![Professor Elizabeth Gillam](/sites/default/files/profiles/351.jpeg)
Overview
Background
The molecular evolution of cytochrome P450 Enzymes: biological catalysts of unprecedented versatility.
Cytochrome P450 enzymes (CYPs, P450s) especially those responsible for drug metabolism in humans, are the unifying theme of the research in our lab. These fascinating enzymes are catalysts of exceptional versatility, and functional diversity. In humans they are principally responsible for the clearance of a practically unlimited variety of chemicals from the body, but are also critical in many important physiological processes. In other organisms (plants, animals, bacteria, fungi, almost everything!) they carry out an unprecedented range of functions, such as defense, chemical communication, neural development and even pigmentation. P450s are involved in the biosynthesis of an unequalled range of potent, biologically active natural products in microbes, plants and animals, including many antibiotics, plant and animal hormones, signalling molecules, toxins, flavours and fragrances. We are studying how P450s have evolved to deal with novel substrates by reconstructing ancestral precursors and evolutionary pathways, to answer such questions as how did the koala evolve to live on eucalyptus leaves, a toxic diet for most mammals.
The capabilities of P450s are only just coming to be fully recognized and structural studies on P450s should yield critical insights into how enzyme structure determines function. For example, recently we discovered that P450s are present within cells in the Fe(II) form, a finding that has led to a radical revision of the dogma concerning the P450 catalytic cycle, and has implications for the control of uncoupling of P450 activity in cells. Importantly, the biotechnological potential of P450s remains yet to be exploited. All of the specific research themes detailed below take advantage of our recognized expertise in the expression of recombinant human cytochrome P450 enzymes in bacteria. Our group is interested in finding out how P450s work and how they can be made to work better.
Artificial evolution of P450s for drug development and bioremediation: a way of exploring the sequence space and catalytic potential of P450s. The demonstrated catalytic diversity of P450 enzymes makes them the ideal starting material for engineering sophisticated chemical reagents to catalyse difficult chemical transformations. We are using artificial (or directed) evolution to engineer enzymes that are more efficient, robust and specialized than naturally occurring enzymes with the aim of selecting for properties that are commercially useful in the areas of drug discovery and development and bioremediation of pollutants in the environment. The approach we are using also allows us to explore the essential sequence and structural features that underpin all ~12000 known P450s so as to determine how they work.
Synthetic biology of enzymes for clean, green, solar-powered chemistry in drug development, bioremediation and biosensors. We have identified ancestral enzymes that are extremely thermostable compared to their modern counterparts, making them potentially very useful in industry, since they can withstand long incubations at elevated temperatures. They can be used as ‘off the shelf’ reagents to catalyse useful chemistry, such as in in drug discovery and development, fine chemicals synthesis, and cleaning up the environment. Working with drug companies, we are exploring how they can be best deployed in chemical processes and what structural features make them efficient, robust and specialized. We are also immobilizing P450s in virus-like-particles as ‘designer’ reagents that can be recovered from reactions and reused. To make such processes cheaper and more sustainable, we are using photosynthesis to power P450 reactions for clean, green biocatalysis in microalgae.
Biosketch:
After graduating from UQ with first class Honours in Biochemistry, Elizabeth took up a Royal Commission for the Exhibition of 1851 Overseas Scholarship to pursue doctoral work at Oxford University then undertook postdoctoral work at the Center in Molecular Toxicology and Department of Biochemistry at Vanderbilt University School of Medicine with Prof. F.P. Guengerich. She returned to UQ in 1993 to take up a position in Pharmacology and joined the School of Chemistry and Molecular Biosciences in 2009 as a Professor of Biochemistry.
Availability
- Professor Elizabeth Gillam is:
- Available for supervision
- Media expert
Fields of research
Qualifications
- Bachelor (Honours) of Science (Advanced), The University of Queensland
- Doctor of Philosophy, University of Oxford
Research interests
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Protein engineering
Enzymes such as cytochromes P450 are powerful, specific catalysts that could be very useful in making chemical industries more sustainable and environmentally benign. However naturally occurring enzymes usually cannot survive the long process times and elevated temperatures used in industry. We are engineering enzymes to be thermostable, to tolerate organic solvents and to use alternative cofactors so that they can be employed as designer biocatalysts for the pharmaceutical and other chemical industries.
