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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. Wenyi Gu’s early education was conducted in China which include his undergraduate and master’s degrees in veterinary medicine. In 1996, he migrated to Australia and pursued his PhD study in biochemistry & molecular biology at the Australian National University (ANU). After a short period of work at John Curtin Medical School ANU as a junior scientist, he moved to Brisbane in 2001 for his post-doc at the University of Queensland and currently a post-doctoral research fellow at AIBN. He held a Peter Doherty Fellowship (2006-2009) and was further supported by NHMRC to spend 7 months at Harvard University as a visiting fellow in 2008. Since his post-doctoral research he has been working in the area of using RNAi to treat viral diseases and cancers. He also has a strong background in immunology and vaccine development.

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.

Dr Li Li is a Senior Research Fellow at Australian Institute for Bioengineering and Nanotechnology. She received her PhD in Chemical Engineering from China University of Petroleum.

In 2007, she joined the University of Queensland (UQ) as a postdoctoral research fellow in the ARC Centre of Excellence for Functional Nanomaterials, working on nanoparticles and nanomaterials for renewable energy production and storage, environment technology and catalysis including hydrogen production and storage, environmental protection, and gas adsorption. In 2011, she was awarded UQ Postdoctoral Fellowship under the supervision of Prof. Zhi Ping (Gordon) Xu, working on engineered nanomaterials in healthcare and environment control. After Postdoctoral Fellowship, she was awarded Advance Queensland Research Fellow in 2016. Her research focuses on design and engineering functional nanomaterials for drug/gene delivery, sustainable release and oral vaccine delivery for human health and animal health management. Since 2011, she has attracted 22+ research funding including Advance Queensland Fellowship (Mid), Queensland smart future fund, UQ Postdoctoral Research Fellowship, 3 UQ grants and 2 international collaboration projects. Moreover, she has a strong linkage with industry partners on the development of functional targeted nano-delivery systems to enhance the health of farm animals.

Dr Mostafa Kamal Masud is a CCQ Next Generation Cancer Research Fellow at the Australian Institute for Bioengineering & Nanotechnology (AIBN), the University of Queensland (UQ). In 2020, he received his PhD in Medical Biotechnology Diagnostics and Nanobiotechnology from AIBN, UQ. He received his MS and B.Sc. (Hons.) in Chemistry from Shahjalal University of Science and Technology (SUST), Sylhet-3114, Bangladesh. After completing his PhD, he was awarded a prestigious JSPS Postdoctoral Fellowship (success rate >10%) from Japan and served as a Postdoctoral Fellow at Japan's National Institute for Materials Science (NIMS).He recently been awarded a highly prestigious ARC DECRA fellowship for the period 2024-2026 and a QLD Cancer Council fellowship for the period 2024–2028. His research focuses on the development of novel nanostructures and nanodiagnostic technologies to address critical issues in medical diagnosis. As an early career researcher, he has an excellent track record with more than 50 peer-reviewed publications in prestigious and high-impact journals in the area that achieve <2400 citations with an h-index of 26 (Scholar google link: https://bit.ly/2Vtv67l). He has developed new classes of superparamagnetic nanostructures and fabricated novel biosensors for the detection of disease-specific biomolecular targets e.g., for miRNA, DNA, exosome and protein biomarker detection that have proven to be easy and effective, allowing for rapid diagnosis with minimal equipment. He made a major contribution to nanotechnology integrated-analytical and diagnostic fields by providing analytical and technological input as well as developing key collaborations with clinicians and biologists for translational research. His strategy is to create nano-architecture point-of-care diagnostic technology for early diagnosis of cancer that could hopefully lead to a healthy and happier life for humans.

Research Interests

• Advanced Drug Delivery and Nanomedicine 1.Advanced drug delivery methods (controlled release dosage forms such as tablets, granules and microspheres) 2. Biomaterials as next generation adjuvant for vaccine delivery 3. Surface modified nanomaterials (Silica, Polymer, Liposomes) 4. Programmable nanoparticales for oral drug delivery and targeting 5. Translocation of nanoparticles after oral drug delivery (In-vitro and In-vivo)

Qualifications

• Master of Pharmaceutical Science, Gujarat University
• Bachelor of Pharmacy, Gujarat University

Dr. Wang completed her MPhil study in the University of Queensland (UQ) in 2016 and PhD study in UQ in October 2020. As an early career researcher, Dr.Wang has demonstrated a high impact track record relative to opportunity with award of Dean's award for Excellence in Higher Degree Research (2016), the high proportion (41%) of first-authored publications, 28% of which in the top 10% most cited publications worldwide (Scopus 24/03/2021). She has been actively engaged in a number of professional activities in the research fields, including RHD student supervision, assessment for the master research projects (BIOX7021), talks at national and international conferences (The Australian Colloid and Interface Symposium Brisbane hub, 2021; The Australasian Society for Stem Cell Research ECR Symposium, 2021; BioNano Innovation, 2020) and conference organization (The Australian Colloid and Interface Symposium Brisbane hub, 2021).