School of Chemistry - Research Publications

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    Continuous flow based catch and release protocol for the synthesis of alpha-ketoesters
    Palmieri, A ; Ley, SV ; Polyzos, A ; Ladlow, M ; Baxendale, IR (BEILSTEIN-INSTITUT, 2009-05-20)
    Using a combination of commercially available mesofluidic flow equipment and tubes packed with immobilised reagents and scavengers, a new synthesis of alpha-ketoesters is reported.
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    Structure of the T109S mutant of Escherichia coli dihydroorotase complexed with the inhibitor 5-fluoroorotate: catalytic activity is reflected by the crystal form
    Lee, M ; Maher, MJ ; Guss, JM (INT UNION CRYSTALLOGRAPHY, 2007-03-01)
    Crystals of a single-point mutant (T109S) of Escherichia coli dihydroorotase (DHOase) with diminished activity grown in the presence of L-dihydroorotate (L-DHO) are tetragonal, with a monomer in the asymmetric unit. These crystals are extremely unstable and disintegrate shortly after formation, which is followed by the growth of orthorhombic crystals from the remnants of the tetragonal crystals or at new nucleation sites. Orthorhombic crystals, for which a structure has previously been reported [Thoden et al. (2001), Biochemistry, 40, 6989-6997; Lee et al. (2005), J. Mol. Biol. 348, 523-533], contain a dimer of DHOase in the asymmetric unit; the active site of one monomer contains the substrate N-carbamyl-L-aspartate (L-CA-asp) and the active site of the other monomer contains the product of the reaction, L-DHO. In the subunit with L-DHO in the active site, a surface loop (residues 105-115) is 'open'. In the other subunit, with L-CA-asp in the active site, the loop folds inwards, forming specific hydrogen bonds from the loop to the L-CA-asp. The tetragonal crystal form can be stabilized by crystallization in the presence of the inhibitor 5-fluoroorotate (FOA), a product (L-DHO) mimic. Crystals of the complex of T109S DHOase with FOA are tetragonal, space group P4(1)2(1)2, with unit-cell parameters a = b = 72.6, c = 176.1 A. The structure has been refined to R and R(free) values of 0.218 and 0.257, despite severe anisotropy of the diffraction. In this structure, the flexible loops are both in the 'open' conformation, which is consistent with FOA, like L-DHO, binding at both sites. The behaviour of the T109S mutant crystals of DHOase in the presence of L-DHO is explained by initial binding of L-DHO to both subunits, followed by slow conversion to L-CA-asp, with consequent movement of the flexible loop and dissolution of the crystals. Orthorhombic crystals are then able to grow in the presence of L-DHO and L-CA-asp.
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    Membrane-targeted strategies for modulating APP and A beta-mediated toxicity
    Price, KA ; Crouch, PJ ; Donnelly, PS ; Masters, CL ; White, AR ; Curtain, CC (WILEY, 2009-02-01)
    Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by numerous pathological features including the accumulation of neurotoxic amyloid-beta (Abeta) peptide. There is currently no effective therapy for AD, but the development of therapeutic strategies that target the cell membrane is gaining increased interest. The amyloid precursor protein (APP) from which Abeta is formed is a membrane-bound protein, and Abeta production and toxicity are both membrane mediated events. This review describes the critical role of cell membranes in AD with particular emphasis on how the composition and structure of the membrane and its specialized regions may influence toxic or benign Abeta/APP pathways in AD. The putative role of copper (Cu) in AD is also discussed, and we highlight how targeting the cell membrane with Cu complexes has therapeutic potential in AD.
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    Self-terminating, oxidative radical cyclizations
    Dreessen, T ; Jargstorff, C ; Lietzau, L ; Plath, C ; Stademann, A ; Wille, U (MDPI, 2004-06-01)
    The recently discovered novel concept of self-terminating, oxidative radical cyclizations, through which alkynes can be converted into carbonyl compounds under very mild reaction conditions using O-centered inorganic and organic radicals as oxidants, is described.
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    Setting and meeting priorities in Indigenous health research in Australia and its application in the Cooperative Research Centre for Aboriginal health.
