DNA Nanoshuttles: A New Class of DNA-Binding Molecules. The interaction of molecules with DNA, the molecule that controls genetic information, is fundamental to drug design, diagnosis of disease and the environment. DNA-nanoshuttles are ring-shaped molecules that thread onto DNA and shuttle from one end to the other. This threading interaction is without precedent and hence DNA-nanoshuttles have significant potential applications in all areas of medicine, biotechnology and nanotechnology that in ....DNA Nanoshuttles: A New Class of DNA-Binding Molecules. The interaction of molecules with DNA, the molecule that controls genetic information, is fundamental to drug design, diagnosis of disease and the environment. DNA-nanoshuttles are ring-shaped molecules that thread onto DNA and shuttle from one end to the other. This threading interaction is without precedent and hence DNA-nanoshuttles have significant potential applications in all areas of medicine, biotechnology and nanotechnology that involve DNA interactions. This research may lead to the design of new diagnostics and applications that will benefit the Australian community, and will provide excellent training of researchers in skills required for employment in the biotechnology and pharmaceutical fields.Read moreRead less
Dinuclear Ruthenium Complexes as Sequence- and Structure-Selective Binding Agents for DNA. Studies of the interaction of mononuclear metal complexes with DNA have greatly increased our understanding of the ways that small molecules recognise particular sites on DNA. However, in order to design drugs that target specific genes, and hence be potentially capable of controlling gene expression, it is necessary to study the binding of metal complexes that can associate with larger segments of DNA. ....Dinuclear Ruthenium Complexes as Sequence- and Structure-Selective Binding Agents for DNA. Studies of the interaction of mononuclear metal complexes with DNA have greatly increased our understanding of the ways that small molecules recognise particular sites on DNA. However, in order to design drugs that target specific genes, and hence be potentially capable of controlling gene expression, it is necessary to study the binding of metal complexes that can associate with larger segments of DNA. Using the combined expertise of the applicants, it is proposed to stereospecifically synthesise dinuclear complexes and study their DNA binding. This will greatly assist in the development of drugs that can selectively target genes and altered DNA.Read moreRead less
Mechanistic Studies on Biologically Active Iron Chelators. The need for orally effective drugs as alternatives to invasive treatment regimens such as subcutaneous infusion is an ongoing concern in health care. This is particularly true in people suffering iron overload. In many cases this condition is present at birth and thus the administration of vital iron chelation therapy via the oral route is a much preferred option. We have unearthed a novel series of candidates for iron chelation therapy ....Mechanistic Studies on Biologically Active Iron Chelators. The need for orally effective drugs as alternatives to invasive treatment regimens such as subcutaneous infusion is an ongoing concern in health care. This is particularly true in people suffering iron overload. In many cases this condition is present at birth and thus the administration of vital iron chelation therapy via the oral route is a much preferred option. We have unearthed a novel series of candidates for iron chelation therapy (the pyridine-2-carboxaldehyde isonicotinoyl hydrazone [PCIH] analogues) which show oral activity. These chelators undergo some interesting iron catalysed oxidation chemistry and it is vital that the mechanism of this reaction be elucidated to determine whether it will be of biological significance upon administration of these compounds as iron chelators.Read moreRead less
Understanding biological nitrogen fixation: an investigation of multi-electron reduction catalysis at novel iron-sulfur clusters. A new class of iron-sulfur clusters held together by a central light atom will be prepared and their reactions thoroughly studied. These clusters are important because they will have the same structure as the iron-molybdenum cluster of the enzyme nitrogenase. This enzyme fixes atmospheric nitrogen as ammonia. It is the primary route of nitrogen entry into all living s ....Understanding biological nitrogen fixation: an investigation of multi-electron reduction catalysis at novel iron-sulfur clusters. A new class of iron-sulfur clusters held together by a central light atom will be prepared and their reactions thoroughly studied. These clusters are important because they will have the same structure as the iron-molybdenum cluster of the enzyme nitrogenase. This enzyme fixes atmospheric nitrogen as ammonia. It is the primary route of nitrogen entry into all living systems. Industrially ammonia is produced in an energy-demanding process on a vast scale. The studies will provide insights into how nitrogenase works and how to design new multi-electron reduction catalysts. The research may lead to new energy-efficient routes to ammonia and to other new alternative fuel sources. Such processes would transform Australian industry and how we live.Read moreRead less
