A bio-enabled synthesis for the glycopeptide antibiotics. This project aims to develop an in vitro biomimetic synthesis for glycopeptide antibiotics (GPAs) by combining peptide synthesis and crosslinking catalysed by biosynthetic Cytochrome P450 enzymes. The crosslinking step in GPA biosynthesis is essential for antibiotic activity but impedes their chemical synthesis. This project will study the in vitro behaviour and characteristics of the biosynthetic P450 enzymes. This will provide direct be ....A bio-enabled synthesis for the glycopeptide antibiotics. This project aims to develop an in vitro biomimetic synthesis for glycopeptide antibiotics (GPAs) by combining peptide synthesis and crosslinking catalysed by biosynthetic Cytochrome P450 enzymes. The crosslinking step in GPA biosynthesis is essential for antibiotic activity but impedes their chemical synthesis. This project will study the in vitro behaviour and characteristics of the biosynthetic P450 enzymes. This will provide direct benefits: the development of new glycopeptide antibiotic derivatives and the identification of new biocatalysts for complex chemical synthesis. Knowledge gained will also directly enable future reengineering of glycopeptide antibiotic production in vivo.Read moreRead less
Understanding the mechanism of two important cytochrome P450 catalysed reactions: dehydrogenation and C-C cleavage. Cytochromes P450 are enzymes that play key roles in drug metabolism and biosynthesis. P450s often catalyse hydroxylation but also carry out important transformations such as dehydrogenation or carbon-carbon bond cleavage. Such reactions are pivotal in many biological pathways. This work will elucidate the mechanism of these transformations and the factors that facilitate their occu ....Understanding the mechanism of two important cytochrome P450 catalysed reactions: dehydrogenation and C-C cleavage. Cytochromes P450 are enzymes that play key roles in drug metabolism and biosynthesis. P450s often catalyse hydroxylation but also carry out important transformations such as dehydrogenation or carbon-carbon bond cleavage. Such reactions are pivotal in many biological pathways. This work will elucidate the mechanism of these transformations and the factors that facilitate their occurrence. This will mainly entail the synthesis of small organic mechanistic probes and determining the structure and stereochemistry of the product of enzymic oxidation. Understanding these mechanisms will allow us to predict when such reactions will occur, enabling their utilisation in for example drug design in the avoidance of the formation of toxic metabolites.Read moreRead less
A new chemotherapeutic target from Leishmania SPP. Understanding and inhibiting CYP61LD, a sterol C22 desaturase. Leishamniasis is a debilitating and often fatal disease that is caused by a parasite, Leishmania sp., which is increasing its range to include Australia. This project aims to explore possible chemotherapeutics for the disease which inhibit a particular and unique enzyme the organism uses to synthesise the sterols it requires to live.
Identification of functionally important autophosphorylation site(s) on ataxia telangiectasia and Rad 3 - related (ATR) protein kinase. The integrity of our genetic material must be maintained so that it can be passed on from one generation to the next and also to minimize the risk of cancer and other pathologies in an individual. There are multiple proteins involved in protecting our DNA including several enzymes that detect and signal DNA damage to a series of pathways involved in halting the ....Identification of functionally important autophosphorylation site(s) on ataxia telangiectasia and Rad 3 - related (ATR) protein kinase. The integrity of our genetic material must be maintained so that it can be passed on from one generation to the next and also to minimize the risk of cancer and other pathologies in an individual. There are multiple proteins involved in protecting our DNA including several enzymes that detect and signal DNA damage to a series of pathways involved in halting the passage of cells through the cell cycle so that repair can occur. This project studies the mechanism of action of one of these enzymes which will be of benefit in designing new compounds to fight disease. Read moreRead less
Role of 3'-phosphorylated phosphoinositides in neurosecretion. Neurons communicate through the release of neurotransmitter by synaptic vesicles. Minute changes underlie normal processes such as memory and modifications of neurotransmitter level contribute to a number of neurological diseases. I am interested in deciphering the role of phosphoinositides, an inner membrane-based lipid, during steps leading to the fusion of a synaptic vesicle with the plasma membrane. I have recently discovered tha ....Role of 3'-phosphorylated phosphoinositides in neurosecretion. Neurons communicate through the release of neurotransmitter by synaptic vesicles. Minute changes underlie normal processes such as memory and modifications of neurotransmitter level contribute to a number of neurological diseases. I am interested in deciphering the role of phosphoinositides, an inner membrane-based lipid, during steps leading to the fusion of a synaptic vesicle with the plasma membrane. I have recently discovered that phosphatidylinositol-3 phosphate production was critical for the vesicle to acquire the competence to fuse with the plasma membrane. This project aim to understand by which mechanism this lipid interacts with the release machinery to promote such priming step.Read moreRead less