School of Physical Sciences
Faculty of Sciences
Eligible to supervise Masters and PhD - email supervisor to discuss availability.
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.
- My Research
- Grants and Funding
- Professional Activities
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.
Date Position Institution name 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
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 —
Date Institution name Country Title — Oxford university United Kingdom DPhil — University of Oxford United Kingdom BA and MA Chemistry (Oxon)
Research InterestsBiocatalysis and Enzyme Technology Biochemistry & Molecular Biology Bioinorganic Chemistry Bioprocessing, Bioproduction and Bioproducts Bioremediation Biotechnology Catalysis and Mechanisms of Reactions Chemical Sciences Enzymes 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
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. (2007). The bacterial cytochrome P450 monooxygenases: P450cam and P450BM-3. In R. Schmid, & V. 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. (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.
— Wong, L. -L., & Bell, S. G. (n.d.). Iron: Heme Proteins, Mono- & DioxygenasesBased in part on the article Iron: Heme Proteins, Mono- & Dioxygenases by Masanori Sono & John H. Dawson which appeared in theEncyclopedia of Inorganic Chemistry, First Edition.. John Wiley & Sons, Ltd.
— Urlacher, V. B., Bell, S. G., & Wong, L. -L. (n.d.). The Bacterial Cytochrome P450 Monooxygenases: P450cam and P450BM-3. In Modern Biooxidation (pp. 99-122). Wiley-VCH Verlag GmbH & Co. KGaA.
Year Citation 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.
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.
Year Citation 2009 Wong, L., Bell, S., & Whitehouse, C. (2009). Mutant Enzymes. Great Britan.
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.
Current Higher Degree by Research Supervision (University of Adelaide)
Date Role Research Topic Program Degree Type Student Load Student Name 2020 Principal Supervisor Investigation and characterisation of the P450 enzymes produced by various mycobacterium species. Doctor of Philosophy Doctorate Full Time Mr Daniel Zocchi Doherty 2020 Principal Supervisor Use of Peroxygenase P450 Enzymes as Oxidative Catalysts in the Synthesis of Natural Products Doctor of Philosophy Doctorate Full Time Ms Jinia Akter 2020 Principal Supervisor Converting cytochrome P450s into efficient peroxygenases for the synthesis of drug metabolites Doctor of Philosophy Doctorate Full Time Mr Matthew Podgorski 2019 Principal Supervisor Protein Engineering of P450 Enzymes into Functional Peroxygenases Doctor of Philosophy Doctorate Full Time Mr Joel Hoong Zhang Lee 2019 Principal Supervisor The Application of Cytochrome P450 Enzyme Biocatalytic Systems in the Hydroxylation of Organic Molecules Doctor of Philosophy Doctorate Part Time Mr Andrew Lesenko 2019 Principal Supervisor Understanding Cytochrome P450 cholesterol metabolism in bacteria Doctor of Philosophy Doctorate Full Time Miss Amna Jamal Saad Mohamed Ghith 2018 Principal Supervisor To study key metabolic pathways of E. coli involved in sustained high expression growth using a metabolic profiling approach to establish optimal fermentation conditions for the improvement of growth and recombinant protein expression efficiency while retaining maximum plasmid stability Doctor of Philosophy Doctorate Part Time Mrs Chandana Naga Suraparaju 2018 Principal Supervisor Optimizing Drug Design by Inhibiting the Steroid Biosynthesis Enzyme CYP51 Doctor of Philosophy Doctorate Full Time Miss Hebatalla Ahmed Ibrahim Mohamed
Past Higher Degree by Research Supervision (University of Adelaide)
Date Role Research Topic Program Degree Type Student Load Student Name 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 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 Mr Joel Hoong Zhang Lee 2016 - 2020 Principal Supervisor Enzyme Immobilisation using Porous Frameworks Doctor of Philosophy Doctorate Full Time Dr Natasha Kate Maddigan 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 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 - 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 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 - 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 - 2018 Principal Supervisor Deciphering Electron Transfer and Cytochrome P450 Activity in Mycobacterium marinum Doctor of Philosophy Doctorate Full Time Ms Stella Agnes Child 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
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