Stephen Bell

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.

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.

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.

  • 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
    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
    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 Converting cytochrome P450s into efficient peroxygenases for the synthesis of drug metabolites Doctor of Philosophy Doctorate Full Time Mr Matthew Podgorski
    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
  • Past Higher Degree by Research Supervision (University of Adelaide)

    Date Role Research Topic Program Degree Type Student Load Student Name
    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 - 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
    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 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 - 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
  • 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 - -
  • Position: Associate Professor/Reader
  • Phone: 83134822
  • Email: stephen.bell@adelaide.edu.au
  • Fax: 83134380
  • Campus: North Terrace
  • Building: Badger, floor G
  • Org Unit: Chemistry

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