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Saunders E.C.,University of Melbourne | De Souza D.P.,University of Melbourne | Naderer T.,University of Melbourne | Sernee M.F.,University of Melbourne | And 8 more authors.
Parasitology | Year: 2010

Leishmania spp. are sandfly-transmitted protozoa parasites that cause a spectrum of diseases in humans. Many enzymes involved in Leishmania central carbon metabolism differ from their equivalents in the mammalian host and are potential drug targets. In this review we summarize recent advances in our understanding of Leishmania central carbon metabolism, focusing on pathways of carbon utilization that are required for growth and pathogenesis in the mammalian host. While Leishmania central carbon metabolism shares many features in common with other pathogenic trypanosomatids, significant differences are also apparent. Leishmania parasites are also unusual in constitutively expressing most core metabolic pathways throughout their life cycle, a feature that may allow these parasites to exploit a range of different carbon sources (primarily sugars and amino acids) rapidly in both the insect vector and vertebrate host. Indeed, recent gene deletion studies suggest that mammal-infective stages are dependent on multiple carbon sources in vivo. The application of metabolomic approaches, outlined here, are likely to be important in defining aspects of central carbon metabolism that are essential at different stages of mammalian host infection. Copyright © 2010 Cambridge University Press.

Macrae J.I.,Bio21 Institute of Molecular Science and Biotechnology | Macrae J.I.,UK National Institute for Medical Research | Lopaticki S.,Walter and Eliza Hall Institute of Medical Research | Maier A.G.,Walter and Eliza Hall Institute of Medical Research | And 5 more authors.
Molecular Microbiology | Year: 2014

Intra-erythrocytic stages of the malaria parasite, Plasmodium falciparum, are thought to be dependent on de novo synthesis of phosphatidylinositol, as red blood cells (RBC) lack the capacity to synthesize this phospholipid. The myo-inositol headgroup of PI can either be synthesized de novo or scavenged from the RBC. An untargeted metabolite profiling of P.falciparum infected RBC showed that trophozoite and schizont stages accumulate high levels of myo-inositol-3-phosphate, indicating increased de novo biosynthesis of myo-inositol from glucose 6-phosphate. Metabolic labelling studies with 13C-U-glucose in the presence and absence of exogenous inositol confirmed that de novo myo-inositol synthesis occurs in parallel with myo-inositol salvage pathways. Unexpectedly, while both endogenous and scavenged myo-inositol was used to synthesize bulk PI, only de novo-synthesized myo-inositol was incorporated into GPI glycolipids. Moreover, gene disruption studies suggested that the INO1 gene, encoding myo-inositol 3-phosphate synthase, is essential in asexual parasite stages. Together these findings suggest that P.falciparum asexual stages are critically dependent on de novo myo-inositol biosynthesis for assembly of a sub-pool of PI species and GPI biosynthesis. These findings highlight unexpected complexity in phospholipid biosynthesis in P.falciparum and a lack of redundancy in some nutrient salvage versus endogenous biosynthesis pathways. © 2013 John Wiley & Sons Ltd.

Bica L.,University of Melbourne | Bica L.,Mental Health Research Institute | Meyerowitz J.,University of Melbourne | Meyerowitz J.,Mental Health Research Institute | And 17 more authors.
BioMetals | Year: 2011

Brain tumors such as neuroblastomas and gliomas are often refractory to current treatments. Development of metal-based drugs may offer an alternative approach due to the ability to deliver radionuclides or cytotoxic metals to the tumor. Previous studies have shown that diacetyl-bis(N(4)- methylthiosemicarbazonato)-copper(II) (CuII(atsm)) can selectively target hypoxic tumors and this feature has been utilized for development of imaging and radiotherapy. However, we have recently shown that glyoxal-bis(N(4)-methylthiosemicarbazonato)-copper(II) (CuII(gtsm)) can target the brain in animal models of neurodegeneration. Unlike Cu II(atsm), CuII(gtsm) is able to release Cu intracellularly under normoxic conditions. Glyoxal-bis(thiosemicarbazones) have reported anticancer effects but little is known about the cellular mechanisms involved. Therefore, in this study, we used protein microarray analysis to investigate the effect of CuII(gtsm) on neuroblastoma cell growth in vitro. Treatment of the human neuroblastoma cell line BE(2)-M17, resulted in cell cycle arrest as assessed by fluorescent activated cell sorting (FACS) analysis. Rapidly arrested growth was not associated with onset of apoptosis. Instead, protein microarray analysis revealed that CuII(gtsm) rapidly and potently reduced cyclin D1 expression, while increasing Kip2 expression. Other changes observed were decreased Cdk7 expression and activation of CHK2. These changes may be associated with the cell cycle arrest. We also observed a potent decrease of total and phosphorylated insulin-like growth factor receptor (IGF-IR) by CuII(gtsm) which is associated with modulation of cyclin D1 expression. Our studies reveal important insights into the potential anticancer activity of CuII(gtsm). Further studies are needed to examine the therapeutic potential of CuII(gtsm) and other bis(thiosemicarbazonato) metal complexes as metallo-drugs for treatment of systemic or brain tumors. © 2010 Springer Science+Business Media, LLC.

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