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Synthetic Biology
We are developing novel systems for biocatalysis to replace energy-intensive steps in chemical processes, such as in the synthesis of drugs, with more sustainable alternatives using enzymes. We are engineering cytochrome P450 enzymes as biocatalysts, attaching them to protein cages and linking them to photosynthesis as a green energy source.
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Molecular evolution
Plants and the animals that consume them are locked in an evolutionary battle involving chemical warfare: plants produce toxins to discourage animals from eating them and in turn, animals develop enzymes to metabolise the plant toxins. We are studying the way enzymes in animals have evolved to respond to the changing chemical environment presented by plant secondary metabolism, processes that have a direct bearing on the ability of people to metabolise drugs and other environmental chemicals.
Research impacts
Our research is leading to the development of more sustainable, environmentally friendly, chemical processes to accelerate drug development and improve the safety of medicines. Our studies into the evolution of catalytic promiscuity in P450s reveal how organisms have evolved to deal with chemicals in the environment and provide insights as to how enzymes develop novel functions. More broadly, the methods that we have developed with colleagues at UQ and in industry for the ancestral reconstruction of P450s and their implementation as sophisticated biocatalysts in industry can be applied to the optimisation of other proteins and enzymes for biotechnological application.
Works
Search Professor Elizabeth Gillam’s works on UQ eSpace
2005
Journal Article
Exploring the potential of xenobiotic-metabolising enzymes as biocatalysts: Evolving designer catalysts from polyfunctional cytochrome P450 enzymes
Gillam, Elizabeth M. J. (2005). Exploring the potential of xenobiotic-metabolising enzymes as biocatalysts: Evolving designer catalysts from polyfunctional cytochrome P450 enzymes. Clinical and Experimental Pharmacology and Physiology, 32 (3), 147-152. doi: 10.1111/j.1440-1681.2005.04165.x
2005
Journal Article
Modified nicotine metabolism in transgenic tobacco plants expressing the human cytochrome P450 2A6 cDNA
Dueckershoff, K., Unger, M., Frank, A., Gillam, E. M. J., Guengerich, F. P. and Warzecha, H. (2005). Modified nicotine metabolism in transgenic tobacco plants expressing the human cytochrome P450 2A6 cDNA. Febs Letters, 579 (11), 2480-2484. doi: 10.1016/j.febslet.2005.02.082
2005
Journal Article
Functional characterisation of an engineered multidomain human P450 E1 by molecular Lego
Fairhead, M., Giannini, S., Gillam, E. M. J. and Gilardi, G. (2005). Functional characterisation of an engineered multidomain human P450 E1 by molecular Lego. Journal of Biological Inorganic Chemistry, 10 (8), 842-853. doi: 10.1007/s00775-005-0033-1
2005
Journal Article
Characterization of the human cytochrome P450 forms involved in metabolism of tamoxifen to its alpha-hydroxy and alpha,4-dihydroxy derivatives
Notley, LM, Crewe, KH, Taylor, PJ, Lennard, MS and Gillam, EMJ (2005). Characterization of the human cytochrome P450 forms involved in metabolism of tamoxifen to its alpha-hydroxy and alpha,4-dihydroxy derivatives. Chemical Research In Toxicology, 18 (10), 1611-1618. doi: 10.1021/tx050140s
2005
Journal Article
P4502C18 catalyzes the metabolic bioactivation of phenytoin
Kinobe, Robert T., Parkinson, Oliver T., Mitchell, Deanne J. and Gillam, Elizabeth M. J. (2005). P4502C18 catalyzes the metabolic bioactivation of phenytoin. Chemical Research In Toxicology, 18 (12), 1868-1875. doi: 10.1021/tx050181o
2004
Journal Article
Assessment of arginine 97 and lysine 72 as determinants of substrate specificity in cytochrome P450 2C9 (CYP2C9)
