Unleashing the Hidden Chemical Diversity in Australian Fungi. This project aims to exploit an exclusive genomic resource consisting of >150 unique Australian filamentous fungi that has been built in a university-industry collaboration for genomic-guided biodiscovery. The genome sequence of these fungi revealed extensive hidden genetic instructions for production of novel biologically active molecules. The project will apply cutting-edge synthetic biology and chemical tools to tap into the hidden ....Unleashing the Hidden Chemical Diversity in Australian Fungi. This project aims to exploit an exclusive genomic resource consisting of >150 unique Australian filamentous fungi that has been built in a university-industry collaboration for genomic-guided biodiscovery. The genome sequence of these fungi revealed extensive hidden genetic instructions for production of novel biologically active molecules. The project will apply cutting-edge synthetic biology and chemical tools to tap into the hidden genomic potential of these Australian fungi. Expected outcomes of this project include new fine chemicals and lead molecules with desirable bioactivies. This will provide significant benefits to Australia's economy through the discovery of new pharmaceuticals, veterinary products and agrichemicals.Read moreRead less
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0346876
Funder
Australian Research Council
Funding Amount
$1,584,000.00
Summary
800 MHz NMR Spectrometer for Molecular Structure-Function Analyses. An 800 MHz high-resolution nuclear magnetic resonance (NMR) spectrometer equipped with a triple-resonance cryoprobe is required to support the research of 5 universities in the NSW/ACT area. The high magnetic field of the spectrometer is necessary for the study of proteins, protein-ligand complexes and other biomolecular systems of molecular weight >30,000. Projects previously inaccessible due to sensitivity, solubility or resol ....800 MHz NMR Spectrometer for Molecular Structure-Function Analyses. An 800 MHz high-resolution nuclear magnetic resonance (NMR) spectrometer equipped with a triple-resonance cryoprobe is required to support the research of 5 universities in the NSW/ACT area. The high magnetic field of the spectrometer is necessary for the study of proteins, protein-ligand complexes and other biomolecular systems of molecular weight >30,000. Projects previously inaccessible due to sensitivity, solubility or resolution problems will become tractable. The increased turn-around times afforded by the high sensitivity of the cryo-enabled spectrometer make it possible to provide access for Australian institutions that would not otherwise have access to comparable equipment.Read moreRead less
A Unique Target in the Purine Biosynthesis of the Pathogen Helicobacter pylori. The uptake systems of purine and analogues of the human pathogen Helicobacter pylori will be characterised because they can be utilised to introduce cytotoxic compounds into the cells. The first step in de novo purine biosynthesis of the bacterium is catalysed by two different enzymes, which are components of other biosynthetic pathways. These unique properties make them excellent potential therapeutic targets. Their ....A Unique Target in the Purine Biosynthesis of the Pathogen Helicobacter pylori. The uptake systems of purine and analogues of the human pathogen Helicobacter pylori will be characterised because they can be utilised to introduce cytotoxic compounds into the cells. The first step in de novo purine biosynthesis of the bacterium is catalysed by two different enzymes, which are components of other biosynthetic pathways. These unique properties make them excellent potential therapeutic targets. Their individual combined activities in purine biosynthesis will be characterised in situ and in vitro. Isogenic mutants with inactivated genes encoding for these enzymes will be constructed to investigate their role in the survival of the organism.Read moreRead less
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0561041
Funder
Australian Research Council
Funding Amount
$347,358.00
Summary
A New Generation Biosensor and Fluorescence Facility for Proteomics. The complete DNA sequence (the genome) is now known for many organisms and advances are being made to identify the complement of messenger RNA (the transcriptome) and the resultant collection of proteins (the proteome). The genome is largely fixed while the transcriptome and proteome differ between cell types in an organism and constantly vary to adapt the cell to changing conditions. The mediators of these variations are prote ....A New Generation Biosensor and Fluorescence Facility for Proteomics. The complete DNA sequence (the genome) is now known for many organisms and advances are being made to identify the complement of messenger RNA (the transcriptome) and the resultant collection of proteins (the proteome). The genome is largely fixed while the transcriptome and proteome differ between cell types in an organism and constantly vary to adapt the cell to changing conditions. The mediators of these variations are proteins, interacting with each other and with signal molecules. The next frontier in molecular biology is to identify and quantify these protein interactions. Our two institutions have a very large cohort of biologists whose research on proteins would be greatly facilitated by the Biacore 3000 and the ISS K2.Read moreRead less
Biosynthesis of nonribosomal peptide toxins in cyanobacteria: A functional characterisation of microcystin synthetase. Microcystins are potent toxins and tumour promoters produced by cyanobacteria associated with blue-green algal blooms. This non-ribosomal peptide is produced by microcystin synthetase, a unique enzyme complex comprised of peptide synthetases, polyketide synthases, and integrated accessory enzymes. We have identified and characterised the extensive gene cluster encoding this enzy ....Biosynthesis of nonribosomal peptide toxins in cyanobacteria: A functional characterisation of microcystin synthetase. Microcystins are potent toxins and tumour promoters produced by cyanobacteria associated with blue-green algal blooms. This non-ribosomal peptide is produced by microcystin synthetase, a unique enzyme complex comprised of peptide synthetases, polyketide synthases, and integrated accessory enzymes. We have identified and characterised the extensive gene cluster encoding this enzyme. This project describes the biochemical characterisation of specific enzyme activities within microcystin synthetase and how they determine the final structure and toxicity of the many forms of microcystin. Interactions between this enzyme complex and its substrate amino acids will provide information for the genetic engineering of this and similar natural products.Read moreRead less
