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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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
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
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
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
Role of the proteasome in eradication of misfolded proteins in fungal cell factories. Filamentous fungi contribute to the well being of modern society as surrogate hosts for the synthesis of vaccines, hormones and enzymes for their application to health, agriculture, industry and the environment. However, attempts to express foreign proteins to the full potential of a given system have been disappointing. It is vital to understand unexplored molecular and physiological factors such as protein ....Role of the proteasome in eradication of misfolded proteins in fungal cell factories. Filamentous fungi contribute to the well being of modern society as surrogate hosts for the synthesis of vaccines, hormones and enzymes for their application to health, agriculture, industry and the environment. However, attempts to express foreign proteins to the full potential of a given system have been disappointing. It is vital to understand unexplored molecular and physiological factors such as protein quality control in the cell to take advantage of the global opportunities that recombinant gene expression indisputably offers in the form of unrestricted supply of proteins of social and economic value. The project will create novel IP and licensing opportunities for Australia.Read moreRead less
Subunit stoichiometry and arrangement in the glycine receptor. Glycine receptors are important for nervous system function. These receptors comprise a mixture of 5 alpha and beta subunits arranged around a central ion-conducting pore. The subunit stoichiometry (i.e., numbers of alpha and beta subunits) and arrangement (i.e., subunit order) are unknown. The first aim of this project is to define these parameters using tethered subunits. The second aim is to use the tethered subunits to probe th ....Subunit stoichiometry and arrangement in the glycine receptor. Glycine receptors are important for nervous system function. These receptors comprise a mixture of 5 alpha and beta subunits arranged around a central ion-conducting pore. The subunit stoichiometry (i.e., numbers of alpha and beta subunits) and arrangement (i.e., subunit order) are unknown. The first aim of this project is to define these parameters using tethered subunits. The second aim is to use the tethered subunits to probe the structure and function of glycine and zinc binding sites at an unprecedented level of resolution. The results will provide crucial new information concerning glycine receptor structure and function.Read moreRead less
The Production of Respiratory Cell Lineages from Human Embryonic Stem Cells: Towards a Cell Replacement Therapy for the Treatment of Respiratory Specific Deficits. Embryonic stem (ES) cells are a primitive embryonic cell type that can be maintained and grown in vitro. Mouse ES cells can be instructed to develop into a wide range of specific adult cell types. Research into human ES cells has more recently commenced and has already resulted in the controlled production of specific nerve cells by o ....The Production of Respiratory Cell Lineages from Human Embryonic Stem Cells: Towards a Cell Replacement Therapy for the Treatment of Respiratory Specific Deficits. Embryonic stem (ES) cells are a primitive embryonic cell type that can be maintained and grown in vitro. Mouse ES cells can be instructed to develop into a wide range of specific adult cell types. Research into human ES cells has more recently commenced and has already resulted in the controlled production of specific nerve cells by our group. The following project aims to create respiratory lineages from both mouse and human ES cells. Such an undertaking thus aims to provide a basis for the treatment of respiratory specific diseases such as cystic fibrosis and emphysema.Read moreRead less