Deciphering Electron Transfer Pathways in Bacteria. Enzyme catalysed oxidation reactions are key players in the production of naturally occurring biologically active molecules. These processes are tightly regulated by their electron transfer partners. This project aims to characterise new electron transfer ferredoxin proteins from a metabolically diverse bacterium. These ferredoxins, important in many bacteria, contain different non-cysteine amino acids in their iron-sulfur cluster binding motif ....Deciphering Electron Transfer Pathways in Bacteria. Enzyme catalysed oxidation reactions are key players in the production of naturally occurring biologically active molecules. These processes are tightly regulated by their electron transfer partners. This project aims to characterise new electron transfer ferredoxin proteins from a metabolically diverse bacterium. These ferredoxins, important in many bacteria, contain different non-cysteine amino acids in their iron-sulfur cluster binding motifs and are poorly defined. The outcomes will advance understandings of electron transfer, a fundamental process. This will allow strategies to combat human and plant pathogens and unlock the potential of these systems as biocatalysts for the green chemical synthesis of complex and valuable chemicals.Read moreRead less
Understanding the mechanism of two important cytochrome P450 catalysed reactions: dehydrogenation and C-C cleavage. Cytochromes P450 are enzymes that play key roles in drug metabolism and biosynthesis. P450s often catalyse hydroxylation but also carry out important transformations such as dehydrogenation or carbon-carbon bond cleavage. Such reactions are pivotal in many biological pathways. This work will elucidate the mechanism of these transformations and the factors that facilitate their occu ....Understanding the mechanism of two important cytochrome P450 catalysed reactions: dehydrogenation and C-C cleavage. Cytochromes P450 are enzymes that play key roles in drug metabolism and biosynthesis. P450s often catalyse hydroxylation but also carry out important transformations such as dehydrogenation or carbon-carbon bond cleavage. Such reactions are pivotal in many biological pathways. This work will elucidate the mechanism of these transformations and the factors that facilitate their occurrence. This will mainly entail the synthesis of small organic mechanistic probes and determining the structure and stereochemistry of the product of enzymic oxidation. Understanding these mechanisms will allow us to predict when such reactions will occur, enabling their utilisation in for example drug design in the avoidance of the formation of toxic metabolites.Read moreRead less
Post-translational control of cell fate decision. Deciphering the multi-layered regulation of cell fate decisions is challenging. While progress has been made in understanding the role of transcriptional regulation, the influence of post-translational modification is poorly understood. Neural precursor cell expressed developmentally down-regulated protein 4 (NEDD4)-mediated ubiquitination is absolute necessary for sex determination, a unique model of cell fate decision where gonadal cell precurs ....Post-translational control of cell fate decision. Deciphering the multi-layered regulation of cell fate decisions is challenging. While progress has been made in understanding the role of transcriptional regulation, the influence of post-translational modification is poorly understood. Neural precursor cell expressed developmentally down-regulated protein 4 (NEDD4)-mediated ubiquitination is absolute necessary for sex determination, a unique model of cell fate decision where gonadal cell precursors differentiate either along the male or the female pathway. Thus, this project aims to analyse in detail at which stage NEDD4 action is required and what are the crucial target proteins. This project could provide a deeper understanding of how post-translational modifications influence cell fate decisions during embryogenesis.Read moreRead less
Unravelling cell wall polysaccharide biosynthesis in pathogenic zygomycetes. This project aims to define mechanisms that control cell wall composition and stability in Rhizopus oryzae, a zygomycete fungus responsible for life-threatening human infections. The biochemical properties and function of vital enzymes involved in a newly discovered cell wall polysaccharide biosynthetic pathway will be determined using innovative approaches at the interface of biochemistry, microbiology, cell biology an ....Unravelling cell wall polysaccharide biosynthesis in pathogenic zygomycetes. This project aims to define mechanisms that control cell wall composition and stability in Rhizopus oryzae, a zygomycete fungus responsible for life-threatening human infections. The biochemical properties and function of vital enzymes involved in a newly discovered cell wall polysaccharide biosynthetic pathway will be determined using innovative approaches at the interface of biochemistry, microbiology, cell biology and structural biology. Expected outcomes include new knowledge on the enzymes that synthesise major fucose-based carbohydrates, to guide the future development of novel strategies for antifungal therapies. The data will also be applicable to animal protection from related zygomycete pathogens.
