Broad Spectrum Inhibition Of An Enzyme Antibiotic Target
Funder
National Health and Medical Research Council
Funding Amount
$321,534.00
Summary
There is a well-documented need to replenish the antibiotic pipeline with new products to combat the rise of drug resistant bacteria. In this project, the enzyme dihydrodipicolinate synthase (DHDPS) is targetted which is essential to bacterial viability. A number of independent but synergistic drug discovery approaches are investigated to develop and test DHDPS inhibitors in the pursuit of a novel class of antibiotics.
Structural Characterization Of A Novel AB5 Cytoxin - SubAB
Funder
National Health and Medical Research Council
Funding Amount
$210,760.00
Summary
The proposed research program, using a combinantion of structural biology and biophysical techniques will provide insight into the role of novel AB5 toxin from E. coli. This study will not only improve our fundamental understanding the mode of action of this toxin from this devastating pathogen, but could lead to the design of rational antimicrobials. The knowledge gained will increase Australian international research profile.
The Molecular Basis Of Cytochrome P450 Ligand Binding: Towards Predicting Enzyme Substrate Selectivity And Drug-drug Interaction Potential
Funder
National Health and Medical Research Council
Funding Amount
$558,447.00
Summary
Cytochrome P450 (CYP) enzymes play a pivotal role in the metabolism (i.e. chemical breakdown) of drugs, a process that is essential for their detoxification and elimination from the body. This project will combine advanced computational and experimental approaches to elucidate the molecular basis for the binding of drugs to CYP enzymes, which is crucial for the design of drugs with favourable metabolic properties and decreased propensity for harmful interactions with co-administered drugs.
Structural And Functional Characterisation Of Human Neurotransmitter Inhibitor Producing Enzymes Glutamate Decarboxylase
Funder
National Health and Medical Research Council
Funding Amount
$35,085.00
Summary
Glutamate decarboxylase (GAD) produces the major inhibitory neurotransmitter in the central nervous system, GABA. GAD dysfunction is associated with mental diseases including epilepsy and schizophrenia. We aim to understand the functional role of structural elements of GAD via x-ray crystallography and kinetic studies. We also aim to produce a high throughput GAD enzyme assay to screen compounds that can modulate GAD activity, which could be potential therapeutic targets for related disease.
Probing UDP-glucuronosyltransferase Protein-protein Interactions: The Power Of Two.
Funder
National Health and Medical Research Council
Funding Amount
$482,710.00
Summary
Drugs and other chemicals (eg. dietary constituents, environmental pollutants, and chemicals that occur naturally in the body - such as steroid hormones) are broken down by specialised proteins called enzymes. This process is referred to as biotransformation, or 'metabolism'. Drug and chemical metabolism serves as a detoxification mechanism (since the products of metabolism generally lack biological activity) and as a means of eliminating these substances from the body. UDP-Glucuronosyltransfera ....Drugs and other chemicals (eg. dietary constituents, environmental pollutants, and chemicals that occur naturally in the body - such as steroid hormones) are broken down by specialised proteins called enzymes. This process is referred to as biotransformation, or 'metabolism'. Drug and chemical metabolism serves as a detoxification mechanism (since the products of metabolism generally lack biological activity) and as a means of eliminating these substances from the body. UDP-Glucuronosyltransferase (UGT) is one of the most important enzymes involved in drug and chemical metabolism. Consistent with its ability to metabolise such a large number of compounds, UGT is known to exist as a 'superfamily' of structurally related proteins. Despite the importance of UGT, little is known about the structural characteristics of these enzymes that are responsible for recognising and binding different classes of chemicals. Accumulating evidence from this and other laboratories indicates that the individual UGT proteins may combine with themselves (to form a homodimer) and with other UGT proteins (to form heterodimers). This project largely seeks to define the scope of UGT homo- and hetero- dimerisation, identify the structural elements of the proteins responsible for association and characterise the functional significance of dimerisation. The project will further explore associations between UGTs and other proteins, namely albumin. Characterisation of UGT dimerisation and associations with other proteins is fundamental to our understanding of how this enzyme functions and selects particular chemicals for metabolism. The work also has important implications for the devlopment and interpretation of in vitro (or 'test-tube') approaches for predicting how drugs are metabolised in humans. Such tests are widely employed in research and pharmaceutical company laboratories to predict how the body 'handles' new drugs prior to their administration to humans.Read moreRead less
Biochemical Analysis Of Akt 3-specific Signal Transduction
Funder
National Health and Medical Research Council
Funding Amount
$349,375.00
Summary
The Akt family of enzymes consists of 3 protein kinases (Akt 1,2 and 3) and has been shown to regulate many normal cellular processes such as cell proliferation, growth, survival and motility, as well as the growth of new blood vessels. All these processes are critical for cancers to grow. However, few studies have distinguished the roles of the individual family members. Our preliminary data revealed Akt3 is far more active than the other two forms. Furthermore, using our unique Akt3 specific a ....The Akt family of enzymes consists of 3 protein kinases (Akt 1,2 and 3) and has been shown to regulate many normal cellular processes such as cell proliferation, growth, survival and motility, as well as the growth of new blood vessels. All these processes are critical for cancers to grow. However, few studies have distinguished the roles of the individual family members. Our preliminary data revealed Akt3 is far more active than the other two forms. Furthermore, using our unique Akt3 specific antibody, we find Akt 3 protein and activity levels are high in rapidly proliferating ovarian cancer cell lines and in primary ovarian tumours. The aim of this proposal is to characterise the mode and role of signalling via Akt3, including the identification of targeted substrates and signaling pathways and the outcomes of Akt3 driven signaling on cellular properties. These studies will provide important clues to understanding how this family member functions in both health and disease. Elucidation of the basis of Akt3 dependent signalling will open the possibility for the development of drugs that interfere with Akt3 function (for example in high Akt 3 expressing tumours like those of the ovary). In the long term, extension of our profiling studies to other tumour types will give a novel insight into the extent of Akt3 de-regulation as a key mediator of cancer formation.Read moreRead less
Regulation Of PtdIns(3,4,5)P3 By Inositol Polyphosphate 5-phosphatases
Funder
National Health and Medical Research Council
Funding Amount
$200,880.00
Summary
Growing cells respond to growth factors by dividing and proliferating. Uncontrolled cell growth leads to cancer. Signals are released from the cell membrane following growth factor stimulation, that communicate via a complex network of intracellular signalling molecules, that instruct the nucleus to divide. One critical signalling network that mediates cell growth are the phosphoinositide messenger molecules. These signals are switched off by a family of proteins called inositol polyphosphate 5- ....Growing cells respond to growth factors by dividing and proliferating. Uncontrolled cell growth leads to cancer. Signals are released from the cell membrane following growth factor stimulation, that communicate via a complex network of intracellular signalling molecules, that instruct the nucleus to divide. One critical signalling network that mediates cell growth are the phosphoinositide messenger molecules. These signals are switched off by a family of proteins called inositol polyphosphate 5-phosphatases. We propose the 5-phosphatases are essential for normal cell growth. Several studies have suggested in their absence tumour formation may occurr. We have identified a new member of this enzyme family called SHIP-2. This proposal aims to investigate the mechanisms by which this enzyme family metabolises signalling molecules and thereby regulates cell growth. We will also characterize how the 5-phosphatases control the normal pathways by which primitive cells differeniate into mature cells.Read moreRead less