Walter A. Szarek

Queens University of Charlotte, New York, United States

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Publications (299)552.8 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The opportunistic pathogen Pseudomonas aeruginosa produces two major cell surface lipopolysaccharides, characterized by distinct O antigens, called Common Polysaccharide Antigen (CPA) and O-specific antigen (OSA). CPA contains a polymer of d-rhamnose (d-Rha) in α-2 and α-3-linkages. Three putative glycosyltransferase genes, wbpX, wbpY, and wbpZ, are part of the CPA biosynthesis cluster. To characterize the enzymatic function of the wbpZ gene product, we chemically synthesized the donor substrate GDP-d-Rha and enzymatically synthesized GDP-D-[(3)H]Rha. Using NMR spectroscopy, we showed that WbpZ transferred one d-Rha residue from GDP-d-Rha in α1-3 linkage to both, GlcNAc- and GalNAc-diphosphate-lipid acceptor substrates. WbpZ is also capable of transferring d-mannose (d-Man) to these acceptors. Therefore, WbpZ has a relaxed specificity with respect to both, acceptor and donor substrates. The diphosphate group of the acceptor, however, is required for activity. WbpZ does not require divalent metal ion for activity and exhibits an unusually high pH optimum of 9. WbpZ from PAO1 is therefore a GDP-d-Rha: GlcNAc/GalNAc-diphosphate-lipid α1,3-d-rhamnosyltransferase that has significant activity of GDP-d-Man: GlcNAc/GalNAc-diphosphate-lipid α1,3-d-mannosyltransferase. We used site-directed mutagenesis to replace the Asp residues of the two DXD motifs with Ala. Neither of the mutant constructs of wbpZ (D172A or D254A) could be used to rescue CPA biosynthesis in the ΔwbpZ knockout mutant in a complementation assay. This suggested that D172 and D254 are essential for WbpZ function. This work is the first detailed characterization study of a d-Rha-transferase and a critical step in the development of CPA synthesis inhibitors. This is the first characterization of a D-rhamnosyltransferase and shows that it is essential in Pseudomonas aeruginosa for the synthesis of the Common Polysaccharide Antigen. Copyright © 2015, American Society for Microbiology. All Rights Reserved.
    Journal of bacteriology 04/2015; DOI:10.1128/JB.02590-14 · 2.69 Impact Factor
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    ABSTRACT: Mesenchymal stem cell (MSC) administration is a promising adjuvant therapy to treat tissue injury. However, MSC survival after administration is often hampered by oxidative stress at the site of injury. Heme oxygenase (HO) generates the cytoprotective effector molecules biliverdin/bilirubin, carbon monoxide (CO) and iron/ferritin by breaking down heme. Since HO-activity mediates anti-apoptotic, anti-inflammatory, and anti-oxidative effects, we hypothesized that modulation of the HO-system affects MSC survival. Adipose-derived MSCs (ASCs) from wild type (WT) and HO-2 knockout (KO) mice were isolated and characterized with respect to ASC marker expression. In order to analyze potential modulatory effects of the HO-system on ASC survival, WT and HO-2 KO ASCs were pre-treated with HO-activity modulators, or downstream effector molecules biliverdin, bilirubin, and CO before co-exposure of ASCs to a toxic dose of H2O2. Surprisingly, sensitivity to H2O2-mediated cell death was similar in WT and HO-2 KO ASCs. However, pre-induction of HO-1 expression using curcumin increased ASC survival after H2O2 exposure in both WT and HO-2 KO ASCs. Simultaneous inhibition of HO-activity resulted in loss of curcumin-mediated protection. Co-treatment with glutathione precursor N-Acetylcysteine promoted ASC survival. However, co-incubation with HO-effector molecules bilirubin and biliverdin did not rescue from H2O2-mediated cell death, whereas co-exposure to CO-releasing molecules-2 (CORM-2) significantly increased cell survival, independently from HO-2 expression. Summarizing, our results show that curcumin protects via an HO-1 dependent mechanism against H2O2-mediated apoptosis, and likely through the generation of CO. HO-1 pre-induction or administration of CORMs may thus form an attractive strategy to improve MSC therapy.