Activation of Tissue Factor by a Disulphide-Bond Switch. This project will define the molecular mechanism of activation of tissue factor, the initiator of blood coagulation, and design and test novel antibody therapeutics that block this activation. The applicant suggests that tissue factor is activated by a disulphide-bond switch. Should this hypothesis prove correct it would be the first example of activation of a mammalian protein by this means and, moreover, would be very amenable to therape ....Activation of Tissue Factor by a Disulphide-Bond Switch. This project will define the molecular mechanism of activation of tissue factor, the initiator of blood coagulation, and design and test novel antibody therapeutics that block this activation. The applicant suggests that tissue factor is activated by a disulphide-bond switch. Should this hypothesis prove correct it would be the first example of activation of a mammalian protein by this means and, moreover, would be very amenable to therapeutic intervention because activation occurs on the membrane surface inside blood vessels. Tissue factor activation and thrombus formation is the precipitating event in acute myocardial infarction, unstable angina and ischemic stroke, which are responsible for the majority of deaths in Australia.Read moreRead less
New Proteins from the Mobile Genome: Structure-Led Discovery. The project will provide full descriptions of proteins with the capacity to become mobilised, as well as providing a source of completely novel genes with commercial potential. The proteins and enzymes discovered, and the metabolic processes with which they are identified, will have applications in a wide range of Australian industries: agriculture, forestry, pollution control and pharmaceutical design. This work therefore offers op ....New Proteins from the Mobile Genome: Structure-Led Discovery. The project will provide full descriptions of proteins with the capacity to become mobilised, as well as providing a source of completely novel genes with commercial potential. The proteins and enzymes discovered, and the metabolic processes with which they are identified, will have applications in a wide range of Australian industries: agriculture, forestry, pollution control and pharmaceutical design. This work therefore offers opportunities for many future directions in biotechnology, an area of growing strength in Australia. Read moreRead less
The control of elongation factor 2 and its role in the regulation of protein synthesis. Protein synthesis is a key process in living cells. The main stage, elongation, is regulated through phosphorylation of elongation factor eEF2 in response to hormones, amino acids and cellular energy status, via changes in the activity of eEF2 kinase. We will study how these conditions control eEF2 kinase by studying its phosphorylation and identifying new kinases that regulate it. We will explore the role of ....The control of elongation factor 2 and its role in the regulation of protein synthesis. Protein synthesis is a key process in living cells. The main stage, elongation, is regulated through phosphorylation of elongation factor eEF2 in response to hormones, amino acids and cellular energy status, via changes in the activity of eEF2 kinase. We will study how these conditions control eEF2 kinase by studying its phosphorylation and identifying new kinases that regulate it. We will explore the role of eEF2 in controlling protein synthesis, seek new substrates for eEF2 kinase and initiate work to elucidate the structure of this unusual enzyme. This will enhance, in a range of ways, fundamental understanding of cell physiology.Read moreRead less
Structures to Solve Conflicts of DNA Replication and RNA Transcription. This project aims to understand how new DNA is made so quickly and without mistakes in cells that are about to divide, in spite of competition from other processes happening at the same time on the DNA that should stop or interfere with it, such as the synthesis of RNA. The project expects to use the latest available methods to uncover what the microscopic natural machines that make DNA and RNA look like, and how they compet ....Structures to Solve Conflicts of DNA Replication and RNA Transcription. This project aims to understand how new DNA is made so quickly and without mistakes in cells that are about to divide, in spite of competition from other processes happening at the same time on the DNA that should stop or interfere with it, such as the synthesis of RNA. The project expects to use the latest available methods to uncover what the microscopic natural machines that make DNA and RNA look like, and how they compete with each other for access to DNA. Potential outcomes include the identification of processes that can be compromised by small molecules that may be developed into new antibiotics. This would be of great benefit - new antibiotics are urgently needed as one approach to countering the threat of antimicrobial resistance.Read moreRead less
Defining mechanisms of action of novel alpha-conotoxins at nicotinic receptor-channels. Marine snails from the waters off the Australian coast produce an amazing variety of mini-proteins in their venoms called conotoxins that they use to capture prey. These conotoxins bind very specifically to receptors in our body associated with the transmission of nerve signals. We will use natural and synthetically modified conotoxins to selectively block particular types of neuronal 'receptors' to gain a gr ....Defining mechanisms of action of novel alpha-conotoxins at nicotinic receptor-channels. Marine snails from the waters off the Australian coast produce an amazing variety of mini-proteins in their venoms called conotoxins that they use to capture prey. These conotoxins bind very specifically to receptors in our body associated with the transmission of nerve signals. We will use natural and synthetically modified conotoxins to selectively block particular types of neuronal 'receptors' to gain a greater understanding of how the nervous system functions. This knowledge will help in the design of new drugs to treat a variety of diseases and disorders. Essentially we will use a chemical armoury developed by the cone snail to design state-of-the-art mini-protein drugs.Read moreRead less