Primary research interest

Biocatalysis and Molecular Toxicology

About me

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.

Research focus and collaborations

Research in the Gillam lab focuses on cytochrome P450 enzymes, especially those responsible for xenobiotic metabolism in humans. These are enzymes of exceptional versatility, able to catalyse over 60 different chemical reactions and being responsible for the clearance of a practically unlimited variety of chemicals from the body. Structural and functional studies on P450s should yield fundamental insights into how enzyme structure determines function. Moreover, the biotechnological potential of P450s remains to be exploited.

Directed (or artificial) evolution: 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 recombinatorial directed evolution to generate libraries of mutants from naturally-occurring P450 forms with the aim of selecting for properties that are commercially useful. This technique has been proven to be able to "breed" enzyme catalysts with properties enhanced by orders of magnitude over those found in naturally occurring enzymes. We are currently evolving enzymes for use in drug discovery and development in collaboration with Dr. Martin Hayes at AstraZeneca, Sweden, and for use in bioremediation with Dr. John Oakeshott from the CSIRO, Canberra.

Factors controlling enzyme catalysis and catalytic promiscuity in P450 enzymes

Collectively P450s of the 3A, 2D and 2C subfamilies handle about 95% of all drugs and other chemicals to which humans are exposed. This substrate range is truly exceptional. We are studying these enzymes to determine how they can metabolise so many substrates – i.e. show catalytic promiscuity - while retaining some degree of regio- and chemoselectivity towards certain substrates. In particular, comparisons of catalytically promiscuous, native forms with evolved enzymes specialised towards one particular substrate, should allow us to understand the structural basis to catalytic promiscuity in these highly versatile enzymes. Recently we have 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.

Enzyme design

In collaboration with Dr. Mikael Boden we are developing novel bioinformatic methods by which to predict functional properties of enzymes based on analysis of enzyme libraries. The aim of this work is to provide accurate models of enzyme properties which can be used to design biocatalysts with desired properties.

Resources

In the course of our research, members of the lab have developed software that is useful for the design, creation and analysis of enzyme libraries for directed evolution studies.

  • RE-cut: a programme to determine optimal restriction enzyme combinations for restriction enzyme-mediated DNA family shuffling
  • Xover: a programme for analysing the crossover patterns of chimaeric (or mosaic) mutant sequences created by recombination of multiple parental DNA sequences
  • CORE: a programme for designing structure-guided gene recombination experiments, an extension and further development of the SCHEMA algorithm developed by the Arnold laboratory (Voigt et al., (2002) Protein building blocks preserved by recombination, Nature Structural Biology, 9, 553-558.)

This software is made available to the wider scientific community for academic research but if you choose to use these programmes in your work, please cite them appropriately. 

Please contact me for download links.

Funded projects

  • ARC Discovery Project 2012-2014
    Tracing nature's template: using statistical machine learning to evolve biocatalysts
    (M. Boden, E. Gillam)
    Total value of grant: $320,000
  • ARC Linkage Project
    Biocatalysts mined from cytochrome P450 libraries: an innovative tool for accelerating drug development
    (E. Gillam, J. De Voss, M. A. Hayes) 
    Total value of grant: $791,000
  • ARC Discovery Project
    Evolving enzymes to harness the clean energy reserves of nature
    (E. Gillam, D. Ollis)
    Total value of grant: $263,000

Achievements and awards 

  • Secretary Elect (2004-2005), Secretary (2006-2007), Chair of the Membership Affairs Committee (2001-2005),International Society of the Study of Xenobiotics
  • Councillor (2000-2003) and member of the Scientific Affairs Committee and Nomination Committee of the International Society of the Study of Xenobiotics
  • International Advisory Board for the International Symposia on Microsomes and Drug Oxidations
  • Member of the Faculty of 1000
  • Editorial Advisory Boards of Chemical Research in Toxicology, Current Drug Metabolism and Drug Metabolism Letters

Teaching interests

Biochemistry, enzymology, drug metabolism and molecular toxicology

Featured publications

Researcher biography

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. Recently we have 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.

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. Moreover, 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.

P450s in brain: relevance to mental illness and neurodegenerative diseases. While P450s are responsible for the metabolic clearance of drugs from the human body, this is not always a benevolent process: sometimes metabolites are generated that are chemically reactive and may cause mutagenic or other toxic effects. Moreover P450s are involved in the synthesis and degradation of important endogenous chemicals, physiological roles which can be affected by drugs and dietary chemicals. We are particularly interested in the role of P450s in brain chemistry. P450s localised in mitochondria have recently been shown to contribute to the neurotoxicity of some drugs and can lead to oxidative damage to mitochondria, possibly contributing to the development of neurodegenerative diseases.

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.