The roles of metal ions in glucose metabolism and the treatment of diabetes. Metal supplements, such as chromium and vanadium are consumed widely for their purported fat reduction and anti-diabetic activities. However, much is still to be learnt about the efficacy and safety of such metal ions when they are taken in supplements and whether they have an essential role in the prevention of diabetes or, in some instances, are a risk factor for cancer. The research will provide an understanding of ....The roles of metal ions in glucose metabolism and the treatment of diabetes. Metal supplements, such as chromium and vanadium are consumed widely for their purported fat reduction and anti-diabetic activities. However, much is still to be learnt about the efficacy and safety of such metal ions when they are taken in supplements and whether they have an essential role in the prevention of diabetes or, in some instances, are a risk factor for cancer. The research will provide an understanding of how these metal complexes exert their anti-diabetic effects and how they can be made safer and/or more efficacious for the treatment of type 2 diabetes, which is a rapidly expanding epidemic in developed countries. Read moreRead less
Design and Mechanistic Studies of Metal-Based Anti-Diabetic Drugs. Metal supplements, such as chromium and vanadium, are consumed widely for their purported fat reduction and anti-diabetic activities. However, much is still to be learnt about the efficacy and safety of such metal ions and whether they have an essential role in the prevention of diabetes or, in some instances, are a risk factor for cancer. The research will provide a fundamental understanding of how these metal complexes exert th ....Design and Mechanistic Studies of Metal-Based Anti-Diabetic Drugs. Metal supplements, such as chromium and vanadium, are consumed widely for their purported fat reduction and anti-diabetic activities. However, much is still to be learnt about the efficacy and safety of such metal ions and whether they have an essential role in the prevention of diabetes or, in some instances, are a risk factor for cancer. The research will provide a fundamental understanding of how these metal complexes exert their anti-diabetic effects and how they can be made safer and/or more efficacious for the treatment of type 2 diabetes, which is a rapidly expanding epidemic in developed countries. Read moreRead less
Understanding aerobic respiration: Models for the catalytic centre in proton-pumping heme-copper oxidases. This project tackles ?head on? a key challenge in contemporary biological inorganic chemistry, understanding how at the atomic level aerobic life uses oxygen. All life we see is aerobic, and thus the conceptual advances from this research will progress understanding of our world and ourselves? an important cultural goal. Advancing knowledge of such fundamental processes sits firmly in the a ....Understanding aerobic respiration: Models for the catalytic centre in proton-pumping heme-copper oxidases. This project tackles ?head on? a key challenge in contemporary biological inorganic chemistry, understanding how at the atomic level aerobic life uses oxygen. All life we see is aerobic, and thus the conceptual advances from this research will progress understanding of our world and ourselves? an important cultural goal. Advancing knowledge of such fundamental processes sits firmly in the area of the Research Priority Goal: Breakthrough Science. Postgraduate research students will be trained in sophisticated state-of-the-art theoretical and synthetic chemical methodologies. The project will enhance Australia's research capability in biological (inorganic) chemistry and promote Australia's standing in the International research community.Read moreRead less
Mechanistic Studies of Dimethylsulfide Dehydrogenase: A Novel Bacterial Molybdoenzyme. The aim of this proposal is to use electrochemical, spectroscopic and molecular biological techniques to understand the mechanism of action of the enzyme dimethylsulfide dehydrogenase. This enzyme is representative of an major group of molybdenum-containing enzymes that have importance in microbial biotransformations. The project will provide fundamental information about a multi-redox centre protein that has ....Mechanistic Studies of Dimethylsulfide Dehydrogenase: A Novel Bacterial Molybdoenzyme. The aim of this proposal is to use electrochemical, spectroscopic and molecular biological techniques to understand the mechanism of action of the enzyme dimethylsulfide dehydrogenase. This enzyme is representative of an major group of molybdenum-containing enzymes that have importance in microbial biotransformations. The project will provide fundamental information about a multi-redox centre protein that has potential application in biosensors and biocatalysis.Read moreRead less
Structural studies of catalysis and electron transfer by copper proteins. We propose to determine the crystal structures of five copper-containing proteins. Three are amine oxidases, enzymes that protect a wide range of organisms against toxic cell products (amines). Novel chemical modifications and crystallographic techniques will be used to test hypotheses for the enzyme mechanism. The results will provide a basis for the future manipulation of the enzymes' activities. Our other targets, s ....Structural studies of catalysis and electron transfer by copper proteins. We propose to determine the crystal structures of five copper-containing proteins. Three are amine oxidases, enzymes that protect a wide range of organisms against toxic cell products (amines). Novel chemical modifications and crystallographic techniques will be used to test hypotheses for the enzyme mechanism. The results will provide a basis for the future manipulation of the enzymes' activities. Our other targets, sulfocyanin and auracyanin-A, perform essential electron-transfer functions in an archaeon and a photosynthetic bacterium, respectively. The determination of their molecular structures will answer exciting questions about electron transfer in primitive organisms, and about the evolution of copper proteins as biological electron-transfer agents.Read moreRead less