    Monk, JM ; Rowley, KG ; Anderson, IP (Springer Science and Business Media LLC, 2009-11-20)
    Priority setting is about making decisions. Key issues faced during priority setting processes include identifying who makes these decisions, who sets the criteria, and who benefits. The paper reviews the literature and history around priority setting in research, particularly in Aboriginal health research. We explore these issues through a case study of the Cooperative Research Centre for Aboriginal Health (CRCAH)'s experience in setting and meeting priorities.Historically, researchers have made decisions about what research gets done. Pressures of growing competition for research funds and an increased public interest in research have led to demands that appropriate consultation with stakeholders is conducted and that research is of benefit to the wider society. Within Australian Aboriginal communities, these demands extend to Aboriginal control of research to ensure that Aboriginal priorities are met.In response to these demands, research priorities are usually agreed in consultation with stakeholders at an institutional level and researchers are asked to develop relevant proposals at a project level. The CRCAH's experience in funding rounds was that scientific merit was given more weight than stakeholders' priorities and did not necessarily result in research that met these priorities. After reviewing these processes in 2004, the CRCAH identified a new facilitated development approach. In this revised approach, the setting of institutional priorities is integrated with the development of projects in a way that ensures the research reflects stakeholder priorities.This process puts emphasis on identifying projects that reflect priorities prior to developing the quality of the research, rather than assessing the relevance to priorities and quality concurrently. Part of the CRCAH approach is the employment of Program Managers who ensure that stakeholder priorities are met in the development of research projects. This has enabled researchers and stakeholders to come together to collaboratively develop priority-driven research. Involvement by both groups in project development has been found to be essential in making decisions that will lead to robust and useful research.
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    Crystal structure of A(3)B(3) complex of V-ATPase from Thermus thermophilus
    Maher, MJ ; Akimoto, S ; Iwata, M ; Nagata, K ; Hori, Y ; Yoshida, M ; Yokoyama, S ; Iwata, S ; Yokoyama, K (WILEY, 2009-12-02)
    Vacuolar-type ATPases (V-ATPases) exist in various cellular membranes of many organisms to regulate physiological processes by controlling the acidic environment. Here, we have determined the crystal structure of the A(3)B(3) subcomplex of V-ATPase at 2.8 A resolution. The overall construction of the A(3)B(3) subcomplex is significantly different from that of the alpha(3)beta(3) sub-domain in F(o)F(1)-ATP synthase, because of the presence of a protruding 'bulge' domain feature in the catalytic A subunits. The A(3)B(3) subcomplex structure provides the first molecular insight at the catalytic and non-catalytic interfaces, which was not possible in the structures of the separate subunits alone. Specifically, in the non-catalytic interface, the B subunit seems to be incapable of binding ATP, which is a marked difference from the situation indicated by the structure of the F(o)F(1)-ATP synthase. In the catalytic interface, our mutational analysis, on the basis of the A(3)B(3) structure, has highlighted the presence of a cluster composed of key hydrophobic residues, which are essential for ATP hydrolysis by V-ATPases.
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    Protein secretion and outer membrane assembly in Alphaproteobacteria
    Gatsos, X ; Perry, AJ ; Anwari, K ; Dolezal, P ; Wolynec, PP ; Likic, VA ; Purcell, AW ; Buchanan, SK ; Lithgow, T (OXFORD UNIV PRESS, 2008-11-01)
    The assembly of beta-barrel proteins into membranes is a fundamental process that is essential in Gram-negative bacteria, mitochondria and plastids. Our understanding of the mechanism of beta-barrel assembly is progressing from studies carried out in Escherichia coli and Neisseria meningitidis. Comparative sequence analysis suggests that while many components mediating beta-barrel protein assembly are conserved in all groups of bacteria with outer membranes, some components are notably absent. The Alphaproteobacteria in particular seem prone to gene loss and show the presence or absence of specific components mediating the assembly of beta-barrels: some components of the pathway appear to be missing from whole groups of bacteria (e.g. Skp, YfgL and NlpB), other proteins are conserved but are missing characteristic domains (e.g. SurA). This comparative analysis is also revealing important structural signatures that are vague unless multiple members from a protein family are considered as a group (e.g. tetratricopeptide repeat (TPR) motifs in YfiO, beta-propeller signatures in YfgL). Given that the process of the beta-barrel assembly is conserved, analysis of outer membrane biogenesis in Alphaproteobacteria, the bacterial group that gave rise to mitochondria, also promises insight into the assembly of beta-barrel proteins in eukaryotes.