    International Journal of Molecular Sciences 10/2014; 15(10):17974-17999. DOI:10.3390/ijms151017974 · 2.34 Impact Factor
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    ABSTRACT: Heme oxygenase-1 (HO-1) encoded by the HMOX1 gene is a 32 kDa stress protein that catabolizes heme to biliverdin, free iron and carbon monoxide. Glial HO-1 is over-expressed in the CNS of subjects with Alzheimer's disease (AD), Parkinson's disease (PD) and multiple sclerosis (MS). The HMOX1 gene is exquisitely sensitive to oxidative stress and is induced in brain and other tissues in various models of disease and trauma. Induction of the glial HMOX1 gene may lead to pathological brain iron deposition, intracellular oxidative damage and bioenergetic failure in AD and other human CNS disorders such as PD and MS. Therefore, targeted suppression of glial HO-1 hyperactivity may prove to be a rational and effective therapeutic intervention in AD and related neurodegenerative disorders. In the present study, we report the effects of QC-47, QC-56 and OB-28, novel azole-based competitive and reversible inhibitors of HO-1, on oxidative damage to whole cell and mitochondrial compartments in rat astrocytes transfected with the HMOX1 gene. We also report the effect of OB-28 on the behavior and neuropathology of APPswe/PS1∆E9 mice. OB-28 was found to reduce oxidative damage to whole cell and mitochondrial compartments in rat astrocytes transfected with the HMOX1 gene. Moreover, OB-28 was found to significantly counter behavioural deficits and neuropathological alterations in APPswe/PS1∆E9 mice. Attenuation of AD-associated behavioural deficits and neuropathological changes suggests that HO-1 may be a promising target for neuro-protective intervention in AD and other neurodegenerative diseases.This article is protected by copyright. All rights reserved.
    Journal of Neurochemistry 08/2014; DOI:10.1111/jnc.12927 · 4.24 Impact Factor
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    ABSTRACT: The development of heme oxygenase (HO) inhibitors, especially those that are isozyme-selective, promises powerful pharmacological tools to elucidate the regulatory characteristics of the HO system. HO is known to have cytoprotective properties with a role in several disease states; thus, it is an enticing therapeutic target. Traditionally, given their structural similarity with heme, the metalloporphyrins have been used as competitive HO inhibitors. However, given heme’s important role in several other proteins (e.g. cytochromes P450, nitric oxide synthase), nonselectivity is an unfortunate side-effect. Reports that azalanstat and other non-porphyrin molecules inhibited HO led to a multi-faceted effort to develop novel compounds as potent, selective inhibitors of HO. This resulted in the creation of non-competitive HO-selective inhibitors, including a subset with isozyme selectivity for HO-1. Using X-ray crystallography, the structures of several complexes of HO-1 with novel inhibitors have been elucidated, providing insightful information regarding the salient features required for inhibitor binding. This included the structural basis for noncompetitive inhibition, flexibility and adaptability of the inhibitor binding pocket, and multiple, potential interaction subsites, all of which can be exploited in future drug-design strategies. The structures revealed a common binding mode, despite different structural fragments, with the flexibility to accommodate bulkier substituents via “induced fit”. Compounds bind to the distal side of heme through an azole ‘‘anchor” which coordinates with the heme iron. Expansion of the distal pocket, mainly due to distal helix flexibility, allows accommodation of the compounds, with a distal hydrophobic pocket providing further stabilization yet without displacing heme or the critical Asp140 residue. Rather, binding displaces a catalytically critical water molecule and disrupts an ordered hydrogen-bond network involving Asp140.
