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Harry Gilbert
Professor and Eminent Scholar in Bioenergy

Structure and function of carbohydrate modifying enzymes

Telephone: 706-583-0655
Fax: 706-542-4412

Short Biography
Research Interests
Lab-personal web site

Short Biography:
Professor Gilbert received a B.Sc. in physiology and a Ph.D. in biochemistry from the University of Southampton, United Kingdom. He worked as a biochemist at the Southampton General Hospital and microbiologist at the PHLS Centre for Applied Microbiology and Research prior to joining the faculty at the University of Newcastle upon Tyne in 1985. Professor Gilbert recently joined the CCRC as Professor of Biochemistry and Molecular Biology and GRA Eminent Scholar in Bioenergy.

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Research Interests:
My major research interests are focused on enzymes that modify complex carbohydrates. I am interested in glycoside hydrolases, which hydrolyse the glycosidic bonds that link sugar monomers in polysaccharides, and glycosyltransferases, which catalyze the synthesis of glycosidic bonds and thus the formation of complex carbohydrates or glycoconjugants. I also have a generic interest in the mechanism of carbohydrate-protein recognition using non-catalytic carbohydrate binding modules (CBMs) as my model system. These protein modules are appended to glycoside hydrolases that attack insoluble composite polysaccharide structures such as the plant cell wall. By delivering their enzymes to the surface of these complex polysaccharide structures, CBMs greatly enhance the catalytic activity of the appended catalytic module against recalcitrant substrates. Glycoside hydrolases play an important role in biology. They are central to the maintenance of the carbon cycle through the turnover of plant biomass, while these enzymes also play an important role in the survival of health promoting gut microbial symbionts and the invasion strategy of several plant and human pathogens. Glycosyltransferases, by catalyzing the synthesis of polysaccharides and other complex sugar structures, are of generic importance in biology exemplified by their role in determining our blood groups and in the synthesis of plant biomass. From an industrial perspective carbohydrate modifying enzymes are of increasing importance. For example the conversion of plant biomass into its constituent simple sugars is central to the production of second generation biofuels from ligno-cellulosic plant biomass. Indeed glycoside hydrolases have an important role within the wider context of bioprocessing whereby valuable chemicals are generated from plant biomass. In addition to harnessing the enzymes in biotechnology, inhibitors of these enzymes are of considerable medical importance exemplified by acarbose, used in the treatment of type II diabetes, and Tamiflu, which is deployed in the treatment of influenza.

My research is focused on understanding the catalytic mechanism and the structural basis for the substrate specificity displayed by these enzymes. We use a combination of structural biology, primarily X-ray crystallography but also NMR, to determine the three dimensional structure of these enzymes, in combination with rational design and forced protein evolution to dissect how these enzymes work. This information is helping us to use protein engineering strategies designed to introduce industrially useful traits into these enzymes, while also underpinning novel inhibitors that target enzymes which modify mannose-containing polymers. Our recent work has shown that beta-mannanases that cleave glycosidic bonds through a double displacement, or “retaining”, mechanism distort the sugar into a Boat2,5 conformation and it is this geometry that confers substrate specificity, not the capacity to recognize the sugar in its relaxed 4C1 conformation. Our recent work on non-catalytic carbohydrate binding modules has shown that some of these modules can deliver enzymes to regions of the cell wall that is undergoing degradation through the action of pectate lyases. We have also shown that the different topologies displayed by xylan binding modules reflect the variation in the context of this polysaccharide within the plant cell wall.

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Publications: Author's Last Name: Gilbert

Journal Articles
Book Chapters are listed at the bottom of this page.

K.W. Moremen, A. Ramiah, M. Stuart, J. Steel, L. Meng, F. Forouhar, H.A. Moniz, G. Gahlay, Z. Gao, D. Chapla, S. Wang, J.Y. Yang, P.K. Prabhakar, R. Johnson, M.D. Rosa, C. Geisler, A.V. Nairn, J. Seetharaman, S.C. Wu, L. Tong, H.J. Gilbert, J. LaBaer, D.L. Jarvis. 2018. Expression system for structural and functional studies of human glycosylation enzymes. Nature Chem. Biol. 14(2): 156-162. PMID:29251719

SP Thapa, S Pattathil, MG Hahn, MA Jacques, RL Gilbertson, G Coaker. 2017. Molecular and genomic investigation of Clavibacter michiganesis reveals insight into virulence strategies of Gram-positive bacterial plant pathogens. PLoS Genetics Submitted: -.

