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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Venomics: Molecular and functional analysis of Australian snake venoms for development of human therapeutics. Australian snake venoms are lethal cocktails with potent effects on mammalian physiological processes, designed to immobilize and kill prey animals. Major targets of venom components are the nervous and blood coagulation systems but there is reason to believe that venoms have many other as yet unrecognized effects on mammalian systems. The project will combine techniques of modern mole ....Venomics: Molecular and functional analysis of Australian snake venoms for development of human therapeutics. Australian snake venoms are lethal cocktails with potent effects on mammalian physiological processes, designed to immobilize and kill prey animals. Major targets of venom components are the nervous and blood coagulation systems but there is reason to believe that venoms have many other as yet unrecognized effects on mammalian systems. The project will combine techniques of modern molecular biology (particularly transcriptomics and proteomics) with functional and structural analysis of purified venom components. Venoms from approximately 20 Australian snakes will be studied to reveal lead compounds for improved human pharmaceuticals against common disorders such as high blood pressure, bleeding and stroke.Read moreRead less
How organisms coordinate energy supply and demand. The metabolic stress sensing protein kinase called the AMP activated protein kinase controls metabolism of all eukaryotes to meet the needs of energy demand and nutrient supply. It is responsible for accelerating metabolism (glucose transport, glycolysis and fatty acid oxidation) in response to energy demand and with caloric restriction it regulates gene transcription to adapt to energy supply. This project is to provide a comprehensive unders ....How organisms coordinate energy supply and demand. The metabolic stress sensing protein kinase called the AMP activated protein kinase controls metabolism of all eukaryotes to meet the needs of energy demand and nutrient supply. It is responsible for accelerating metabolism (glucose transport, glycolysis and fatty acid oxidation) in response to energy demand and with caloric restriction it regulates gene transcription to adapt to energy supply. This project is to provide a comprehensive understanding of the AMP activated protein kinase (enzyme isoforms, genes, physiological roles and regulation). This knowledge will have major benefits in biopharmaceutical development, the livestock, plant and sport/racing industries.Read moreRead less
One of the most amazing engineering achievements in nature is how over 2 meters of genetic material (DNA) can be compacted and squeezed nearly a million times to fit into a human cell. The remarkable structure that achieves this is the chromosome. Fundamental to the survival of a multicellular organism is that the chromosome is stably maintained throughout out the life of an organism. For example, defects in maintaining chromosome stability can lead to aneuploidy (cells with an abnormal number o ....One of the most amazing engineering achievements in nature is how over 2 meters of genetic material (DNA) can be compacted and squeezed nearly a million times to fit into a human cell. The remarkable structure that achieves this is the chromosome. Fundamental to the survival of a multicellular organism is that the chromosome is stably maintained throughout out the life of an organism. For example, defects in maintaining chromosome stability can lead to aneuploidy (cells with an abnormal number of chromosomes), a feature exhibited by many forms of cancer. This packaging of genomic DNA that produces a chromosome is achieved by a complex scheme of folding. At the first level, DNA is first wrapped around a mixture of proteins (called histones) to form a complete unit known as a nucleosome. About 30 million of these building blocks are required in every human cell to compact our DNA. Higher, more complicated levels of organization exist in which a linear array of nucleosomes fold to various extents to form distinct functional and structural domains. Importantly, specialised chromosomal domains, like the telomere and centromere, are assembled that keep the ends of the chromosomes stable and enable a chromosome to copy itself every time our cells divide and grow, respectively. How a chromosome is divided into these different compartments remains a mystery. This investigation will show that a key cellular mechanism that determines how the chromosome is organised into stable domains is by changing the make-up of chromosomal domains through the replacement of histone proteins with specialised forms of histones called variants . These histone variants control the way a linear array of nucleosomes fold into complex three-dimensional structures to perform a specialised function. This fundamental research will provide important new information on how chromosomes become unstable in cancer. It will also enable new strategies, which stabilise the chromosome, to be explored.Read moreRead less
