Michael Stephenson

Dr

  • 3.03 Chemistry

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Postgraduate Research Opportunities

*** Current competitively funded PhD opportunity in my lab: ELUCIDATING THE CONTROL MECHANISMS OF NATURE'S MOST COMPLEX ENZYMATIC REACTIONS ***

Click here for all current PhD opportunities within the School of Chemistry. Michael also welcomes enquiries to discuss alternative sources of funding from prospective PhD candidates with a passion for organic chemistry who are interested in working in an interdisciplinary field.

Biography

Dr Michael Stephenson is a Lecturer in Organic Medicinal Chemistry at UEA. His research focuses on utilising the plant-based transient expression of biosynthetic enzymes to investigate, explore, and ultimately manipulate the biosynthesis of high-value natural products.

Michael received his MPharm degree (1st Class) from the University of East Anglia in 2010. He then went on to complete his pre-registration training at the Queen Elizabeth Hospital in Kings Lynn, qualifying as a fully registered Pharmacist in 2011. Michael then returned to academia to pursue a PhD in Medicinal Chemistry under the supervision of Professor Mark Searcey in the School of Pharmacy at the University of East Anglia. This was awarded in 2015 for the development of novel methodology for the rapid synthesis of analogues of the potent antitumor-antibiotic duocarmycin. Michael then moved to the Department of Metabolism and Biochemistry at John Innes Centre in Norwich as Postdoctoral Scientist. Here he was the lead Organic Chemist in the research group of Professor Anne Osbourn (FRS, OBE) working at the interface between Natural Product Chemistry and Synthetic Biology. In September 2022 Michael returned to the University of East Anglia to take up his current post in the School of Chemistry

Career

  • MPharm (1st Class) | UEA - School of Pharmacy | 2006-2010
  • Pre-registration Pharmacist | Queen Elizabeth Hospital Kings Lynn | 2010-2011
  • PhD Medicinal Chemistry | UEA - School of Pharmacy | 2011-2015
  • Postdoctoral Scientist | John Innes Centre – Department of Metabolism and Biochemistry | 2015-2022
  • Lecturer in Organic Medicinal Chemistry | UEA – School of Chemistry | 2022Present

Key Research Interests

Michael’s research sits at the interface between Natural Product Chemistry and Synthetic Biology. His lab utilises agrobacterium-mediated transient expression in Nicotiana benthamiana to study the biosynthesis of plant natural products. This is a powerful and convenient technique for the functional characterisation of biosynthetic enzymes. It also has substantial preparative utility with potential to improve access to difficult to synthesize natural products.     

The current focus of Michael’s group is studying the biosynthesis of triterpenes and triterpene-derived natural products; in particular, the enzymatically controlled cyclisation and rearrangement of 2,3-oxidosqualene. The triterpenes represent an incredibly diverse and important family of natural products. Despite the immense structural diversity observed, all triterpene alcohols are derived from the same linear precursor known as 2,3-oxidosqualene. The differential cyclisation of this substate represents the first level of triterpenoid diversification and is a process initiated and controlled by a superfamily of enzymes known as oxidosqualene cyclases (OSCs). These reactions are some of the most complex single-enzyme transformations observed in nature. Indeed, the underpinning reaction mechanisms have captured the interest of organic chemists for the best part of a century. Michael’s group works on elucidating how OSCs control the key reaction steps that differentiate between major classes of basal triterpene scaffolds, exploring the diversity of this chemical space by prospecting for OSCs displaying novel product profiles, and utilising the knowledge gained to manipulate these enzymes to perform unnatural reactions. A major focus of the group is the exploration of a novel cyclisation route that Michael and colleagues discovered in 2019 through studying OSCs mined from the Rice genome. This unprecedented discovery represents a transformative divergence from a central dichotomy in the reactions pathways of polycyclic triterpenes which had stood for over 60 years. If widespread in nature, this novel third cyclisation route widens the theoretical scope of natural triterpenoid diversity. It could also call into question the reliability of stereochemical assignments of existing triterpene structures when supported by only limited spectroscopic evidence. The group is also interested in elucidating the biosynthetic pathways of triterpene-derived natural products, particularly those with medicinally relevant biological activity, to improve preparative access to these compounds for biological evaluation and drug development.

Selected Publications: 

Making drugs out of sunlight and ‘thin air’: an emerging synergy of synthetic biology and natural product chemistry Biochem, 2020, 42 (4): 34-39

Identification of key enzymes responsible for protolimonoid biosynthesis in plants: Opening the door to azadirachtin production PNAS, 2019, 116 (34): 17096-17104

The protosteryl and dammarenyl cation dichotomy in polycyclic triterpene biosynthesis revisited: has this ‘rule’ finally been broken? Nat Prod Rep, 2019, 36: 1044-1052

Transient Expression in Nicotiana Benthamiana Leaves for Triterpene Production at a Preparative Scale JoVE, 2018, 138, e58169 

A translational synthetic biology platform for rapid access to gram-scale quantities of novel drug-like molecules Met Eng, 2017, 42: 185-193

Solid-Phase Synthesis of Duocarmycin Analogues and the Effect of C-Terminal Substitution on Biological Activity J Org Chem, 2015, 80 (19): 9454–9467 

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