Davies, C., Witham, K., Scott, J. R., Pearson, A., De Voss, J. J., Graham, S. E. and Gillam, E. M. J. (2004). Assessment of arginine 97 and lysine 72 as determinants of substrate specificity in cytochrome P450 2C9 (CYP2C9). Drug Metabolism and Disposition, 32 (4), 431-436. doi: 10.1124/dmd.32.4.431
2003
Journal Article
Rabbit CYP4B1 engineered for high-level expression in Escherichia coli: ligand stabilization and processing of the N-terminus and heme prosthetic group
Cheesman, Matthew J., Baer, Brian R., Zheng, Yi-Min, Gillam, Elizabeth M. J. and Rettie, Allan E. (2003). Rabbit CYP4B1 engineered for high-level expression in Escherichia coli: ligand stabilization and processing of the N-terminus and heme prosthetic group. Archives of Biochemistry And Biophysics, 416 (1), 17-24. doi: 10.1016/S0003-9861(03)00278-9
2003
Conference Publication
Cytochrome P4501B1: a target for inhibition in anticarcinogenesis strategies
Guengerich, F. Peter, Chun, Young-Jin, Kim, Donghak, Gillam, Elizabeth M. J. and Shimada, Tsutomu (2003). Cytochrome P4501B1: a target for inhibition in anticarcinogenesis strategies. Conference on Dietary and Medicinal Antimutagens and Anticarcinogens, Seoul, South Korea, 17-19 October, 2001. Amsterdam: Elseiver. doi: 10.1016/S0027-5107(02)00333-0
2003
Journal Article
Molecular modelling of human CYP1B1 substrate interactions and investigation of allelic variant effects on metabolism
Lewis, DFV, Gillam, EMJ, Everett, SA and Shimada, T (2003). Molecular modelling of human CYP1B1 substrate interactions and investigation of allelic variant effects on metabolism. Chemico-biological Interactions, 145 (3), 281-295. doi: 10.1016/S0009-2797(03)00021-8
2003
Journal Article
Evaluation of recombinant cytochromes P450 activity in metabolic pathways - Response
Gillam, EMJ and Lennard, MS (2003). Evaluation of recombinant cytochromes P450 activity in metabolic pathways - Response. Drug Metabolism and Disposition, 31 (1), 146-146.
2003
Conference Publication
Web-based problem-solving exercises in assessment
Henly, D. C., Gillam, E. M. J., Huxham, G. J. and Forrest, A. (2003). Web-based problem-solving exercises in assessment. 3rd International Symposium on PBL in Dental Education, Victor Harbour, SA, January, 2003.
2003
Journal Article
Role of glutamic acid 216 in cytochrome P450 2D6 substrate binding and catalysis
Guengerich, F. Peter, Hanna, Imad H., Martin, Martha V. and Gillam, Elizabeth M. J. (2003). Role of glutamic acid 216 in cytochrome P450 2D6 substrate binding and catalysis. Biochemistry, 42 (5), 1245-1253. doi: 10.1021/bi027085w
2003
Conference Publication
Directed evolution of mammalian cytochrome P450 enzymes involved in xenobiotic metabolism
Rosic, Nedeljka, Lonhienne, Thierry G.A., DeVoss, James J. and Gillam, Elizabeth M.J. (2003). Directed evolution of mammalian cytochrome P450 enzymes involved in xenobiotic metabolism. 8th European Meeting of the International-Society-for-the-Study-of-Xenobiotics (ISSX), Dijon, France, 27 April - 1 May, 2003. New York: Marcel Dekker. doi: 10.1081/DMR-120020120
2002
Journal Article
DNA–protein adducts: hijacking one repair process to examine another
Gillam, E. M. J. (2002). DNA–protein adducts: hijacking one repair process to examine another. Trends in Pharmacolgical Sciences, 23 (5), 210-210. doi: 10.1016/S0165-6147(02)02033-3
2002
Journal Article
Bioactivation of tamoxifen by recombinant human cytochrome P450 enzymes
Notely, Lisa M., de Wolf, Cornelia J. F., Wunsch, Rebecca M., Lancaster, Roy G. and Gillam, Elizabeth M. J. (2002). Bioactivation of tamoxifen by recombinant human cytochrome P450 enzymes. Chemical Research in Toxicology, 15 (5), 614-622. doi: 10.1021/tx0100439
2002
Journal Article
S-SXR-RMs? Selective SXR response modulators - the future of designer drug interactions?
