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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.

Dr. Richard Gordon leads a multi-disciplinary, industry-partnered research program in Translational Neuroscience which integrates immunology, drug development, pharmacology, metabolomics and microbial metagenomics. His group aims to understand and therapeutically target key pathological mechanisms which drive the onset and progression of neurodegenerative disorders such as Parkinson’s disease (PD) and Amyotrophic Lateral Sclerosis (ALS). Their work combines target validation studies in human patients with mechanistic insights from disease models to develop and test novel therapeutic strategies that can be translated towards clinical trials.

Key research themes within this program include:

• Understanding how chronic immune and inflammasome activation contribute to neurodegeneration in the CNS
• The role of gut dysbiosis and gastrointestinal dysfunction in Parkinson’s disease pathophysiology
• Therapeutic targeting of the gut-brain axis for neuroprotection
• Drug discovery, development and repositioning for novel therapeutic targets
• Discovery and validation of clinical biomarkers for PD and ALS
• Clinical trials for disease-modifying therapeutic strategies

I am a Research Fellow and Leader in Pain Relief Innovation at AIBN, UQ. My research interests sit at the interface of drug delivery and the pain field. My overarching research goal is to improve the quality of day to day life of patients suffering from chronic pain, by applying nanotechnology to the development of novel highly effective pain-killer products for improving chronic pain management. I am looking for highly motivated postgraduate students.

I also enjoy volunteering within the academic community, most notably as Head of the SBMS ECR Committee and Treasurer for The Queensland Chinese Association of Scientists and Engineers (QCASE). I am currently serving as guest editor of Pain Research and Management.and JoVE Methods Collection.

Research Interests

My research is focusing on nano-based drug formulation and development to improve chronic pain management. I have a broad and unique background in both pharmacology and drug delivery systems, with specific expertise in the development of novel drug products and testing their analgesic efficacy and safety including pharmacokinetic and pharmacodynamic studies. To date, I have established five different techniques to produce painkiller–loaded nanoparticles and nanofibers aimed at improving pain relief for patients where currently available pain-killers either lack efficacy or produce dose-limiting side-effects. For example, there is a small and very potent peptide that has been on the market as a chemical for over 10 years but which cannot be used as a therapeutic due to its short half-life and poor oral bioavailability. In the form of my nanoparticles, that peptide has the potential to become an oral treatment for improving pain management in patients whose pain is currently poorly alleviated by clinically used pain-killers. I have significant expertise in the use of rodent pain models to assess novel analgesics, and I have received excellent training in conducting research in accordance with the stringent requirements of the Quality Management System (quality accreditations (GLP and ISO17025) from NATA). Together, my knowledge, skills and experience will facilitate the efficient translation of my research from the bench to the clinic.

The current focus of the lab is on the development of drug-products to solve one of the largest unmet medical needs in the pain field through use of sustainable materials. 1) We are developing multifunctional sutures including biodegradable pain relief sutures. 2) We are developing my innovative novel nanoparticles, which deliver innate-immune targeting peptides for the treatment of cancer and cancer-related pain. We are establishing a platform for the development of safe, effective delivery for other small molecule peptide drugs in general to pave their way to clinical trials. 3) Our research also investigates the role of C5a and C3a, estrogen, etc. in the pathogenesis of chronic pain including neuropathic pain, cancer-related pain, low back pain and OA pain.

We work in collaboration with other leading Australian and international researchers to stay at the forefront of the drug delivery systems field and the pain field. We also provide preclinical evaluation of novel compounds and formulations.

Treasure McGuire graduated with a Bachelor of Pharmacy and a Bachelor of Science (Pharmacology) from the University of Queensland UQ). She also completed a Postgraduate Diploma in Clinical Pharmacy and Graduate Certificate in Higher Education at UQ. In 2005, she completed her PhD in the School of Population Health, UQ, entitled Consumer medicines call centres: a medication liaison model of pharmaceutical care.

She has held a sennior conjoint appointment between the School of Pharmacy, UQ and Mater Pharmacy, Mater Health, Brisbane since 1996, and was appointed as a Senior Lecturer in 2006. In her Mater role, she has been Assistant Director of Pharmacy (Practice and Development) over this same time period. At UQ, she coordinates a graduate clinical pharmacy course within the Master of Clinical Pharmacy program. In 2016, this program received a UQ Faculty of Health and Behavioural Sciences Team Award for Programs that Enhance Learning and in 2017 a citation in the University of Queensland Award for Excellence in Teaching and Learning.

Treasure’s research is translational, focussing on patient centred-care and quality use of medicines in the domains of medicines information, evidence-based practice, medication safety, reproductive health, complementary medicines, communicable diseases and interprofessional education. She is a Fellow of the Australian College of Pharmacy and a Fellow of the Pharmaceutical Society of Australia.In recognition of her services to medicines information, she received the Lilly International Fellowship in Hospital Pharmacy and the Bowl of Hygeia of the Pharmaceutical Society of Australia. In 2015, she was the recipient of the Sr Eileen Pollard Medal (Mater Research-UQ) for excellence in incorporating research into clinical care provision.

Dr Osborne, BSc(Hons), MAgSc, PhD is an epidemiologist and toxicologist with research interests in using environmental epidemiology to examine aetiology and pathological pathways of disease. He has worked on a range of projects examining environmental exposures and health outcomes including exposure to metals, pollen, mould, chronic exposures to low levels of chemicals, pesticide and cyanotoxins. He also has experience examining how exposure to the environment may increase health and wellbeing (green/bluespace and solar irradiance and vitamin D).

He has developed skills in the linkage of environmental and population health data in an interdisciplinary context, and has expertise in design, linkage, hypothesis formulation, analysis, interpretation, translation and dissemination.

He has experience in designing and collecting epidemiological data and initiating studies of primary collected data (HealthIron, HealthNuts, Cornwall Housing Study, Survey of Recreational Water Users, Monitoring of Meniere’s Symptoms).

He also has used secondary data from existing cohorts (NHANES, UK Biobank, 1958 Birth Cohort, British Household Survey, Melbourne Collaborative Cohort Study, South Asian Clinical Toxicology Research Collaboration), as well as linkage of previously unconnected “big data” sets in mashups on novel platforms (MEDMI project). He has used traditional statistical methods such as linear/logistic regression, time series analysis, interrupted time series and Cox regression to ascertain associations between exposures and outcomes, as well as integrating confirmatory structured equation modelling with environmental/health data sets to construct conceptual diagrams of associations and assess pathway directions.

He currently researches pollen and health outcomes as well as chronic kidney disease in low to middle income countries.

He has supervised 6 PhD students to completion (2 primary supervisor, 4 co-supervisor) and currently supervises 4 PhD student. He has been associate editor of Archives of Environmental and Occupational Health since 2011 and is on the editorial board of International Journal of Epidemiology and Pediatric Allergy, Immunology and Pulmonology. He is a member of Australasian Epidemiology Association, International Society of Environmental Epidemiology and International Epidemiology Association.

He has previously worked at the Universities of NSW, Sydney, Exeter, Melbourne, Portsmouth, Queensland and Flinders, the Murdoch Children’s Research Institute and the Cancer Council Victoria. He completed his PhD at the School of Population Health, University of Queensland/National Research Centre of Environmental Toxicology working on the toxicology and public health effects of cyanobacterial toxins in southeast Queensland.