Associate Professor Stephen Bell
Associate Professor/Reader
School of Physics, Chemistry and Earth Sciences
Faculty of Sciences, Engineering and Technology
Eligible to supervise Masters and PhD - email supervisor to discuss availability.
Enzyme Catalysis
Students are working on wide range of projects related to the application of enzyme for chemical synthesis using interdisciplinary methods from Biochemistry, Synthetic Biology and Chemistry suitable for students with a background in Chemistry and Biological Science with an interest in enzyme biocatalysis, chemical synthesis, the structure of metalloproteins, microbiology of secondary metabolite synthesis and how proteins/enzymes have evolved to function.
The screening, engineering and directed evolution of enzymes holds great promise for biotechnological applications. In the lab we study enzymes for biocatalysis and organic synthesis applications. The ultimate goal is to develop these systems as biocatalysts for clean, sustainable, low energy oxidation processes with applications in natural product synthesis (for example generation of valuable flavour and fragrance compounds) and then bioremediation of recalcitrant compounds such as aromatic hydrocarbons.
We engineer cytochrome P450 enzymes to alter their function and identify new enzymes from metabolically diverse bacteria and archaea which are capable of binding and oxidising a wide range of organic compounds. We currently focus on steroid and terpenoid oxidising enzymes from a range of microorganisms. Many of these microbes have evolved to survive in extreme conditions (e.g. temperature and pH) and we are exploring these robust enzymes as biocatalysts using new methods developed by graduate students here at Adelaide.
We also identify new electron transfer partners (e.g. iron-sulphur ferredoxin proteins and flavoproteins) in order to improve the efficiency of the enzymes which is essential for scale-up of their activity. We develop whole cell oxidation systems, which enable the easy screening, scale-up and production of oxygenated organic products.
We are involved in collaborative work with other researchers to
1) to study the mechanism of action of these enzymes which is important in understanding drug metabolism and design
2) Determine the structure of the enzymes by X-ray crystallography and other techniques such as NMR and Mass Spectroscopy
3) Immobilise the enzymes on different solid state supports to enhance their stability and lifetime.
- My Research
- Career
- Publications
- Grants and Funding
- Teaching
- Supervision
- Professional Activities
- Contact
The isolation and study of cytochrome P450 enzymes for biocatalysis and medicinal chemistry
The cytochrome P450 superfamily of haem iron monooxygenases is found in virtually all living organisms. They catalyse the oxidation of numerous endogenous and exogenous organic compounds and perform vital functions such as the biosynthesis of steroids and antibiotics and oxidative detoxification of xenobiotics. These monooxygenase enzymes catalyse the insertion of one atom of atmospheric oxygen into a carbon hydrogen bond.
R–H + 2H+ + 2e– + O2 → R–OH + H2O
The screening, engineering and directed evolution of cytochrome P450 enzymes for oxidation reactions holds great promise for biotechnological applications as these reactions are challenging to perform using traditional chemical synthesis. In the lab we study these cytochrome P450 enzymes for biocatalysis and organic synthesis applications. The ultimate goal is to develop these systems as robust biocatalysts for clean, sustainable, low energy oxidation processes in natural product synthesis (e.g. flavour and fragrance compounds) and bioremediation of recalcitrant compounds (e.g. polyaromatic hydrocarbons and lignin mononmers).
We identify new enzymes from a wide range of bacteria and archaea and assess their function and potential applications. Projects include
1) designing and testing inhibitors for P450 enzymes from pathogenic bacteria such as Mycobacterium tuberculosis
2) assessing the role of P450 enzymes from bacteria in secondary metabolism (steroids and terpenoid oxidation)
3) the development of efficient and thermostable oxygenase bicatalysts from extremophile organisms
We alter the sequence of these cytochrome P450 enzymes to change their function. We identify new enzymes from metabolically diverse bacteria which are capable of binding and oxidising a wide range of organic compounds. For example we have recently isolated P450 enzymes that are capable of selectively hydroxylating terpenoids and steroids. We have recently identified P450 enzymes which can tolerate conditions not usually suited for enzyme chemistry (high temperature, organic solvent and pH extremes). Using a method developed in Adelaide we modify these enzymes so they can efficiently use hydrogen peroxide to catalyse their reactions. Together this simplifies their application.
We have an interest in their electron transfer partners (e.g. iron-sulphur ferredoxin proteins and flavoproteins) in order to improve the efficiency of the purified enzymes and which is essential to design efficient whole-cell oxidation systems using synthetic biology. We have developed whole cell oxidation systems, which enable the easy screening, scale-up and production of oxygenated organic products. We aim to further optimise and scale-up these systems (in vitro and in vivo) using fermentor technology and bioprocess engineering to generate products on a large scale.