    23rd Congress and General Assembly of the International Union, Montreal, PQ, Canada; 08/2014
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    ABSTRACT: E. coli display O antigens on the outer membrane that play an important role in bacterial interactions with the environment. The O antigens of enterohemorrhagic E. coli O104 and O5 contain a Galβ1-3GalNAc- disaccharide at the reducing end of the repeating unit. Several other O antigens contain this disaccharide which is identical to the mammalian O-glycan core 1 or the cancer-associated Thomsen-Friedenreich (TF) antigen. We identified the wbwC genes responsible for the synthesis of the disaccharide in E. coli serotypes O104 and O5. To functionally characterize WbwC, an acceptor substrate analog, GalNAcα-diphosphate-phenylundecyl, was synthesized. WbwC reaction products were isolated by high pressure liquid chromatography and analyzed by mass spectrometry, nuclear magnetic resonance, galactosidase and O-glycanase digestion and anti-TF antibody. The results clearly showed that the Galβ1-3GalNAcα- linkage was synthesized, confirming WbwCECO104 and WbwCECO5 as UDP-Gal: GalNAcα-diphosphate-lipid β1,3-Gal-transferases. Sequence analysis revealed a conserved DxDD motif, and mutagenesis showed the importance of these Asp residues in catalysis. The purified enzymes require divalent cations (Mn(2+)) for activity and are specific for UDP-Gal and GalNAc-diphosphate-lipid substrates. WbwC was inhibited by bis-imidazolium salts having aliphatic chains of 18 to 22 carbons. This work will help to elucidate mechanisms of polysaccharide synthesis in pathogenic bacteria and provide technology for vaccine synthesis.
    Journal of Bacteriology 06/2014; 196(17). DOI:10.1128/JB.01698-14 · 2.69 Impact Factor
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    ABSTRACT: Previously, we reported that menadione activated rat, native heme oxygenase-2 (HO-2) and human recombinant heme oxygenase-2 selectively; it did not activate spleen, microsomal heme oxygenase-1. The purpose of this study was to explore some structure-activity relationships of this activation and the idea that redox properties may be an important aspect of menadione efficacy. Heme oxygenase activity was determined in vitro using rat spleen and brain microsomes as the sources of heme oxygenase-1 and -2, respectively, as well as recombinant, human heme oxygenase-2. Menadione analogs with bulky aliphatic groups at position-3, namely vitamins K1 and K2, were not able to activate HO-2. In contrast, several compounds with similar bulky but less lipophilic moieties at position-2 (and -3) were able to activate HO-2 many fold; these compounds included polar, rigid, furan-containing naphthoquinones, furan-benzoxazine naphthoquinones, 2-(aminophenylphenyl)-3-piperidin-1-yl naphthoquinones. To explore the idea that redox properties might be involved in menadione efficacy, we tested analogs such as 1,4-dimethoxy-2-methylnaphthalene, pentafluoromenadione, monohalogenated naphthoquinones, alpha-tetralone and 1,4-naphthoquinone. All of these compounds were inactive except for 1,4-naphthoquinone. Menadione activated full-length recombinant human heme oxygenase-2 (FL-hHO-2) as effectively as rat brain enzyme, but it did not activate rat spleen heme oxygenase. These observations are consistent with the idea that naphthoquinones such as menadione bind to a receptor in HO-2 and activate the enzyme through a mechanism that may involve redox properties.
    02/2014; 4(1):4. DOI:10.1186/2045-9912-4-4
  • Gheorghe Roman, Ian E Crandall, Walter A Szarek
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    ABSTRACT: A series of compounds structurally related to astemizole were designed and synthesized with the goal of determining their anti-Plasmodium activity. Several modifications of the astemizole structure, namely the removal of the 4-fluorobenzyl and/or 4-methoxyphenethyl moieties, substitution of the benzene ring of the benzimidazole scaffold, replacement of the fluorine atom in the 4-fluorobenzyl group, and variation of the 4-aminopiperidine moiety, were explored. In vitro evaluation of the anti-Plasmodium activity of these compounds using the ItG strain showed that astemizole and some of its structurally similar derivatives have IC50 values in the nanomolar range and exhibit toxicity towards the parasite over Chinese ovarian hamster (CHO) cells with a selectivity as high as 200. The presence of a secondary cyclic amine at position 2 and substitution with chlorine at positions 4 and 5 in the benzimidazole moiety are two modifications that resulted in potent and selective antimalarials based on astemizole.
