BREAKING IT DOWN: DISSECTING THE MECHANISM AND EXPLORING NEW INHIBITION STRATEGIES FOR POLYSACCHARIDE CLEAVING ENZYMES
Grant number: FT130100103 | Funding period: 2014 - 2017
Mannose, a common carbohydrate building block, is present in a wide variety of complex polysaccharides including energy storage polymers and glycans attached to proteins. The enzymes that degrade these mannose-rich polymers, termed mannosidases, are important in biofuel production and human health and disease. This project will study a range of mannosidases to chemically and structurally define their mechanisms and establish strategies to allow intervention in mannosidase-specific disease processes. This work will inform strategies to engineer new enzymes for future biotechnology and industrial applications including sustainable chemical manufacturing, and underpin the development of innovat..View full description
Related publications (24)
Structure of human endo-alpha-1,2-mannosidase (MANEA), an antiviral host-glycosylation target
Lukasz F Sobala, Pearl Z Fernandes, Zalihe Hakki, Andrew J Thompson, Jonathon D Howe, Michelle Hill, Nicole Zitzmann, Scott Davies, Zania Stamataki, Terry D Butters, Dominic S Alonzi, Spencer J Williams, Gideon J Davies
Mammalian protein N-linked glycosylation is critical for glycoprotein folding, quality control, trafficking, recognition, and func..
An Epoxide Intermediate in Glycosidase Catalysis
Lukasz F Sobala, Gaetano Speciale, Sha Zhu, Lluis Raich, Natalia Sannikova, Andrew J Thompson, Zalihe Hakki, Dan Lu, Saeideh Shamsi Kazem Abadi, Andrew R Lewis, Victor Rojas-Cervellera, Ganeko Bernardo-Seisdedos, Yongmin Zhang, Oscar Millet, Jesus Jimenez-Barbero, Andrew J Bennet, Matthieu Sollogoub, Carme Rovira, Gideon J Davies, Spencer J Williams
Retaining glycoside hydrolases cleave their substrates through stereochemical retention at the anomeric position. Typically, this ..
alpha-Glucuronosyl and alpha-glucosyl diacylglycerides, natural killer T cell-activating lipids from bacteria and fungi
Satvika Burugupalli, Catarina F Almeida, Dylan GM Smith, Sayali Shah, Onisha Patel, Jamie Rossjohn, Adam P Uldrich, Dale I Godfrey, Spencer J Williams
Natural killer T cells express T cell receptors (TCRs) that recognize glycolipid antigens in association with the antigen-presenti..
Distinct CD1d docking strategies exhibited by diverse Type II NKT cell receptors
Catarina F Almeida, Srinivasan Sundararaj, Jerome Le Nours, T Praveena, Benjamin Cao, Satvika Burugupalli, Dylan GM Smith, Onisha Patel, Manfred Brigl, Daniel G Pellicci, Spencer J Williams, Adam P Uldrich, Dale I Godfrey, Jamie Rossjohn
Type I and type II natural killer T (NKT) cells are restricted to the lipid antigen-presenting molecule CD1d. While we have an und..
Diazepam is not a direct allosteric modulator of alpha(1)-adrenoceptors, but modulates receptor signaling by inhibiting phosphodiesterase-4
Lisa M Williams, Xiaoji He, Tasneem M Vaid, Alaa Abdul-Ridha, Alice R Whitehead, Paul R Gooley, Ross AD Bathgate, Spencer J Williams, Daniel J Scott
α1A- and α1B-adrenoceptors (ARs) are G protein-coupled receptors (GPCRs) that are activated by adrenaline and noradrenaline to mod..
Structural and Biochemical Insights into the Function and Evolution of Sulfoquinovosidases
Palika Abayakoon, Yi Jin, James P Lingford, Marija Petricevic, Alan John, Eileen Ryan, Janice Wai-Ying Mui, Douglas E Pires, David B Ascher, Gideon J Davies, Ethan D Goddard-Borger, Spencer J Williams
An estimated 10 billion tonnes of sulfoquinovose (SQ) are produced and degraded each year. Prokaryotic sulfoglycolytic pathways ca..
Exploration of Strategies for Mechanism-Based Inhibitor Design for Family GH99 endo--1,2-Mannanases
Pearl Z Fernandes, Marija Petricevic, Lukasz Sobala, Gideon J Davies, Spencer J Williams
endo-α-1,2-Mannosidases and -mannanases, members of glycoside hydrolase family 99 (GH99), cleave α-Glc/Man-1,3-α-Man-OR structures..
Structure-reactivity correlations of the abnormal Beckmann reaction of dihydrolevoglucosenone oxime
Amani Alhifthi, Benjamin L Harris, Lars Goerigk, Jonathan M White, Spencer J Williams
A structural, spectroscopic and computational study of a series of oximes was undertaken to investigate how geometric and structur..
Conformational Analysis of the Mannosidase Inhibitor Kifunensine: A Quantum Mechanical and Structural Approach
Alexandra Males, Lluis Raich, Spencer J Williams, Carme Rovira, Gideon J Davies
The varied yet family-specific conformational pathways used by individual glycoside hydrolases (GHs) offer a tantalising prospect ..