This work has led to the formation of a spin out company Oxford Biotrans (http://oxfordbiotrans.com/) which has been set up to use biocatalysis to generate compounds on a tonne scale which are used in the flavour and fragrance industry.
Students undertake a wide range of activities at the interface of Chemistry, Biochemistry, Synthetic Biology including protein synthesis and enzyme assays (biochemistry), and protein engineering (molecular biology). Scale-up of the enzyme activity and inhibitor synthesis requires organic chemistry techniques (synthesis) and analytical chemistry (HPLC, GC-MS etc.). This provides an excellent platform for students seeking jobs outside of academia. We also explore the structure of these enzymes using X-ray crystallography (variable temperature studies). Members of the group have also undertakem other spectroscopic techniques including, electrochemistry and EPR (electron paramagnetic resonance) studies of these cytochrome P450 enzymes at Adelaide and in collaboration with others.
The Australian Research Council are currently funding our research into P450 mechanism through a Discovery Project Grants. My research into isolating and understanding novel P450 electron transfer partners has been funded through an ARC Future Fellowship.
My group currently consists of 7-8 PhD Students and I have extensive experience in supervising Honours students.
Potential research students are directed to the Adelaide Graduate Centre for information on admissions, applications and scholarship
https://www.adelaide.edu.au/graduate-research/
Questions regarding typical research projects can be directed to Dr Bell.
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Appointments
Date Position Institution name 2017 - 2019 Associate Professor and ARC Future Fellow University of Adelaide 2017 - ongoing Associate Professor University of Adelaide 2015 - 2016 Senior Lecturer and ARC Future Fellow University of Adelaide 2012 - 2014 Lecturer University of Adelaide -
Awards and Achievements
Date Type Title Institution Name Country Amount 2016 Teaching Award OLT Citation for Outstanding Contributions to Student Learning University of Adelaide/Australian Government Department of Education and Training Australia - 2015 Fellowship ARC Future Fellowship University of Adelaide Australia - 2013 Achievement Founding Shareholder of Oxford Biotrans - United Kingdom - -
Education
Date Institution name Country Title Oxford university United Kingdom DPhil University of Oxford United Kingdom BA and MA Chemistry (Oxon) -
Research Interests
Biocatalysis and Enzyme Technology Biochemistry & Molecular Biology Bioinorganic Chemistry Bioprocessing, Bioproduction and Bioproducts Bioremediation Biotechnology Catalysis and Mechanisms of Reactions Chemical Sciences Enzymes Industrial Microbiology Industrial Molecular Engineering of Nucleic Acids and Proteins Inorganic Chemistry Medical Biochemistry: Proteins and Peptides Organic Chemical Synthesis Organic Chemistry Proteins and Peptides Structural Chemistry and Spectroscopy Synthetic Biology
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Journals
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Book Chapters
Year Citation 2017 Harbort, J. S., De Voss, J. J., Stok, J. E., Bell, S. G., & Harmer, J. R. (2017). CW and Pulse EPR of Cytochrome P450 to Determine Structure and Function. In L. Berliner, & G. Hanson (Eds.), Future Directions in Metalloprotein and Metalloenzyme Research (Vol. 13, pp. 103-142). Switzerland: Springer.
2007 Urlacher, V., Bell, S., & Wong, L. L. (2007). The bacterial cytochrome P450 monooxygenases: P450cam and P450BM-3. In R. D. Schmid, & V. B. Urlacher (Eds.), Modern Biooxidation: Enzymes, Reactions and Applications (pp. 99-122). Federal Republic of Germany: Wiley.
Scopus142007 Bell, S., Hoskins, N., Whitehouse, C., & Wong, L. (2007). Design and engineering of cytochrome P450 systems. In A. Sigel, H. Sigel, & R. Sigel (Eds.), The Ubiquitous Roles of Cytochrome P450 Proteins: Metal Ions in Life Sciences (Volume 3) (Vol. 3, pp. 437-476). West Sussex, England: Wiley.
Scopus282005 Wong, L., & Bell, S. G. (2005). Iron: Heme Proteins, Mono‐ & DioxygenasesBased in part on the article Iron: Heme Proteins, Mono‐ & Dioxygenases by Masanori Sono & John H. Dawson which appeared in the<i>Encyclopedia of Inorganic Chemistry, First Edition</i>.. Wiley.
