Functional and structural diversity of the cathepsin L peptidase from the human blood fluke Schistosoma mansoni. Peptidases are enzymes that are important in many infectious and physiological disease states. For example, they are used by infectious pathogens to enter human tissues and survive inside their bodies. The same type of enzymes also contribute to tissue damage in many pathological processes in humans such as cancer, arithritis and osteoporosis. There is an urgent need to define their s ....Functional and structural diversity of the cathepsin L peptidase from the human blood fluke Schistosoma mansoni. Peptidases are enzymes that are important in many infectious and physiological disease states. For example, they are used by infectious pathogens to enter human tissues and survive inside their bodies. The same type of enzymes also contribute to tissue damage in many pathological processes in humans such as cancer, arithritis and osteoporosis. There is an urgent need to define their structure and properties so that we can employ rational approaches to develop new drugs that can combat these diseases and ailments. Read moreRead less
Aminopeptidases involved in regulating the amino acid pool in malaria parasites. Aminopeptidases are pivotal to the normal functions of all cells. Abnormalities in their function and/or structure results in tissue damage in many pathological processes in humans such as cancer, neuronal diseases and hormonal action. They are also critical to viral, bacterial and parasitic infections as they are employed to remove amino acids from the host for use in building their own proteins. This project bring ....Aminopeptidases involved in regulating the amino acid pool in malaria parasites. Aminopeptidases are pivotal to the normal functions of all cells. Abnormalities in their function and/or structure results in tissue damage in many pathological processes in humans such as cancer, neuronal diseases and hormonal action. They are also critical to viral, bacterial and parasitic infections as they are employed to remove amino acids from the host for use in building their own proteins. This project brings national and international expertise together to define the structure and biological properties of these essential enzymes so that in the future we can employ rational approaches to develop new drugs that can combat these diseases and ailments.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
Understanding and exploiting bacterial sulfatases. Bacterial sulfatases participate in environmental nutrient cycling and are implicated in bacterial pathogenesis mechanisms. These enzymes catalyze the hydrolysis of sulfate esters and possess an unusual posttranslational active-site modification where a cysteine residue is oxidized to formylglycine. We will study the mechanism of these enzymes in detail and design inhibitors that exploit the reactivity of this aminoacid. This work has significan ....Understanding and exploiting bacterial sulfatases. Bacterial sulfatases participate in environmental nutrient cycling and are implicated in bacterial pathogenesis mechanisms. These enzymes catalyze the hydrolysis of sulfate esters and possess an unusual posttranslational active-site modification where a cysteine residue is oxidized to formylglycine. We will study the mechanism of these enzymes in detail and design inhibitors that exploit the reactivity of this aminoacid. This work has significance because of application to areas that include the treatment of cancer and bacterial infections. Additionally, we will clone novel carbohydrate sulfatases from the heparin-degrading bacterium Flavobacterium heparinum. These sulfatases will have use in biotechnology for characterization of sulfated glycoconjugates.Read moreRead less
Regulation of cell surface sialylation by targeting the CMP-sialic acid transporter and sialyltransferase: Towards the development of anti-metastatic agents. The mortality rates for many of the cancers afflicting the world's population are mirrored in Australia, particularly colon cancer. It's generally accepted that colon cancer, and cancers as a whole, are a significant healthcare issue in this country, representing a major challenge to biomedical researchers and healthcare professional. The e ....Regulation of cell surface sialylation by targeting the CMP-sialic acid transporter and sialyltransferase: Towards the development of anti-metastatic agents. The mortality rates for many of the cancers afflicting the world's population are mirrored in Australia, particularly colon cancer. It's generally accepted that colon cancer, and cancers as a whole, are a significant healthcare issue in this country, representing a major challenge to biomedical researchers and healthcare professional. The economic and social impact is immense, placing a huge strain on the healthcare system, as well as on the families affected. Any alternative treatment reducing cancer metastasis would be of enormous national and international benefit. It's believed that the significant studies outlined in this proposal, which are based on exciting preliminary data, will make a sizeable contribution to achieving this goal.Read moreRead less
Host-pathogen interactions: the role of mimicry. The proposed research program, using a combination of structure and functional analysis will provide insight into the mechanism of nucleotide hydrolysis by the enzymes NTPDases. This study will not only improve our fundamental understanding of NTPDase action but could lead to the rational design of antimicrobials.