Gas-Phase Intercluster Thiyl-Radical Induced C-H Bond Homolysis Selectively Forms Sugar C2-Radical Cations of Methyl D-Glucopyranoside: Isotopic Labeling Studies and Cleavage Reactions
Sandra Osburn, Gaetano Speciale, Spencer J Williams, Richard AJ O'Hair
A suite of isotopologues of methyl D-glucopyranosides is used in conjunction with multistage mass spectrometry experiments to dete..
Selective Manipulation of Discrete Mannosidase Activities in the Endoplasmic Reticulum by Using Reciprocally Selective Inhibitors
Taiki Kuribara, Makoto Hirano, Gaetano Speciale, Spencer J Williams, Yukishige Ito, Kiichiro Totani
Within the endoplasmic reticulum, immature glycoproteins are sorted into secretion and degradation pathways through the sequential..
Computational Design of Experiment Unveils the Conformational Reaction Coordinate of GH125 alpha-Mannosidases
Santiago Alonso-Gil, Alexandra Males, Pearl Z Fernandes, Spencer J Williams, Gideon J Davies, Carme Rovira
Conformational analysis of enzyme-catalyzed mannoside hydrolysis has revealed two predominant conformational itineraries through B..
Contribution of Shape and Charge to the Inhibition of a Family GH99 endo-alpha-1,2-Mannanase
Marija Petricevic, Lukasz F Sobala, Pearl Z Fernandes, Lluis Raich, Andrew J Thompson, Ganeko Bernardo-Seisdedos, Oscar Millet, Sha Zhu, Matthieu Sollogoub, Jesus Jimenez-Barbero, Carme Rovira, Gideon J Davies, Spencer J Williams
Inhibitor design incorporating features of the reaction coordinate and transition-state structure has emerged as a powerful approa..
Quantitation in the regioselectivity of acylation of glycosyl diglycerides: total synthesis of a Streptococcus pneumoniae alpha-glucosyl diglyceride
Mark B Richardson, Dylan GM Smith, Spencer J Williams
The fidelity of acylation regioselectivity in the synthesis of mixed glycosyl diacylglycerols can be accurately measured by quanti..
Total Synthesis of Mycobacterium tuberculosis Dideoxymy-cobactin-838 and Stereoisomers: Diverse CD1a-Restricted T Cells Display a Common Hierarchy of Lipopeptide Recognition
Janice MH Cheng, Ligong Liu, Daniel G Pellicci, Scott JJ Reddiex, Rachel N Cotton, Tan-Yun Cheng, David C Young, Ildiko Van Rhijn, D Branch Moody, Jamie Rossjohn, David P Fairlie, Dale I Godfrey, Spencer J Williams
Mycobacterium tuberculosis produces dideoxymycobactin-838 (DDM-838), a lipopeptide that potently activates T cells upon binding to..
A beta-Mannanase with a Lysozyme-like Fold and a Novel Molecular Catalytic Mechanism
Yi Jin, Marija Petricevic, Alan John, Lluis Raich, Huw Jenkins, Leticia Portela De Souza, Fiona Cuskin, Harry J Gilbert, Carme Rovira, Ethan D Goddard-Borger, Spencer J Williams, Gideon J Davies
The enzymatic cleavage of β-1,4-mannans is achieved by endo-β-1,4-mannanases, enzymes involved in germination of seeds and microbi..
C2-Oxyanion Neighboring Group Participation: Transition State Structure for the Hydroxide-Promoted Hydrolysis of 4-Nitrophenyl alpha-D-Mannopyranoside
Gaetano Speciale, Marco Farren-Dai, Fahimeh S Shidmoossavee, Spencer J Williams, Andrew J Bennet
The hydroxide-catalyzed hydrolysis of aryl 1,2-trans-glycosides proceeds through a mechanism involving neighboring group participa..
Lipid structure influences the ability of glucose monocorynomycolate to signal through Mincle
Phillip L van der Peet, Masahiro Nagata, Sayali Shah, Jonathan M White, Sho Yamasaki, Spencer J Williams
Mincle (macrophage-inducible C-type lectin) is a C-type lectin receptor that provides the capacity for immune sensing of a range o..
Structural and mechanistic insights into a Bacteroides vulgatus retaining N-acetyl-beta-galactosaminidase that uses neighbouring group participation
C Roth, M Petricevic, A John, ED Goddard-Borger, GJ Davies, SJ Williams
Bacteroides vulgatus is a member of the human microbiota whose abundance is increased in patients with Crohn's disease. We show th..
Formation of sugar radical cations from collision-induced dissociation of non-covalent complexes with S-nitroso thiyl radical precursors
Sandra Osburn, Spencer J Williams, Richard AJ O'Hair
Abstract A 'bio-inspired' method has been developed for generating sugar radical cations by multistage mass spectrometry (MS4) exp..
An improved method to prepare an injectable microemulsion of the galanin-receptor 3 selective antagonist, SNAP 37889, using Kolliphor(®) HS 15.
Karlene J Scheller, Spencer J Williams, Andrew J Lawrence, Bevyn Jarrott, Elvan Djouma
Research into the galanin-3 (GAL3) receptor has many challenges, including the lack of commercially available selective ligands. W..