    ChemMedChem 11/2013; 8(11):1795-1804. DOI:10.1002/cmdc.201300172 · 3.05 Impact Factor
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    ABSTRACT: Several analogs based on the lead structure of 1-(4-chlorobenzyl)-2-(pyrrolidin-1-ylmethyl)-1H-benzimidazole (clemizole) were synthesized and evaluated as novel inhibitors of heme oxygenase (HO). Many of the compounds were found to be potent and highly selective for the HO-2 isozyme (constitutive), and had substantially less inhibitory activity on the HO-1 isozyme (inducible). The compounds represent the first report of highly potent and selective inhibitors of HO-2 activity, and complement our suite of selective HO-1 inhibitors. The study has revealed many candidates based on the inhibition of heme oxygenases for potentially useful pharmacological and therapeutic applications.
    Bioorganic & medicinal chemistry 08/2013; DOI:10.1016/j.bmc.2013.07.050 · 2.95 Impact Factor
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    ABSTRACT: BACKGROUND: Modifications of proteins by O-glycosylation determine many of the properties and functions of proteins. We wish to understand the mechanisms of O-glycosylation and develop inhibitors that could affect glycoprotein functions and alter cellular behavior. METHODS: We expressed recombinant soluble human Gal- and GlcNAc-transferases that synthesize the O-glycan cores 1 to 4 and are critical for the overall structures of O-glycans. We determined the properties and substrate specificities of these enzymes using synthetic acceptor substrate analogs. Compounds that were inactive as substrates were tested as inhibitors. RESULTS: Enzymes significantly differed in their recognition of the sugar moieties and aglycone groups of substrates. Core 1 synthase was active with glycopeptide substrates but GlcNAc-transferases preferred substrates with hydrophobic aglycone groups. Chemical modifications of the acceptors shed light on enzyme - substrate interactions. Core 1 synthase was weakly inhibited by its substrate analog benzyl 2-butanamido-2-deoxy-α-D-galactoside while two of the three GlcNAc-transferases were selectively and potently inhibited by bis-imidazolium salts which are not substrate analogs. CONCLUSIONS: This work delineates the distinct specificities and properties of the enzymes that synthesize the common O-glycan core structures 1 to 4. New inhibitors were found that could selectively inhibit the synthesis of core 1, 2 and 3 but not core 4. General significance These studies help our understanding of the mechanisms of action of enzymes critical for O-glycosylation. The results may be useful for the re-engineering of O-glycosylation to determine the roles of O-glycans and the enzymes critical for O-glycosylation, and for biotechnology with potential therapeutic applications.
    Biochimica et Biophysica Acta 04/2013; 1830(8). DOI:10.1016/j.bbagen.2013.04.001 · 4.66 Impact Factor
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    ABSTRACT: Galactosyltransferases (GalTs) extend the glycan chains of mammalian glycoproteins by adding Gal to terminal GlcNAc residues, and thus build the scaffolds for biologically important glycan structures. We have shown that positively charged bivalent imidazolium salts in which the two imidazolium groups are linked by an aliphatic chain of 20 or 22 carbons form potent inhibitors of purified human β3-GalT5, using GlcNAcβ-benzyl as acceptor substrate. The inhibitors are not substrate analogs and also inhibited a selected number of other glycosyltransferases. These bis-imidazolium compounds represent a new class of glycosyltransferase inhibitors with potential as anti-cancer and anti-inflammatory drugs.
    Bioorganic & medicinal chemistry 01/2013; 21(5). DOI:10.1016/j.bmc.2012.12.034 · 2.95 Impact Factor
  • Gheorghe Roman, Ian E. Crandall, Walter A. Szarek
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    ABSTRACT: AbstractA series of compounds structurally related to astemizole were designed and synthesized with the goal of determining their anti‐Plasmodium activity. Several modifications of the astemizole structure, namely the removal of the 4‐fluorobenzyl and/or 4‐methoxyphenethyl moieties, substitution of the benzene ring of the benzimidazole scaffold, replacement of the fluorine atom in the 4‐fluorobenzyl group, and variation of the 4‐aminopiperidine moiety, were explored. In vitro evaluation of the anti‐Plasmodium activity of these compounds using the ItG strain showed that astemizole and some of its structurally similar derivatives have IC50 values in the nanomolar range and exhibit toxicity towards the parasite over Chinese ovarian hamster (CHO) cells with a selectivity as high as 200. The presence of a secondary cyclic amine at position 2 and substitution with chlorine at positions 4 and 5 in the benzimidazole moiety are two modifications that resulted in potent and selective antimalarials based on astemizole.