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Three-dimensional structures, substrate specificities and catalytic mechanisms of polysaccharide synthases. Plant wall polysaccharides are extensively used for food and fibre, and are important dietary components in human nutrition. A precise knowledge of mechanisms used by plants to synthesize these polysaccharides is unavailable, but would reveal potential routes to manipulate their biosynthesis in important crop species. For example, the levels or structures of polysaccharides might be modif ....Three-dimensional structures, substrate specificities and catalytic mechanisms of polysaccharide synthases. Plant wall polysaccharides are extensively used for food and fibre, and are important dietary components in human nutrition. A precise knowledge of mechanisms used by plants to synthesize these polysaccharides is unavailable, but would reveal potential routes to manipulate their biosynthesis in important crop species. For example, the levels or structures of polysaccharides might be modified to improve their efficacy as anti-cancer agents in human diets, to enhance digestibility of animal stock feeds, or to synthesise pharmologically valuable compounds. Thus, economic, social and environmental benefits will flow to both producers and consumers. Read moreRead less
Striving for the path of least herbicide resistance. This project aims to investigate novel strategies to mitigate the rise in herbicide resistance threatening Australian agricultural production and exports. The project expects to pioneer long-term strategies for the development of herbicides that “resist” resistance generation in weeds to prolong their effectiveness. Expected outcomes include advances in the development of single- and multi-target herbicidal compounds with new modes of action, ....Striving for the path of least herbicide resistance. This project aims to investigate novel strategies to mitigate the rise in herbicide resistance threatening Australian agricultural production and exports. The project expects to pioneer long-term strategies for the development of herbicides that “resist” resistance generation in weeds to prolong their effectiveness. Expected outcomes include advances in the development of single- and multi-target herbicidal compounds with new modes of action, and validation of their potential to yield synergistic combinations and delay the evolution of resistance. This should lay the foundations for significant long-term benefits to farmers and consumers, both in Australia and globally, including increased crop yields and improved food security.Read moreRead less
New Insights into the Structure and Function of Pyruvate Carboxylase. Pyruvate carboxylase plays an essential roles in insulin secretion by pancreatic islets and in normal brain function, but excess expression of this enzyme in liver and adipose tissue is associated with diabetes and obesity.
Understanding the function of each structural feature in the reaction mechanism of an enzyme is essential to designing safe and effective pharmaceuticals that are required to modulate its activity.
Th ....New Insights into the Structure and Function of Pyruvate Carboxylase. Pyruvate carboxylase plays an essential roles in insulin secretion by pancreatic islets and in normal brain function, but excess expression of this enzyme in liver and adipose tissue is associated with diabetes and obesity.
Understanding the function of each structural feature in the reaction mechanism of an enzyme is essential to designing safe and effective pharmaceuticals that are required to modulate its activity.
This project, which will use cutting edge techniques in an experimental model, seeks to characterise this important enzyme's function so that better treatments can be developed in future for diabetes and obesity.
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Defining peptide structure and function: the shape of things to come. In this project we develop new and general ways of chemically defining the structure and function of natural peptides. This then provides a basis of potential therapies to treat a number of diseases currently confronting Australia's aging population, for example, cataract, Alzheimer's disease, cancer, and cardiovascular disease.
Regulation of autophagy dependent cell and tissue deletion. This project aims to elucidate novel mechanisms that regulate autophagy-depdendent cell death during animal development. It will combine the power of Drosophila genetics with multidisciplinary approaches, such as proteomics, bioinformatics and cell biology. Given the conserved nature of autophagy the oucomes will provide highly topical and exciting new knowledge of broad biological significance. The project will help establishing inter ....Regulation of autophagy dependent cell and tissue deletion. This project aims to elucidate novel mechanisms that regulate autophagy-depdendent cell death during animal development. It will combine the power of Drosophila genetics with multidisciplinary approaches, such as proteomics, bioinformatics and cell biology. Given the conserved nature of autophagy the oucomes will provide highly topical and exciting new knowledge of broad biological significance. The project will help establishing international collaborations, enhancing Australia’s competitiveness and reputation in an important area of research, and provide training of HDR students in skills across a range of areas. In the long-term the research findings may translate into improved agriculture, food production and human health outcomes.Read moreRead less
Structural and Functional Aspects of the Allosteric Regulation of Pyruvate Carboxylase by Acyl-CoA Compounds. Pyruvate carboxylase occupies a central location in intermediary metabolism catalysing the formation of oxaloacetate, a key component of the Krebs' tricarboxylic acid cycle especially in its synthetic modes in gluconeogenesis, lipogenesis and in the synthesis of neurotransmitters.
This project aims: (i) To produce crystals of pyruvate carboxylase for determining its structure by X-ra ....Structural and Functional Aspects of the Allosteric Regulation of Pyruvate Carboxylase by Acyl-CoA Compounds. Pyruvate carboxylase occupies a central location in intermediary metabolism catalysing the formation of oxaloacetate, a key component of the Krebs' tricarboxylic acid cycle especially in its synthetic modes in gluconeogenesis, lipogenesis and in the synthesis of neurotransmitters.
This project aims: (i) To produce crystals of pyruvate carboxylase for determining its structure by X-ray diffraction; (ii) To use affinity-labelling to determine the amino acid residues in the binding site of the enzyme's allosteric activator, acetyl-CoA; (iii) To construct chimeric enzymes from different species to define regions of the enzyme which affect its responses to its important allosteric activator, acetyl-CoA.
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