Gillam, E. M. J. (2002). S-SXR-RMs? Selective SXR response modulators - the future of designer drug interactions?. Trends in Pharmacological Sciences, 23 (8), 355-355. doi: 10.1016/s0165-6147(02)02092-8
2002
Journal Article
Metabolism of tamoxifen by recombinant human cytochrome P450 enzymes: Formation of the 4-hydroxy, 4′-hydroxy andN-desmethyl metabolites and isomerization oftrans-4-hydroxytamoxifen
Crewe, H. K., Notley, L. M., Wunsch, R. M., Lennard, M. S. and Gillam, E. M. J. (2002). Metabolism of tamoxifen by recombinant human cytochrome P450 enzymes: Formation of the 4-hydroxy, 4′-hydroxy andN-desmethyl metabolites and isomerization oftrans-4-hydroxytamoxifen. Drug Metabolism and Disposition, 30 (8), 869-874. doi: 10.1124/dmd.30.8.869
2002
Journal Article
Coordinating clearance - the many phases of PXR!
Gillam, E. M. J. (2002). Coordinating clearance - the many phases of PXR!. Trends in Pharmacological Sciences, 23 (12), 548-549. doi: 10.1016/s0165-6147(02)02158-2
2002
Journal Article
Effect of tamoxifen on the enzymatic activity of human cytochrome CYP2B6
Sridar, C, Kent, UM, Notley, LM, Gillam, EMJ and Hollenberg, PF (2002). Effect of tamoxifen on the enzymatic activity of human cytochrome CYP2B6. Journal of Pharmacology And Experimental Therapeutics, 301 (3), 945-952. doi: 10.1124/jpet.301.3.945
2002
Journal Article
Opposites attract, or do they? Rethinking the P450 2D6 pharmacophore model
Gillam, E. M. J. (2002). Opposites attract, or do they? Rethinking the P450 2D6 pharmacophore model. Trends in Pharmacological Sciences, 23 (11), 501-501. doi: 10.1016/s0165-6147(02)02121-1
Funding
Current funding
Supervision
Availability
- Professor Elizabeth Gillam is:
- Available for supervision
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Available projects
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Engineering enzymes for bioremediation of microplastics
Plastics such as polyethylene (PE) are major pollutants in both terrestrial and aquatic environments because they are not easily degraded in nature. Physico-chemical methods for PE remediation are energy intensive and not economically sustainable, raising the possibility of bioremediation instead. The larvae of the greater wax moth (GWM, Galleria mellonella) feed on beeswax, which is rich in long-chain alkanes, and have recently been shown to consume chemically similar low-density PE at considerably higher rates than those currently reported for PE-degrading microbes. Recent work suggests that P450 enzymes may be involved but the mechanism by which this occurs is not yet clear and there is no consensus on how the degradation is achieved biochemically, or even whether it is carried out entirely by the caterpillars themselves or with a contribution from the gut microbiota. Intriguingly, PE breakdown appears to involve a shift to high pH in the lumen of the insect gut, suggesting these enzymes may operate extracellularly and under very alkaline conditions, both of which are highly unusual for P450 enzymes. This project will involve expressing these enzymes and analysing their activity under the high pH and low oxygen conditions of the gut environment. We will then engineer them by ancestral sequence reconstruction (ASR) to identify thermostable and more pH-neutral forms of the PE-degrading P450s to develop a system in which these enzymes can be used for breakdown of microplastics in wastes.
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How did koalas evolve to exist entirely on eucalyptus leaves, which are toxic to most mammals?