    ChemMedChem 01/2013; 8(11). · 3.05 Impact Factor
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    ABSTRACT: The interaction between DNA and members of series of bivalent imidazole compounds, monovalent and bivalent imidazolium compounds, and monovalent and bivalent tetrazolium compounds, which had been synthesized and evaluated for their anti-Plasmodium activity, has been examined using the displacement of SYBR Green I as a measure of competitive binding. The degree of interaction with DNA appears to be dependent on both hydrophobic and charge-pairing interactions.
    Bioorganic & medicinal chemistry letters 12/2012; DOI:10.1016/j.bmcl.2012.11.106 · 2.33 Impact Factor
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    ABSTRACT: The development of heme oxygenase (HO) inhibitors, especially those that are isozyme-selective, promises powerful pharmacological tools to elucidate the regulatory characteristics of the HO system. It is already known that HO has cytoprotective properties and may play a role in several disease states, making it an enticing therapeutic target. Traditionally, the metalloporphyrins have been used as competitive HO inhibitors owing to their structural similarity with the substrate, heme. However, given heme's important role in several other proteins (e.g. cytochromes P450, nitric oxide synthase), non-selectivity is an unfortunate side-effect. Reports that azalanstat and other non-porphyrin molecules inhibited HO led to a multi-faceted effort to develop novel compounds as potent, selective inhibitors of HO. This resulted in the creation of non-competitive inhibitors with selectivity for HO, including a subset with isozyme selectivity for HO-1. Using X-ray crystallography, the structures of several complexes of HO-1 with novel inhibitors have been elucidated, which provided insightful information regarding the salient features required for inhibitor binding. This included the structural basis for non-competitive inhibition, flexibility and adaptability of the inhibitor binding pocket, and multiple, potential interaction subsites, all of which can be exploited in future drug-design strategies.
    Journal of The Royal Society Interface 10/2012; DOI:10.1098/rsif.2012.0697 · 3.86 Impact Factor
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    ABSTRACT: The enterohemorrhagic O157 strain of Escherichia coli, which is one of the most well-known bacterial pathogens, has an O-antigen repeating unit structure with the sequence [-2-d-Rha4NAcα1-3-l-Fucα1-4-d-Glcβ1-3-d-GalNAcα1-]. The O-antigen gene cluster of E. coli O157 contains the genes responsible for the assembly of this repeating unit and includes wbdN. In spite of cloning many O-antigen genes, biochemical characterization has been done on very few enzymes involved in O-antigen synthesis. In this work, we expressed the wbdN gene in E. coli BL21, and the His-tagged protein was purified. WbdN activity was characterized using the donor substrate UDP-[(14)C]Glc and the synthetic acceptor substrate GalNAcα-O-PO(3)-PO(3)-(CH(2))(11)-O-Ph. The enzyme product was isolated by high pressure liquid chromatography, and mass spectrometry showed that one Glc residue was transferred to the acceptor by WbdN. Nuclear magnetic resonance analysis of the product structure indicated that Glc was β1-3 linked to GalNAc. WbdN contains a conserved DxD motif and requires divalent metal ions for full activity. WbdN activity has an optimal pH between 7 and 8 and is highly specific for UDP-Glc as the donor substrate. GalNAcα derivatives lacking the diphosphate group were inactive as substrates, and the enzyme did not transfer Glc to GlcNAcα-O-PO(3)-PO(3)-(CH(2))(11)-O-Ph. Our results illustrate that WbdN is a specific UDP-Glc:GalNAcα-diphosphate-lipid β1,3-Glc-transferase. The enzyme is a target for the development of inhibitors to block O157-antigen synthesis.