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Conference Papers
Year Citation 2017 Wong, S. H., Bell, S. G., & De Voss, J. J. (2017). P450 catalysed dehydrogenation. In Proceedings of the 23rd International Conference on Physical Organic Chemistry (ICPOC-23 2016) as published in Pure and Applied Chemistry Vol. 89 (pp. 841-852). Germany: Walter de Gruyter.
Scopus16 WoS112010 Wong, L. L., Whitehouse, C. J. C., Yang, W., Yorke, J. A., Blanford, C. F., Bell, S. G., . . . Rao, Z. (2010). Engineering P450s by Rational Design. In DRUG METABOLISM REVIEWS Vol. 42 (pp. 20). Istanbul, TURKEY: INFORMA HEALTHCARE. -
Conference Items
Year Citation 2015 Williamson, N. M., Huang, D. M., Bell, S. G., & Metha, G. F. (2015). Guided Inquiry Learning in an Introductory Chemistry Course. Poster session presented at the meeting of International Chemical Congress of Pacific Basin Societies (Pacifichem). Honolulu, USA. 2012 Williamson, N. M., Metha, G. F., Huang, D. M., & Bell, S. G. (2012). Development of POGIL-Style Organic Chemistry Activities. Poster session presented at the meeting of Proceedings of the Australian Conference on Science and Mathematics Education. Sydney. -
Patents
Year Citation 2009 Wong, L., Bell, S., & Whitehouse, C. (2009). Mutant Enzymes. Great Britan. -
Preprint
Year Citation 2024 Harlington, A. C., Das, T., Shearwin, K. E., Bell, S. G., & Whelan, F. (2024). The S-lignin<i>O</i>-demethylase SyoA: Structural insights into a new class of heme peroxygenase enzymes.
2023 Akter, J., Hayball, E., & Bell, S. (2023). Efficient regio- and stereo-selective C-H bond hydroxylation of steroids using an engineered heme-thiolate peroxygenase biocatalyst.
2023 Lee, J., Bruning, J., & Bell, S. (2023). In Crystallo Reactions with an Engineered Cytochrome P450 Peroxygenase.
Grants and Funding
The Australian Research Council are currently funding our research into P450 mechanism through Discovery Project Grants and a Future Fellowship
We have grants to understand
1) the role of cholesterol metabolism in Mycobacterium tuberculosis in an effort to inhibit this pathogenic bacterium which cause tuberculosis.
2) the isolation of new thermostable biocatalyst and methods to apply these (immoblisation) for synthetic applications.
3) the design of inhibitors for steroid oxidising P450 enzymes in humans which play a role in prostate cancer.
Teaching
I have taught a broad range of courses across all Levels of Chemistry with a focus on Inorganic Chemistry.
Chem III Inorganic Reaction Mechanisms and Organometallic Chemistry - with a focus on the reaction kinetics of ligand exchange in metal complexes and how this can be applied to design of metal complexes which can be used in biology and medicine.
Medicinal and Biological Chemistry III - Electron transfer - focus on electron transfer in Chemistry and Biology. Understanding the mechanism, significance and roles of electron transfer in metal-ligand complexes and biological systems. How biological systems have been optimised to regulate electron transfer processes which are critical to life.
I also teach a range of first year courses - Transition metal chemistry, Kinetics and Electrochemistry.
