Associate Professor Stephen Bell
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 which are capable of binding and oxidising a wide range of organic compounds. We 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.
Eligible to supervise Masters and PhD, but is currently at capacity — email supervisor to discuss availability.
Genome mining and protein engineering of cytochrome P450 enzymes for biocatalysis
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 the oxidation of non-natural substrates holds great promise for biotechnological applications. In the lab we study these cytochrome P450 enzymes and their electron transfer partners for biocatalysis and organic synthesis applications. The ultimate goal is to develop these systems as biocatalysts for clean, sustainable, low energy oxidation processes in natural product synthesis and bioremediation of recalcitrant compounds.
We identify new enzymes from a wide range of bacteria and aim to work out their function and potential applications. This could range from
1) work with designing inhibitors for P450s which play an important role in pathogenic bacteria
2) P450s involved in the synthesis of important secondary metabolites in the bacteria.
We engineer cytochrome P450 enzymes to alter their function and 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 CYP enzymes that are capable of hydroxylating sesquiterpenoids, steroids, alkanes, polyaromatic hydrocarbons and substituted aromatics. We also identify new and engineer existing 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 also develop 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 of use to the flavour and fragrance industry.
Students undertake a wider range of activities at the interface of Chemistry and Biochemistry including protein synthesis and engineering (molecular biology), analytical and organic chemistry techniques, enzyme assays structure function studies. Members of the group undertake crystallographic, electrochemical and EPR (electron paramagnetic resonance) studies of these cytochrome P450 enzymes and their electron transfer partners at Adelaide and in collaboration with others. This provides gain a better understanding of different steps in the catalytic cycle and the protein-protein interactions in these systems.
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 is funded through an ARC Future Fellowship.
My group currently consists of 5 PhD Students and 2 M. Phil Students.
Potential research students are directed to the Adelaide Graduate Centre for information on admissions, applications and scholarship
Questions regarding typical research projects can be directed to Dr Bell.
|2017||Associate Professor and ARC Future Fellow||University of Adelaide|
|2015 - 2016||Senior Lecturer and ARC Future Fellow||University of Adelaide|
|2012 - 2014||Lecturer||University of Adelaide|
|Oxford university||United Kingdom||DPhil|
|University of Oxford||United Kingdom||BA and MA Chemistry (Oxon)|
|2017||Harbort, J., De Voss, J., Stok, J., Bell, S., & Harmer, J. (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.
|2007||Bell, S., Hoskins, N., Whitehouse, C., & Wong, L. L. (2007). Design and engineering of cytochrome P450 systems. In A. Sigel, H. Sigel, & R. K. O. 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.
|2010||Wong, L. L., Whitehouse, C. J., 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.|
|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.|
The Australian Research Council are currently funding our research into P450 mechanism through Discovery Project Grants and a Future Fellowship
ARC Discovery Project (2017-2019) DP170103531 Metal-organic Frameworks at the Biointerface (Christian Doonan. Chris Sumby, Stephen Bell, Paolo Falcaro)
This research will yield a detailed understanding of the chemistry that governs the crystallisation of Metal-organic Frameworks around functional biomacromolecules and explore the potential applications of these novel biocomposites. Functional biomacromolecules, such as proteins, show great promise for application to areas of significant commercial and social interest, like biotechnology and Industrial biocatalysis. The research will make significant advances toward the widespread commercial application of biocatalysts and biosensors by developing unique MOF-encapsulated biocatalytic platform materials that will allow inherently fragile biomacromolecules to retain activity in conditions typically required for industrial processes.
My research into isolating and understanding novel P450 electron transfer partners is funded through an ARC Future Fellowship (FT140100355).
ARC Future Fellow, (2014-2018) FT140100355 .
Enzyme catalysed oxidation reactions are key players in the production of naturally occurring biologically active molecules. These processes are tightly regulated by their electron transfer partners. This project will characterise new electron transfer ferredoxin proteins from a metabolically diverse bacterium. The outcomes will advance our understanding of electron transfer, a fundamental process. This will allow strategies to combat human and plant pathogens and unlock the potential of these systems as biocatalysts for the green chemical synthesis of complex and valuable chemicals.
ARC Discovery Project (2014-2016) DP140103229 (James De Voss, Stephen Bell, Mark Bartlam)
Cytochromes P450 are enzymes that play key roles in drug metabolism and biosynthesis. P450s often catalyse hydroxylation but also carry out important transformations such as dehydrogenation or carbon-carbon bond cleavage. Such reactions are pivotal in many biological pathways. This work will elucidate the mechanism of these transformations and the factors that facilitate their occurrence. This will mainly entail the synthesis of small organic mechanistic probes and determining the structure and stereochemistry of the product of enzymic oxidation. Understanding these mechanisms will allow us to predict when such reactions will occur, enabling their utilisation in for example drug design in the avoidance of the formation of toxic metabolites.
I have taught a broad range of courses across all Levels of Chemistry with a focus on Inorganic Chemistry.
Currently whilst on a Future Fellowship I am teaching two level III course
Chem III Inorganic Reaction Mechanisms - 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.
|Date||Role||Research Topic||Program||Degree Type||Student Load||Student Name|
|2018||Principal Supervisor||Genome Mining and Protein Engineering of Cytochrome Enzymes for Biocatalysis||Master of Philosophy||Master||Full Time||Mr Saurabh Kumar Ahirwar|
|2017||Principal Supervisor||Investigation of the mechanism of multiple P450 enzyme catalysed reactions||Master of Philosophy||Master||Full Time||Mr Matthew Podgorski|
|2017||Co-Supervisor||Spiropyran-Based Photoswitchable Protease Inhibitors||Doctor of Philosophy||Doctorate||Full Time||Miss Kathryn Angela Palasis|
|2016||Principal Supervisor||Protein Encapsulation in Metal Organic frameworks (MOFS)||Doctor of Philosophy||Doctorate||Full Time||Miss Natasha Kate Maddigan|
|2015||Principal Supervisor||Synthesis of Novel Substrates from Different Acetate Using Cytochrome P- 450 Enzymes||Doctor of Philosophy||Doctorate||Full Time||Mr Md Raihan Sarkar|
|2015||Principal Supervisor||Biocatalysis Using Bacterial Cytochrome P450 Enzymes||Doctor of Philosophy||Doctorate||Full Time||Ms Shaghayegh Dezvarei|
|2014||Principal Supervisor||Cytochrome P450 Proteins||Doctor of Philosophy||Doctorate||Full Time||Tom Coleman|
|2014||Principal Supervisor||Deciphering Electron Transfer in Bacteria||Doctor of Philosophy||Doctorate||Full Time||Ms Stella Agnes Child|
|Date||Role||Research Topic||Program||Degree Type||Student Load||Student Name|
|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||Utilising CYP199A4 from Rhodopseudomonas Palustris HaA2 for Biocatalysis and Mechanistic Studies||Master of Philosophy||Master||Full Time||Miss Rebecca Chao|
|2014 - 2016||Co-Supervisor||Investigations and Applications of Self-Sufficient Cytochrome P450 Monooxygenases||Master of Philosophy||Master||Full Time||Mr Samuel Munday|
|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|