Vicky Just

University of Bath, Press office, Department Member

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Press & PR Officer at the University of Bath, with responsibility for the Faculty of Science:
-Department of Biology & Biochemistry
- Department of Chemistry
- Department of Pharmacy & Pharmacology
- Department of Physics
- Department of Mathematical Sciences
Phone: 01225 386883
Address: University of Bath,
Bath
BA2 7AY

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Richard Sessions

University of Bristol

Mitchell Avery

University of Mississippi

Blake Watkins

Dr A K Tripathi

Aline Oliveira

Universidade Federal de Sergipe

Laura Betti

Università di Pisa

León Lg

Elisa Giovannetti

Vrije Universiteit Amsterdam

Deborah Shoemark

Madhu Sudhana Saddala

Sri Venkateswara University

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Papers by Vicky Just

Identification and Activity of a Series of Azole-based Compounds with Lactate Dehydrogenase-directed Anti-malarial Activity

by Silvestre Garcia-Ochoa and Vicky Just

Journal of Biological Chemistry, 2004

Plasmodium falciparum, the causative agent of malaria, relies extensively on glycolysis coupled w... more Plasmodium falciparum, the causative agent of malaria, relies extensively on glycolysis coupled with homolactic fermentation during its blood-borne stages for energy production. Selective inhibitors of the parasite lactate dehydrogenase (LDH), central to NAD ؉ regeneration, therefore potentially provide a route to new antimalarial drugs directed against a novel molecular target. A series of heterocyclic, azole-based compounds are described that preferentially inhibit P. falciparum LDH at sub-micromolar concentrations, typically at concentrations about 100-fold lower than required for human lactate dehydrogenase inhibition. Crystal structures show these competitive inhibitors form a network of interactions with amino acids within the active site of the enzyme, stacking alongside the nicotinamide ring of the NAD ؉ cofactor. These compounds display modest activity against parasitized erythrocytes, including parasite strains with known resistance to existing anti-malarials and against Plasmodium berghei in BALB/c mice. Initial toxicity data suggest the azole derivatives have generally low cytotoxicity, and preliminary pharmocokinetic data show favorable bioavailability and circulation times. These encouraging results suggest that further enhancement of these structures may yield candidates suitable for consideration as new therapeutics for the treatment of malaria. In combination these studies also provide strong support for the validity of targeting the Plasmodium glycolytic pathway and, in particular, LDH in the search for novel anti-malarials.

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Identification and Activity of a Series of Azole-based Compounds with Lactate Dehydrogenase-directed Anti-malarial Activity

by Vicky Just and Richard Sessions

Journal of Biological Chemistry, 2004

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Identification and activity of a series of azole-based compounds with lactate dehydrogenase-directed anti-malarial activity

The Journal of biological chemistry, 2004

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A divergent external loop confers antagonistic activity on floral regulators FT and TFL1

The EMBO journal, 2006

The Arabidopsis genes FT and TERMINAL FLOWER1 (TFL1) encode related proteins with similarity to h... more The Arabidopsis genes FT and TERMINAL FLOWER1 (TFL1) encode related proteins with similarity to human Raf kinase inhibitor protein. FT, and likely also TFL1, is recruited to the promoters of floral genes through interaction with FD, a bZIP transcription factor. FT, however, induces flowering, while TFL1 represses flowering. Residues responsible for the opposite activities of FT and TFL1 were mapped by examining plants that overexpress chimeric proteins. A region important in vivo localizes to a 14-amino-acid segment that evolves very rapidly in TFL1 orthologs, but is almost invariant in FT orthologs. Crystal structures show that this segment forms an external loop of variable conformation. The only residue unambiguously distinguishing the FT and TFL1 loops makes a hydrogen bond with a residue near the entrance of a potential ligand-binding pocket in TFL1, but not in FT. This pocket is contacted by a C-terminal peptide, which also contributes to the opposite FT and TFL1 activities. In combination, these results identify a molecular surface likely to be recognized by FT-and/or TFL1-specific interactors.