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Current Higher Degree by Research Supervision (University of Adelaide)
Date Role Research Topic Program Degree Type Student Load Student Name 2024 Principal Supervisor Characterization of peroxygenase activity in CYP154 enzymes from the thermophilic bacterium Thermobifida fusca Doctor of Philosophy Doctorate Full Time Ms Oghenesivwe Osiebe 2024 Principal Supervisor Exploration and Exploitation of Novel Thermally Adapted Cytochromes P450 and their Biotechnological Uses Doctor of Philosophy Doctorate Full Time Mr Delroy Sheng Yu Huang 2023 Principal Supervisor Engineering CYP17A1 inhibitors for castrate-resistant prostate cancer Doctor of Philosophy Doctorate Full Time Mr Nikita Yevstigneyev 2023 Principal Supervisor Characterization and Structural Study of Cytochrome P450 enzymes from thermophilic bacteria Doctor of Philosophy Doctorate Full Time Mr Tuhin Das 2023 Co-Supervisor Naphtalimide Scaffolds for Optical+XRF multimodal Probes Doctor of Philosophy Doctorate Full Time Mr Terry Koh 2023 Co-Supervisor The Controlled Release of Therapeutic Agents Utilising Nucleic Acid Analogs Master of Philosophy Master Full Time Mr Liam Matthew Carson 2022 Principal Supervisor Combining machine-learning and rational design for engineering heme enzyme biocatalysts and biosensors. Doctor of Philosophy Doctorate Full Time Miss Alecia Rachel Gee 2022 Principal Supervisor Synthesis of inhibitors for steroid metabolising enzymes Doctor of Philosophy Doctorate Full Time Miss Eva Hayball -
Past Higher Degree by Research Supervision (University of Adelaide)
Date Role Research Topic Program Degree Type Student Load Student Name 2020 - 2024 Principal Supervisor The Application of Peroxygenase P450 Enzymes as Selective Oxidation Catalysts Doctor of Philosophy Doctorate Full Time Ms Jinia Akter 2020 - 2024 Principal Supervisor Evolution and inhibition of cholesterol catabolising P450 enzymes in pathogenic mycobacteria Doctor of Philosophy Doctorate Full Time Mr Daniel Zocchi Doherty 2019 - 2023 Principal Supervisor Protein and Reaction Engineering of P450 Enzymes for Selective Oxidations Doctor of Philosophy Doctorate Full Time Dr Joel Hoong Zhang Lee 2019 - 2023 Principal Supervisor Understanding cytochrome P450 cholesterol metabolism in bacteria Doctor of Philosophy Doctorate Full Time Dr Amna Jamal Saad Mohamed Ghith 2018 - 2020 Principal Supervisor Exploring the Monooxygenase Activity and Selectivity of Two Related Cytochrome P450 Enzymes Master of Philosophy Master Full Time Mr Saurabh Kumar Ahirwar 2018 - 2023 Principal Supervisor Structural and Functional Investigations of Cytochrome P450 Enzymes from Mycobacterium Species Doctor of Philosophy Doctorate Full Time Miss Hebatalla Ahmed Ibrahim Mohamed 2017 - 2020 Principal Supervisor Investigation of the Mechanism of Multiple Cytochrome P450-catalysed Reactions Master of Philosophy Master Full Time Mr Matthew Podgorski 2016 - 2018 Principal Supervisor Harnessing P450 Enzymes as Biocatalysts for Selective C-H Bond Hydroxylation Master of Philosophy Master Full Time Dr Joel Hoong Zhang Lee 2016 - 2020 Principal Supervisor Enzyme Immobilisation using Porous Frameworks Doctor of Philosophy Doctorate Full Time Dr Natasha Kate Maddigan 2015 - 2019 Principal Supervisor Strategies to improve the efficiency of oxidation reactions of the enzyme Cytochrome P450Bm3 Doctor of Philosophy Doctorate Full Time Ms Shaghayegh Dezvarei 2015 - 2019 Principal Supervisor Application of the Monooxygenase Enzymes CYP101B1 and CYP101C1 from Novosphingobium aromaticivorans for Selective and Efficient Functionalisation of Inert C-H Bonds Doctor of Philosophy Doctorate Full Time Mr Md Raihan Sarkar 2015 - 2017 Co-Supervisor Isolation of New P450s and the Modification of Existing P450s for Biocatalysis Master of Philosophy Master Full Time Mr Ian Cheuk-Kei Lau 2014 - 2016 Co-Supervisor Investigations and Applications of Self-Sufficient Cytochrome P450 Monooxygenases Master of Philosophy Master Full Time Mr Samuel Munday 2014 - 2018 Principal Supervisor Deciphering Electron Transfer and Cytochrome P450 Activity in Mycobacterium marinum Doctor of Philosophy Doctorate Full Time Ms Stella Agnes Child 2014 - 2018 Principal Supervisor Utilising CYP199A4 from Rhodopseudomonas palustris HaA2 for investigation of the mechanism of cytochrome P450-catalysed oxidations Doctor of Philosophy Doctorate Full Time Tom Coleman 2014 - 2016 Co-Supervisor Utilising CYP199A4 from Rhodopseudomonas Palustris HaA2 for Biocatalysis and Mechanistic Studies Master of Philosophy Master Full Time Miss Rebecca Chao 2013 - 2015 Co-Supervisor The Efficient and Selective Catalytic Oxidation of Terpenoids and Aromatic Hydrocarbons by the P450 Monooxygenase CYP101B1 Master of Philosophy Master Full Time Emma Ashleigh Hall
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Committee Memberships
Date Role Committee Institution Country 2013 - ongoing Member Steering committee of the Adelaide Integrated Bioscience Laboratories - Australia -
Editorial Boards
Date Role Editorial Board Name Institution Country 2016 - ongoing Member Scientific Reports - -
Connect With Me
External Profiles