    Glycobiology 05/2012; 22(8):1092-102. DOI:10.1093/glycob/cws081 · 3.75 Impact Factor
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    ABSTRACT: Several α-(1H-imidazol-1-yl)-ω-phenylalkanes were synthesized and evaluated as novel inhibitors of heme oxygenase (HO). These compounds were found to be potent and selective for the stress-induced isozyme HO-1, showing mostly weak activity toward the constitutive isozyme HO-2. The introduction of an oxygen atom in the alkyl linker produced analogues with decreased potency toward HO-1, whereas the presence of a sulfur atom in the linker gave rise to analogues with greater potency toward HO-1 than the carbon-containing analogues. The most potent compounds studied contained a five-atom linker between the imidazolyl and phenyl moieties, whereas the most HO-1-selective compounds contained a four-atom linker between these groups. The compounds with a five-atom linker containing a heteroatom (O or S) were found to be the most potent inhibitors of HO-2; 1-(N-benzylamino)-3-(1H-imidazol-1-yl)propane dihydrochloride, with a nitrogen atom in the linker, was found to be inactive.
    ChemMedChem 05/2012; 7(5):897-902. DOI:10.1002/cmdc.201100602 · 3.05 Impact Factor
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    ABSTRACT: The development of heme oxygenase (HO) inhibitors is critical in dissecting and understanding the HO system and for potential therapeutic applications. We have established a program to design and optimize HO inhibitors using structure-activity relationships in conjunction with X-ray crystallographic analyses. One of our previous complex crystal structures revealed a putative secondary hydrophobic binding pocket which could be exploited for a new design strategy by introducing a functional group that would fit into this potential site. To test this hypothesis and gain further insights into the structural basis of inhibitor binding, we have synthesized and characterized 1-(1H-imidazol-1-yl)-4,4-diphenyl-2-butanone (QC-308). Using a carbon monoxide (CO) formation assay on rat spleen microsomes, the compound was found to be ∼15 times more potent (IC(50) = 0.27±0.07 µM) than its monophenyl analogue, which is already a potent compound in its own right (QC-65; IC(50) = 4.0±1.8 µM). The crystal structure of hHO-1 with QC-308 revealed that the second phenyl group in the western region of the compound is indeed accommodated by a definitive secondary proximal hydrophobic pocket. Thus, the two phenyl moieties are each stabilized by distinct hydrophobic pockets. This "double-clamp" binding offers additional inhibitor stabilization and provides a new route for improvement of human heme oxygenase inhibitors.
    PLoS ONE 01/2012; 7(1):e29514. DOI:10.1371/journal.pone.0029514 · 3.53 Impact Factor
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    ABSTRACT: Cell surface mucins configure the cell surface by presenting extended protein backbones that are heavily O-glycosylated. The glycopeptide structures establish physicochemical properties at the cell surface that enable and block the formation of biologically important molecular complexes. Some mucins, such as MUC1, associate with receptor tyrosine kinases and other cell surface receptors, and engage in signal transduction in order to communicate information regarding conditions at the cell surface to the nucleus. In that context, the MUC1 cytoplasmic tail (MUC1CT) receives phosphorylation signals from receptor tyrosine kinases and serine/threonine kinases, which enables its association with different signaling complexes that conduct these signals to the nucleus and perhaps other subcellular organelles. We have detected the MUC1CT at promoters of over 500 genes, in association with several different transcription factors, and have shown that promoter occupancy can vary under different growth factor conditions. However, the full biochemical nature of the nuclear forms of MUC1 and its function at these promoter regions remain undefined. I will present evidence that nuclear forms of the MUC1CT include extracellular and cytoplasmic tail domains. In addition, I will discuss evidence for a hypothesis that the MUC1CT possesses a novel catalytic function that enables remodeling of the transcription factor occupancy of promoters, and thereby engages in regulation of gene expression.