D. Ndeh, A. Rogowski, A. Cartmell, A.S. Luis, A. Basle, J. Gray, I. Venditto, J. Briggs, X. Zhang, A. Labourel, N. Terrapon, F. Buffetto, S. Nepogodiev, Y. Xiao, R.A. Field, Y. Zhu, M.A. O'Neill, B.R. Urbanowicz, W.S. York, G.J. Davies, D.W. Abbott, M.C. Ralet, E.C. Martens, B. Henrissat, H.J. Gilbert. 2017. Complex pectin metabolism by gut bacteria reveals novel catalytic functions. Nature 544: 65-70. PMID:28329766

F. Cuskin, E.C. Lowe, M.J. Temple, Y. Zhu, E.A. Cameron, N.A. Pudio, N.T. Porter, K. Urs, A.J. Thompson, A. Cartmell, A. Rogowski, B.S. Hamilton, R. Chen, T.J. Tolbert, K. Piens, D. Bracke, W. Vervecken, Z. Hakki, G. Speciale, C.J. Munoz-Munoz, A. Day, M.J. Pena, R. McLean, M.D. Suits, A.B. Boraston, T. Atherly, C.J. Ziemer, S.J. Williams, G.J. Davies, D.W. Abbott, E.C. Martens, H. Gilbert. 2015. human gut bacteroidetes can utilize yeast mannan through a selfish mechanism. Nature 517: 165-169. PMID:25567280

XA Zhang, A Rogowski, MG Hahn, U Avci, JP Knox, HJ Gilbert. 2014. Understanding how the complex molecular architecture of manna degrading hydrolyses contributes to plant cell wall degradation. J Biol Chem 289: 2002-2012. PMID:24297170

X. Zhang, A. Rogowski, M.G. Hahn, U. Avci, J.P. Knox, H.J. Gilbert. 2013. Understanding how the complex molecular architecture of mannan degrading hydrolases contributes to plant cell wall degradation. J. Biol. Chem. In press.

L.S. McKee, M.J. Pena, A. Rogowski, K.A. Jackson, R.J. Lewis, W.S. York, K.B.R.M. Krogh, A. Vikso-Nielsen, M. Skjot, H.J. Gilbert, J. Marles-Wright. 2012. Introducing endo-xylanase activity into an exo-acting arabinofuranosidase that targets side chains. Proc. Natl. Acad. Sci. USA 109: 6537-6542. PMID:22492980

B.R. Urbanowicz, M.J. Pena, S. Ratnaparkhe, U. Avci, J. Backe, H.F. Steet, M. Foston, H. Li, M.A. O'Neill, A.J. Ragauskas, A.G. Darvill, C. Wyman, H.J. Gilbert, W.S. York. 2012. 4-O-Methylation of glucuronic acid in Arabidopsis glucuronoxylan is catalyzed by a domain of unknown function family 579 protein. Proc. Natl. Acad. Sci. USA 109: 14253-14258. PMID:22893684

M.A.S. Correia, K. Mazumder, J.L.A. Bras, S.J. Firbank, Y. Zhu, R.J. Lewis, W.S. York, C.M.G.A. Fontes, H.J. Gilbert. 2011. The structure and function of arabionoxylan-specific xylanase. J. Biol. Chem. 286: 22510-22520. PMID:21378160

A. Cartmell, L.S. McKee, M.J. Pena, J. Larsbring, H. Brumer, S. Kaneko, H. Ichinose, R.J. Lewis, A. Vikso-Nielsen, H.J. Gilbert, J. Marles-Wright. 2011. The structure and function of an arabinan-specific alpha-fucosidase, underscoring the importance of apoplastic metabolism on the fine structure of Arabidopsis cell wall polysaccharides. J. Biol. Chem. 286: 15483-15495. PMID:21339299

Y. Zhu, M.D. Suits, A.J. Thompson, S. Chavan, Z. Dinev, C. Dumon, N.L. Smith, K. Moremen, Y. Xiang, A. Siriwardena, S.J. Williams, H.J. Gilbert, G.J. Davies. 2010. Mechanistic insights into a Ca2+-dependent family of a-mannosidases in a human gut symbiont. Nature Chem. Biol. 6: 125-132. PMID:20081828

K. Emami, E. Topakas, T. Nagy, J. Henshaw, K.A. Jackson, K.E. Nelson, E.F. Mongodin, J.W. Murray, R.J. Lewis, H.J. Gilbert. 2009. Regulation of the xylan-degrading apparatus of Cellvibrio japonicus by a novel two-component system. J. Biol. Chem. 284: 1086-1096. PMID:18922794

W.A. Offen, L. Zechel, S.G. Withers, H.J. Gilbert, C.J. Davies. 2009. Structure of the Michaelis complex of b-mannosidase Man2A provides insight into the conformational itinery of mannoside hydrolysis. Chem. Commun. 18: 2484-2486. PMID:19532864

C. Montanier, L.A. Van Bueren, C. Dumon, J.E. Flint, M.A. Correia, J.A. Prates, S.J. Firbank, R.J. Lewis, G.G. Grondin, M.G. Ghinet, T.M. Gloster, C. Herve, M.P. Knox., B.G. Talbot, J.P. Turkenburg, J. Kerovuo, R. Brzezinski, C.M.G.A. Fontes, G.J. Davies, A.B. Boraston, H.J. Gilbert. 2009. Evidence that family 35 carbohydrate binding modules display conserved specificity but divergent function. Proc. Natl. Acad. Sci. USA 106: 3065-3070. PMID:19218457