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    The incidence and outcome of septic shock patients in the absence of early-goal directed therapy
    Ho, BCH ; Bellomo, R ; McGain, F ; Jones, D ; Naka, T ; Wan, L ; Braitberg, G (BIOMED CENTRAL LTD, 2006-01-01)
    INTRODUCTION: The purpose of the present study was to measure the incidence and outcome of septic patients presenting at the emergency department (ED) with criteria for early goal-directed therapy (EGDT). METHOD: This hospital-based, retrospective, observational study using prospectively collected electronic databases was based in a teaching hospital in Melbourne, Australia. We conducted outcome-blinded electronic screening of patients with infection admitted via the ED from 1 January 2000 to 30 June 2003. We obtained data on demographics, laboratory and clinical features on admission. We used paper records to confirm electronic identification of candidates for EGDT and to study their treatment. We followed up all patients until hospital discharge or death. RESULTS: Of 4,784 ED patients with an infectious disease diagnosis, only 50 fulfilled published clinical inclusion criteria for EGDT (EGDT candidates). Of these patients, 37 (74%) survived their hospital admission, two (4%) died in the ED, eight (16%) died in the intensive care unit and three (6%) died in the ward. After review of all ward cardiac arrests and non-NFR ('not for resuscitation') ward deaths, we identified a further two potential candidates for EGDT for an overall mortality of 28.8% (15 out of 52 patients). Analysis of treatment showed that twice as many (70%) of the EGDT candidates received vasopressor therapy in the ED, and their initial mean central venous pressure (10.8 mmHg) was almost twice that in patients from the EGDT study conducted by Rivers and coworkers. CONCLUSION: In an Australian teaching hospital candidates for EGDT were uncommon and, in the absence of an EGDT protocol, their mortality was lower than that reported with EGDT.
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    4-Chloroanilinium 2-carboxy-4,5-dichlorobenzoate
    Smith, G ; Wermuth, UD ; White, JM (WILEY-BLACKWELL, 2009-09-01)
    The structure of the 1:1 proton-transfer compound of 4-chloro-aniline with 4,5-dichloro-phthalic acid (DCPA), viz. C(6)H(7)ClN(+)·C(8)H(3)Cl(2)O(4) (-), has been determined at 130 K. The non-planar hydrogen phthalate anions and the 4-chloro-anilinium cations form two-dimensional O-H⋯O and N-H⋯O hydrogen-bonded substructures which have no peripheral extension. Between the sheets there are weak π-π associations between alternating cation-anion aromatic ring systems [shortest centroid-centroid separation = 3.735 (4) Å].
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    1,10-Phenanthrolin-1-ium 2-carboxy-4,5-dichlorobenzoate
    Smith, G ; Wermuth, UD ; White, JM (WILEY-BLACKWELL, 2009-10-01)
    In the structure of the 1:1 proton-transfer compound of 1,10-phenanthroline with 4,5-dichloro-phthalic acid, C(12)H(9)N(2) (+)·C(8)H(3)Cl(2)O(4) (-), determined at 130 K, the 1,10-phenanthrolinium cation and the hydrogen 4,5-dichloro-phthalate anion associate through a single N-H⋯O(carbox-yl) hydrogen bond giving discrete units which have no extension except through a number of weak cation C-H⋯O(anion) associations and weak cation-anion aromatic ring π-π inter-actions [minimum centroid-centroid separation = 3.6815 (12) Å]. The anions are essentially planar "[maximum deviation 0.214 (1) Å (a carboxyl O)] with the syn-related H atom of the carboxyl group, forming a short intra-molecular O-H⋯O(carbox-yl) hydrogen bond.