    Glycobiology 11/2011; 21(11):1454-531. DOI:10.1093/glycob/cwr126 · 3.75 Impact Factor
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    ABSTRACT: While substantial progress has been made in elucidating the roles of heme oxygenases-1 (HO-1) and -2 (HO-2) in mammals, our understanding of the functions of these enzymes in health and disease is still incomplete. A significant amount of our knowledge has been garnered through the use of nonselective inhibitors of HOs, and our laboratory has recently described more selective inhibitors for HO-1. In addition, our appreciation of HO-1 has benefitted from the availability of tools for increasing its activity through enzyme induction. By comparison, there is a paucity of information about HO-2 activation, with only a few reports appearing in the literature. This communication describes our observations of the up to 30-fold increase in the in-vitro activation of HO-2 by menadione. This activation was due to an increase in V(max) and was selective, in that menadione did not increase HO-1 activity.
    Canadian Journal of Physiology and Pharmacology 11/2011; 89(11). DOI:10.1139/y11-091 · 1.55 Impact Factor
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    ABSTRACT: A series of compounds containing bivalent imidazolium rings and one triazolium analog were synthesized and evaluated for their ability to inhibit the replication of Plasmodium falciparum cultures. The activity and selectivity of the compounds for P. falciparum cultures were found to depend on the presence of electron-deficient rings that were spaced an appropriate distance apart. The activity of the compounds was not critically dependent on the nature of the linker between the electron-deficient rings, an observation that suggests that the rings were responsible for the primary interaction with the molecular target of the compounds in the parasite. The bivalent imidazolium and triazolium compounds disrupted the process whereby merozoites gain entry into erythrocytes, however, they did not appear to prevent merozoites from forming. The compounds were also found to be active in a murine Plasmodium berghei infection, a result consistent with the compounds specifically interacting with a parasite component that is required for replication and is conserved between two Plasmodium species.
    Bioorganic & medicinal chemistry 06/2011; 19(21):6525-42. DOI:10.1016/j.bmc.2011.06.002 · 2.95 Impact Factor
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    ABSTRACT: A new and improved procedure for the preparation of (R)-2-alkoxycarbonyl-1-formyl-1,2,3,4-tetrahydro-6,7-dimethoxyisoquinolines has been developed beginning from D-(−)-tartaric acid. The utility of these aldehydes in the asymmetric synthesis of isoquinoline alkaloids of high enantiomeric purity has been extended to the synthesis of phenylethylisoquinolines, which have been further transformed in straightforward steps into the homoprotoberberine and homoaporphine ring systems. In this manner, (S)-homolaudanosine, (S)-5′-methoxyhomolaudanosine, (S)-2,3,9,10,11-pentamethoxyhomoprotoberberine, and (S)-O-methylkreysigine have been synthesized. The conversion of (S)-laudanosine to (S)-glaucine, an aporphine alkaloid, has also been realized.
    Canadian Journal of Chemistry 02/2011; 65(10):2356-2361. DOI:10.1139/v87-393 · 1.01 Impact Factor

Publication Stats

2k Citations
552.80 Total Impact Points

Institutions

  • 1982–2015
    • Queens University of Charlotte
      • Chemistry
      New York, United States
  • 1964–2014
    • Queen's University
      • • Department of Chemistry
      • • Department of Medicine
      Kingston, Ontario, Canada
  • 2011
    • Dalhousie University
      • Department of Chemistry
      Halifax, Nova Scotia, Canada
    • Queen's University Belfast
      Béal Feirste, Northern Ireland, United Kingdom
    • Binghamton University
      • Department of Chemistry
      Binghamton, New York, United States
  • 1987–2011
    • McMaster University
      Hamilton, Ontario, Canada
  • 2009
    • Lady Davis Institute for Medical Research
      Montréal, Quebec, Canada
  • 1996–2009
    • McGill University
      • Department of Anatomy and Cell Biology
      Montréal, Quebec, Canada
  • 2004–2007
    • Kingston General Hospital
      Kingston, Ontario, Canada
  • 2006
    • Loma Linda University
      Loma Linda, California, United States