The diet of koalas is unique in comprising effectively 100% eucalyptus leaves, which contain a variety of toxic terpenes. Despite the interest in koala conservation and many years of study, we still do not understand how koalas can exist on such a this toxic diet. However a clue has come in the sequencing of the koala genome: compared to other marsupials and mammals more generally, koalas show a dramatic expansion in the CYP2C subfamily of cytochrome P450 enzymes. P450s are regarded as responsible for the metabolism of dietary and other environmental xenobiotics, so we hypothesise that the CYP2C forms in koalas have expanded to deal with the terpenes present in their diet and can oxidise these chemicals to facilitate their clearance from the koala’s circulation.
This project will test this hypothesis by synthesising the CYP2C enzymes from koalas then expressing them in E. coli with the extant reductase accessory enzyme. We will determine how well the recombinant enzymes metabolise cineole and other eucalyptus terpenes. In so doing, we hope to answer a fundamental question about the biology of this iconic Australian animal, and one that has implications for koala conservation.
If the hypothesis is proven to be correct (i.e. the extant koala CYP2C forms metabolise terpenes), selected ancestors of these CYP2C enzymes will be inferred, reconstructed and expressed to determine how the ability to metabolise eucalyptus terpenes arose during koala evolution, a model of how proteins evolve new functions.
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Engineering a sustainable source of strigolactone hormones to improve food security across the world.
Strigolactones (SLs) are a class of plant hormones that control many traits important for agriculture including shoot and root architecture, nutrient uptake and responses to parasitic weeds. Parasitic weeds stimulated by plant-derived SLs are widespread in arable lands of many developing countries and have devastating impacts on food production. Application of synthetic SLs to infested soils would provide a way to clear arable land of parasitic weeds and greatly enhance food security in the third world. Biotechnological sources of natural or chemically modified SLs would also improve agricultural crop yield and reduce manual labour costs in horticultural industries. The overall objective of this project is to develop means for SL production in biofactories and to improve the potency of synthetic and/or biofactory/engineered SLs. We will do so by analysing the evolution of naturally occurring SL-synthesising enzymes and leveraging ancestral sequence reconstruction to engineer robust novel 'designer' enzymes with specific desired activities.
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Crystallisation of thermostable ancestral cytochrome P450 enzymes
We have developed ancestral P450 enzymes that are extremely thermostable compared to modern enzymes, making them potentially very useful in industry, since they can withstand long incubations at elevated temperatures. They can be used as ‘off the shelf’ reagents to catalyse useful chemistry, such as in in drug discovery and development, fine chemicals synthesis, and cleaning up the environment. Working with drug companies, we are exploring how they can be best deployed in chemical processes and what structural features make them efficient, robust and specialized. Key to this is obtaining crystal structures of the enzymes to determine why they are more stable.
We have already obtained crystals of a number of different thermostable P450s so this project would allow a student to make accelerated progress towards the goal of obtaining a structure for high impact publications that would be of great interest to industry as well as the field of protein structural biology and engineering.
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Scaling up cytochrome P450-mediated biocatalysis for industry
We have developed ancestral P450 enzymes that can be used as ‘off the shelf’ reagents to catalyse useful chemistry, such as in in drug discovery and development, fine chemicals synthesis, and cleaning up the environment. Working with drug companies, we are exploring how they can be best deployed in chemical processes. This synthetic biology project is part of a collaboration with the Danish Technocal University and the multinational drug company, AstraZeneca, to further engineer these enzymes to be stable to oxidising conditions that currently limit reaction scale-up. It would suit students with a biochemistry, molecular biology or biochemical/process engineering background. A competitive UQ-DTU scholarship is currently open to support this project which would involve the succesful student spending some time in Copenhagen.
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Synthetic biology of P450s for clean, green, solar-powered chemistry in drug development, bioremediation and biosensors
We have developed ancestral P450 enzymes that can be used as ‘off the shelf’ reagents to catalyse useful chemistry, such as in in drug discovery and development, fine chemicals synthesis, and cleaning up the environment. Working with drug companies, we are exploring how such biocatalytic processes can be made cheaper and more sustainable. In particular, we can replace the requirement for an expensive redox cofactor (NADPH) by linking the P450s to photosynthesis, to power P450 reactions for clean, green biocatalysis in microalgae.