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Bacillus subtilis YxaG is a novel Fe-containing quercetin 2,3-dioxygenase

FEBS letters, 2004

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A closed conformation of Bacillus subtilis oxalate decarboxylase OxdC provides evidence for the true identity of the active site

The Journal of biological chemistry, 2004

Oxalate decarboxylase (EC 4.1.1.2) catalyzes the conversion of oxalate to formate and carbon diox... more Oxalate decarboxylase (EC 4.1.1.2) catalyzes the conversion of oxalate to formate and carbon dioxide and utilizes dioxygen as a cofactor. By contrast, the evolutionarily related oxalate oxidase (EC 1.2.3.4) converts oxalate and dioxygen to carbon dioxide and hydrogen peroxide. Divergent free radical catalytic mechanisms have been proposed for these enzymes that involve the requirement of an active site proton donor in the decarboxylase but not the oxidase reaction. The oxidase possesses only one domain and manganese binding site per subunit, while the decarboxylase has two domains and two manganese sites per subunit. A structure of the decarboxylase together with a limited mutagenesis study has recently been interpreted as evidence that the C-terminal domain manganese binding site (site 2) is the catalytic site and that Glu-333 is the crucial proton donor (Anand, R., Dorrestein, P. C., Kinsland, C., Begley, T. P., and Ealick, S. E. . The N-terminal binding site (site 1) of this structure is solvent-exposed (open) and lacks a suitable proton donor for the decarboxylase reaction. We report a new structure of the decarboxylase that shows a loop containing a 3 10 helix near site 1 in an alternative conformation. This loop adopts a "closed" conformation forming a lid covering the entrance to site 1. This conformational change brings Glu-162 close to the manganese ion, making it a new candidate for the crucial proton donor. Sitedirected mutagenesis of equivalent residues in each domain provides evidence that Glu-162 performs this vital role and that the N-terminal domain is either the sole or the dominant catalytically active domain.

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The identity of the active site of oxalate decarboxylase and the importance of the stability of active-site lid conformations

The Biochemical journal, 2007

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Oxalate decarboxylase and oxalate oxidase activities can be interchanged with a specificity switch of up to 282,000 by mutating an active site lid

Biochemistry, 2007

Oxalate decarboxylases and oxalate oxidases are members of the cupin superfamily of proteins that... more Oxalate decarboxylases and oxalate oxidases are members of the cupin superfamily of proteins that have many common features: a manganese ion with a common ligand set, the substrate oxalate, and dioxygen (as either a unique cofactor or a substrate). We have hypothesized that these enzymes share common catalytic steps that diverge when a carboxylate radical intermediate becomes protonated. The Bacillus subtilis decarboxylase has two manganese binding sites, and we proposed that Glu162 on a flexible lid is the site 1 general acid. We now demonstrate that a decarboxylase can be converted into an oxidase by mutating amino acids of the lid that include Glu162 with specificity switches of 282,000 (SEN161-3DAS), 275,000 (SENS161-4DSSN), and 225,000 (SENS161-4DASN). The structure of the SENS161-4DSSN mutant showed that site 2 was not affected. The requirement for substitutions other than of Glu162 was, at least in part, due to the need to decrease the Km for dioxygen for the oxidase reaction. Reversion of decarboxylase activity could be achieved by reintroducing Glu162 to the SENS161-4DASN mutant to give a relative specificity switch of 25,600. This provides compelling evidence for the crucial role of Glu162 in the decarboxylase reaction consistent with it being the general acid, for the role of the lid in controlling the Km for dioxygen, and for site 1 being the sole catalytically active site. We also report the trapping of carboxylate radicals produced during turnover of the mutant with the highest oxidase activity. Such radicals were also observed with the wild-type decarboxylase.

Identification and Activity of a Series of Azole-based Compounds with Lactate Dehydrogenase-directed Anti-malarial Activity

by Silvestre Garcia-Ochoa and Vicky Just

Journal of Biological Chemistry, 2004

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Identification and Activity of a Series of Azole-based Compounds with Lactate Dehydrogenase-directed Anti-malarial Activity

by Vicky Just and Richard Sessions

Journal of Biological Chemistry, 2004

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Identification and activity of a series of azole-based compounds with lactate dehydrogenase-directed anti-malarial activity

The Journal of biological chemistry, 2004

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A divergent external loop confers antagonistic activity on floral regulators FT and TFL1