of Chemistry, Interdisciplinary Prize (2022)[23]

Royal Society of Chemistry, Bader Award (2019)[24]

References

  1. ↑ 1.0 1.1 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" (in en). Nature Communications 12 (1): 6872. doi:10.1038/s41467-021-27139-1. ISSN 2041-1723. PMID 34824225. PMC 8616955. https://www.nature.com/articles/s41467-021-27139-1. 
  2. ↑ 2.0 2.1 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" (in en). Nature 593 (7859): 391–398. doi:10.1038/s41586-021-03447-w. ISSN 1476-4687. https://www.nature.com/articles/s41586-021-03447-w. 
  3. ↑ 3.0 3.1 Law, Brian J. C.; Zhuo, Ying; Winn, Michael; Francis, Daniel; Zhang, Yingxin; Samborskyy, Markiyan; Murphy, Annabel; Ren, Lujing et al. (December 2018). "A vitamin K-dependent carboxylase orthologue is involved in antibiotic biosynthesis" (in en). Nature Catalysis 1 (12): 977–984. doi:10.1038/s41929-018-0178-2. ISSN 2520-1158. https://www.nature.com/articles/s41929-018-0178-2. 
  4. ↑ 4.0 4.1 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" (in en). Nature Catalysis 4 (5): 385–394. doi:10.1038/s41929-021-00603-3. ISSN 2520-1158. https://www.nature.com/articles/s41929-021-00603-3. 
  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" (in en). Nature Communications 13 (1): 380. doi:10.1038/s41467-022-28005-4. ISSN 2041-1723. PMID 35046426. PMC 8770729. https://www.nature.com/articles/s41467-022-28005-4. 
  6. ↑ 6.0 6.1 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" (in en). Nature Communications 7 (1): 11873. doi:10.1038/ncomms11873. ISSN 2041-1723. PMID 27283121. PMC 4906404. https://www.nature.com/articles/ncomms11873. 
  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" (in en). Angewandte Chemie International Edition 51 (29): 7181–7184. doi:10.1002/anie.201202043. https://onlinelibrary.wiley.com/doi/10.1002/anie.201202043. 
  8. ↑ Winn, Michael; Francis, Daniel; Micklefield, Jason (2018-06-04). "De novo Biosynthesis of "Non-Natural" Thaxtomin Phytotoxins" (in en). Angewandte Chemie International Edition 57 (23): 6830–6833. doi:10.1002/anie.201801525. PMID 29603527. PMC 6001691. https://onlinelibrary.wiley.com/doi/10.1002/anie.201801525. 
  9. ↑ 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" (in en). Angewandte Chemie International Edition 56 (39): 11841–11845. doi:10.1002/anie.201706342. PMID 28722773. PMC 5637929. https://onlinelibrary.wiley.com/doi/10.1002/anie.201706342. 
  10. ↑ Shepherd, Sarah A.; Karthikeyan, Chinnan; Latham, Jonathan; Struck, Anna-Winona; Thompson, Mark L.; Menon, Binuraj R. K.; Styles, Matthew Q.; Levy, Colin et al. (2015-05-18). "Extending the biocatalytic scope of regiocomplementary flavin-dependent halogenase enzymes" (in en). Chemical Science 6 (6): 3454–3460. doi:10.1039/C5SC00913H. ISSN 2041-6539. PMID 29511510. PMC 5659210. https://pubs.rsc.org/en/content/articlelanding/2015/sc/c5sc00913h. 
  11. ↑ 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. et al. (2018-08-13). "Structure and Biocatalytic Scope of Coclaurine N ‐Methyltransferase" (in en). Angewandte Chemie International Edition 57 (33): 10600–10604. doi:10.1002/anie.201805060. ISSN 1433-7851. PMID 29791083. PMC 6099451. https://onlinelibrary.wiley.com/doi/10.1002/anie.201805060. 
  12. ↑ 12.0 12.1 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" (in en). Angewandte Chemie International Edition 59 (35): 14950–14956. doi:10.1002/anie.202004963. ISSN 1433-7851. PMID 32402113. PMC 7496830. https://onlinelibrary.wiley.com/doi/10.1002/anie.202004963. 
  13. ↑ 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" (in en). Chemical Science 6 (5): 2885–2892. doi:10.1039/C5SC00164A. ISSN 2041-6539. PMID 29403635. PMC 5729408. https://pubs.rsc.org/en/content/articlelanding/2015/sc/c5sc00164a. 
  14. ↑ 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" (in en). Angewandte Chemie International Edition 55 (8): 2683–2687. doi:10.1002/anie.201508287. PMID 26797714. PMC 4770447. https://onlinelibrary.wiley.com/doi/10.1002/anie.201508287. 
  15. ↑ 15.0 15.1 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" (in en). Journal of the American Chemical Society 138 (9): 3038–3045. doi:10.1021/jacs.5b10928. ISSN 0002-7863. https://pubs.acs.org/doi/10.1021/jacs.5b10928. 
  16. ↑ 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" (in en). Angewandte Chemie International Edition 48 (41): 7691–7694. doi:10.1002/anie.200904112. https://onlinelibrary.wiley.com/doi/10.1002/anie.200904112. 
  17. ↑ Chesters, Christopher; Wilding, Matthew; Goodall, Mark; Micklefield, Jason (2012-04-27). "Thermal Bifunctionality of Bacterial Phenylalanine Aminomutase and Ammonia Lyase Enzymes" (in en). Angewandte Chemie International Edition 51 (18): 4344–4348. doi:10.1002/anie.201200669. https://onlinelibrary.wiley.com/doi/10.1002/anie.201200669. 
  18. ↑ 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" (in en). ChemBioChem 18 (4): 382–386. doi:10.1002/cbic.201600471. https://onlinelibrary.wiley.com/doi/10.1002/cbic.201600471. 
  19. ↑ 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" (in en). Proceedings of the National Academy of Sciences 107 (7): 2830–2835. doi:10.1073/pnas.0911209107. ISSN 0027-8424. PMID 20133756. PMC 2840279. https://pnas.org/doi/full/10.1073/pnas.0911209107. 
  20. ↑ 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" (in en). Journal of the American Chemical Society 137 (28): 9015–9021. doi:10.1021/jacs.5b03405. ISSN 0002-7863. https://pubs.acs.org/doi/10.1021/jacs.5b03405. 
  21. ↑ 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" (in en). Journal of the American Chemical Society 136 (30): 10615–10624. doi:10.1021/ja502873j. ISSN 0002-7863. https://pubs.acs.org/doi/10.1021/ja502873j. 
  22. ↑ "Enzyme discovery - 2023 Chemistry Biology Interface Horizon Prize: Rita and John Cornforth Award winner" (in en-GB). https://www.rsc.org/prizes-funding/prizes/2023-winners/enzyme-discovery/. 
  23. ↑ "Professor Jason Micklefield - 2022 Interdisciplinary Prize winner" (in en-GB). https://www.rsc.org/prizes-funding/prizes/2022-winners/professor-jason-micklefield/. 
  24. ↑ "Bader Prize - previous winners" (in en-GB). https://www.rsc.org/prizes-funding/prizes/find-a-prize/bader-award/previous-winners/. 



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