This synthetic biology project would suit a student with a biochemistry, molecular biology, plant biology or biochemical engineering background and will be undertaken in collaboration with the pharmaceutical company, AstraZeneca.
Supervision history
Current supervision
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Doctor Philosophy
Nano-scale bioreactors: Protein cages as reusable scaffolds for designer enzymes
Principal Advisor
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Doctor Philosophy
Development of Cytochrome P450 Enzymes as Biocatalysts for Metabolite and Novel Drug Candidate Synthesis for the Pharmaceutical Industry.
Principal Advisor
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Doctor Philosophy
Nano-bioreactors for sustainable biopolymer production
Principal Advisor
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Doctor Philosophy
Coupling of P450 ancestors with the photosynthetic machinery of Chlamydomonas reinhardtii for light-driven biocatalysis in vitro
Principal Advisor
Other advisors: Dr Ian Ross, Professor Ben Hankamer
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Doctor Philosophy
Evolution of cytochrome P450 enzymes in response to dietary and environmental chemicals
Principal Advisor
Other advisors: Dr Gabriel Foley
Completed supervision
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2022
Doctor Philosophy
Ancestral reconstruction and characterisation of the CYP2U subfamily
Principal Advisor
Other advisors: Professor Mikael Boden
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2021
Doctor Philosophy
Engineering stable cytochrome P450 2D forms as competent biocatalysts for industrial applications
Principal Advisor
Other advisors: Professor Luke Guddat
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2021
Doctor Philosophy
Structural and functional characterisation of ancestral cytochromes P450 from family 2 in tetrapods
Principal Advisor
Other advisors: Professor Luke Guddat
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2020
Doctor Philosophy
Ancestral reconstruction of cytochrome P450 family 1, 4 and cytochrome P450 reductase: Insights into evolution and applications in biocatalysis
Principal Advisor
Other advisors: Professor Mikael Boden
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2020
Doctor Philosophy
Development and Characterisation of Cytochrome P450 Support Systems
Principal Advisor
Other advisors: Professor James De Voss
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2013
Doctor Philosophy
Characterisation of the expression of indole-metabolising cytochrome P450 enzymes in the human brain
Principal Advisor
Other advisors: Dr Simon Worrall
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2012
Doctor Philosophy
Directed evolution of enzymes of cytochrome P450 catalysis: Evolving CYP1A, CYP2D and P450 reductase
Principal Advisor
Other advisors: Professor James De Voss
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2011
Doctor Philosophy
Investigations of cytochromes P450 using the DNA family shuffling method.
Principal Advisor
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2007
Doctor Philosophy
REDOX PROPERTIES AND MEMBRANE LOCALIZATION OF HUMAN RECOMBINANT CYTOCHROME P450 SYSTEMS
Principal Advisor
Other advisors: Professor James De Voss, Professor Paul Bernhardt
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2005
Doctor Philosophy
MOLECULAR BREEDING OF CYTOCHROME P450s FOR INDIGOID PIGMENT PRODUCTION
Principal Advisor
Other advisors: Professor James De Voss
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2004
Doctor Philosophy
THE INITIATION OF AUTO-IMMUNE REACTIONS ON ANTI-CONVULSANT INDUCED HYPERSENSITIVITY: THE ROLE OF CYTOCHROME P450 ENZYMES
Principal Advisor
Other advisors: Dr Simon Worrall
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2023
Doctor Philosophy
Novel terpene based agrochemicals: Exploring cytochromes P450 mediated diversification of the strigolactone structure
Associate Advisor
Other advisors: Dr Birgitta Ebert
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2022
Doctor Philosophy
Methods for ancestral sequence reconstruction of large and complex protein families
Associate Advisor
Other advisors: Emeritus Professor Ross Barnard, Associate Professor Michael Landsberg, Professor Mikael Boden
Media
Enquiries
Contact Professor Elizabeth Gillam directly for media enquiries about:
- Bacterial expression
- Biocatalysis
- Bioremediation
- Chemical industries
- Drug discovery
- Drug metabolism
- Enzymes
- Human cytochrome P450 enzymes
- Molecular toxicology
- P450 enzymes
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