New Techniques for Structural Biology and Directed Molecular Evolution. This PhD program will equip an Australian graduate with advanced training in techniques in molecular genetics and protein chemistry that are currently in high demand by the biotechnology industry, and also provide him/her with direct experience of an industrial R&D laboratory environment. Moreover, it will establish a basis for further collaboration between a leading University-based research laboratory and an established R& ....New Techniques for Structural Biology and Directed Molecular Evolution. This PhD program will equip an Australian graduate with advanced training in techniques in molecular genetics and protein chemistry that are currently in high demand by the biotechnology industry, and also provide him/her with direct experience of an industrial R&D laboratory environment. Moreover, it will establish a basis for further collaboration between a leading University-based research laboratory and an established R&D company that will lead to development of new techniques for use in biotechnology in Australia and overseas.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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MOLECULAR BREEDING OF CYTOCHROME P450 ENZYMES. Cytochrome P450s are enzymes that catalyse an impressive array of oxidative transformations. However, there is little available data on how to modify their substrate specificity and generate tailored biocatalysts. We plan to use an emerging technology known as DNA shuffling to create libraries of P450s with varying activities. These will then be screened for enzymes that can catalyse the formation of indigo (a blue dye) and indirubin (a chemother ....MOLECULAR BREEDING OF CYTOCHROME P450 ENZYMES. Cytochrome P450s are enzymes that catalyse an impressive array of oxidative transformations. However, there is little available data on how to modify their substrate specificity and generate tailored biocatalysts. We plan to use an emerging technology known as DNA shuffling to create libraries of P450s with varying activities. These will then be screened for enzymes that can catalyse the formation of indigo (a blue dye) and indirubin (a chemotherapeutic agent). The enzymes that catalyse indigo formation will be useful in the production of coloured transgenic plants and those that produce indirubin will have a role in gene therapy.Read moreRead less
How does clusterin protect cells from stresses? We recently discovered that clusterin: (i) is the only known secreted (ie extracellular) mammalian chaperone and (ii) can protect proteins and cells from stresses.These breakthrough advances provide the first unifying biological function for this protein - in whole organisms, clusterine is likely to protect tissues and organs form biologyical stresses. The work proposed will provide quantum advances in our understanding of the molecular basis by wh ....How does clusterin protect cells from stresses? We recently discovered that clusterin: (i) is the only known secreted (ie extracellular) mammalian chaperone and (ii) can protect proteins and cells from stresses.These breakthrough advances provide the first unifying biological function for this protein - in whole organisms, clusterine is likely to protect tissues and organs form biologyical stresses. The work proposed will provide quantum advances in our understanding of the molecular basis by which clusterin effects its protective actions. We expect to demonstrate that clusterin protects cells form stresses by exerting its chaperone action at or near the cell surface and to identify specific regions and structural features of the clusterine molecule important in its chaperone action.Read moreRead less
Enantioselective nitrilases from filamentous fungi. The optical characteristics (chirality) of chemical precursors are important for many fine chemicals. Chiral intermediates are in high demand by the pharmaceutical and agrochemical industries for the preparation of bulk drug intermediates and agricultural products. Nitriles are attractive starting points but their conversion to corresponding amides and carboxylic acids generates significant wastes. Their hydrolysis can be performed under mil ....Enantioselective nitrilases from filamentous fungi. The optical characteristics (chirality) of chemical precursors are important for many fine chemicals. Chiral intermediates are in high demand by the pharmaceutical and agrochemical industries for the preparation of bulk drug intermediates and agricultural products. Nitriles are attractive starting points but their conversion to corresponding amides and carboxylic acids generates significant wastes. Their hydrolysis can be performed under mild conditions by enzymes termed nitrilases. We will work on fungal nitrilases as they present a globally attractive, yet untapped commercial target. The outcome for Applimex will be a suite of biocatalysts specific for the production of key intermediates for drug and agrochemical syntheses.Read moreRead less