Molecular mechanisms of pilin glycosylation in Neisseria: a model system for protein glycosylation in bacteria. The disease causing bacteria Neisseria meningitidis and Neisseria gonorrhoeae are important human pathogens. Cell surface structures, called pili, are known to be important in allowing the bacteria to stick to host cells. Genetic and structural studies have identified that the protein subunits, which make up pili, are glycosylated - modified by the addition of sugars. Until recently ....Molecular mechanisms of pilin glycosylation in Neisseria: a model system for protein glycosylation in bacteria. The disease causing bacteria Neisseria meningitidis and Neisseria gonorrhoeae are important human pathogens. Cell surface structures, called pili, are known to be important in allowing the bacteria to stick to host cells. Genetic and structural studies have identified that the protein subunits, which make up pili, are glycosylated - modified by the addition of sugars. Until recently glycosylation of Gram-negative bacterial proteins was not thought to occur, however our recent work with these bacteria, and other groups studying Pseudomonas and Campylobacter, have shown that this process may be widespread. In our previous studies, we have identified and analysed a number of genes involved in pili glycosylation, in bacteria, which make known sugar structures. We have used this information to developed models for how the biochemistry and physiology of the glycosylation system may work. With a well-established structure and many genes already identified, glycosylation in Neisseria represents the best available model system to study this novel and important process. In the proposed study we describe experiments planned to test our models and reveal the molecular detail of this process. This study could lead to major advances in our understanding of this process and, when understood, may have future applications in biotechnology.Read moreRead less
Insect development : the role of cytochrome P450s. Pest insects vector human diseases such as malaria and impose a massive burden in agriculture due to control costs and production losses. The intelligent control of insect pests requires an understanding of their development that is controlled by hormones. This project will provide an in depth understanding of insect hormone synthesis/degradation that is controlled by a class of enzymes, the cytochrome P450s. This will increase the potential ....Insect development : the role of cytochrome P450s. Pest insects vector human diseases such as malaria and impose a massive burden in agriculture due to control costs and production losses. The intelligent control of insect pests requires an understanding of their development that is controlled by hormones. This project will provide an in depth understanding of insect hormone synthesis/degradation that is controlled by a class of enzymes, the cytochrome P450s. This will increase the potential for new insect-specific control strategies with a decreased environmental impact.Read moreRead less
Explaining the differences in affinity and of carbohydrate binding of the glycogen-sensing enzyme, AMP-protein activated kinase (AMPK). This project will provide fundamental molecular knowledge of how a complex enzyme, AMPK is controlled by the major sugar molecule, glycogen. Our research will increase our understanding of its role in metabolic diseases such as Type 2 diabetes and obesity.
To gain insight into the molecular mechanisms involved in antibiotic resistance shown by Gram-negative bacteria. Bacterial infections can strike anyone and usually the body's immune system, which is designed to fight infection, defeats the invading bacteria. Sometimes however, the burden of infection proves too great, so these infections can prove fatal. For 50 years, we have relied on antibiotics to successfully treat the majority of common bacterial infections. As a result, emphasis must be pl ....To gain insight into the molecular mechanisms involved in antibiotic resistance shown by Gram-negative bacteria. Bacterial infections can strike anyone and usually the body's immune system, which is designed to fight infection, defeats the invading bacteria. Sometimes however, the burden of infection proves too great, so these infections can prove fatal. For 50 years, we have relied on antibiotics to successfully treat the majority of common bacterial infections. As a result, emphasis must be placed on the disquieting reality whilst enjoy the use of antibiotics, an inescapable cost is the development of bacterial resistance. The increasing prevalence of bacterial tolerance against beta-lactams is a problem and as a result is a most pressing health issue. Read moreRead less