C. Montanier, V.A. Money, V.M. Pires, J.E. Flint, B.A. Pinheiro, A. Goyal, J.A. Prates, A. Izumi, H. Stalbrand, C. Morland, A. Cartmell, K. Kolenova, E. Topakas, E.J. Dodson, D.N. Bolam, G.J. Davies, C.M. Fontes, H.J. Gilbert. 2009. The active site of a carbohydrate esterase displays divergent catalytic and noncatalytic binding functions. PLoS Biol. 7: 0687-0697. PMID:19338387

L.E. Tailford, V.M. Ducros, J.E. Flint, S.M. Roberts, C. Morland, D.L. Zechel, N. Smith, M.E. Bjørnvad, T.V. Borchert, K.S. Wilson, G.J. Davies, H.J. Gilbert. 2009. Understanding how diverse b-mannanases recognize heterogeneous substrates. Biochemistry 48: 7009-7018. PMID:19441796

Y. Verherbruggen, S.E. Marcus, A. Haeger, R. Verhoef, H.A. Schols, B.V. McCleary, L. McKee, H.J. Gilbert, J.P. Knox. 2009. Developmental complexity of Arabian polysaccharides and their processing in plant cell walls. Plant J. 59: 413-425. PMID:19392693

C. Hervé, A. Rogowski, H.J. Gilbert, J.P. Knox. 2009. Enzymatic treatments reveal differential capacities for xylan recognition and degradation in primary and secondary plant cell walls. Plant J. 58: 413-422. PMID:198144002

D.W. Abbott, E. Ficko-Blean, A.L. Van Bueren, A. Rogowski, A. Carmell, P.M. Coutinho, B. Henrissat, H.J. Gilbert, A.B. Boraston . 2009. Analysis of the structural and functional diversity of plant cell wall specific family 6 carbohydrate binding modules. Biochemistry 48: 10395-10404. PMID:19788273

B.A. Pinheiro, H.J. Gilbert, K. Sakka, V.O. Fernandes, J.A. Prates, V.D. Alves, D.N. Bolam, L.M. Ferreira, C.M. Fontes. 2009. Functional insights into the role of nove type I cohesin and dockerin domains from Clostridium thermocellum. Biochem. J. 424: 375-384. PMID:19758121

L.E. Tailford, W.A. Offen, N.L. Smith, C. Dumon, C. Morland, J. Gratien, M.P. Heck, R.V. Stick, Y. Bleriot, A. Vassella, H.J. Gilbert, G.J. Davies. 2008. Structural and biochemical evidence for a boat-like transition state in b-mannosidases. Nature Chem. Biol. 4: 306-312. PMID:18408714

M. Vardakou, C. Dumon, J.W. Murray, P. Christakopoulos, D.P. Weiner, N. Juge, R.J. Lewis, H.J. Gilbert, J.E. Flint. 2008. Understanding the structural basis for substrate and inhibitor recognition in eukaryotic GH11 xylanses. J. Mol. Biol. 375: 1293-1305. PMID:18078955

A. Cartmell, E. Topakas, V.M. Ducros, M.D. Suits, G.J. Davies, H.J. Gilbert. 2008. The Cellvibrio japonicus mannanase CjMan26C displays a unique exo-mode of action that is conferred by subtle changes to the distal region of the active site. J. Biol. Chem. 283: 34403-34413. PMID:18799462

H.J. Gilbert. 2008. Sus out sugars in. Structure. 16: 987-989. PMID:18611370

M.A. Correia, J.A. Prates, J. Brás, C.M. Fontes, J.A. Newman, R.J. Lewis, H.J. Gilbert, J.E. Flint. 2008. Crystal structure of a cellulosomal family 3 carbohydrate esterase from Clostridium thermocellum provides insights into the mechanism of substrate recognition. J. Mol. Biol. 379: 64-72. PMID:18436237

V.A. Money, A. Cartmell, C.I. Guerreiro, V.M. Ducros, C.M. Fontes, H.J. Gilbert, G.J. Davies. 2008. Probing the b-1,3:1,4 glucanase CtLic26A with a thio-oligosaccharide and enzyme variants. Org. Biomol. Chem. 6: 851-853. PMID:18292875

R.T. DeBoy, E.F. Mongodin, D.E. Fouts, L.E. Tailford, H. Khouri, J.B. Emerson, Y. Mohamoud, K. Watkins, B. Henrissat, H.J. Gilbert, K.E. Nelson. 2008. Insights into plant cell wall degratation from the genome sequence of the soil bacterium Cellvibrio japonicus. J. Bacteriol. 190: 5455-5463. PMID:18556790

R.M. Weiner, L.E.II Taylor, B. Henrissat, L. Hauser, M. Land, P.M. Coutinho, C. Rancurel, E.H. Saunders, A.G. Longmire, H. Zhang, E.A. Bayer, H.J. Gilbert, F. Larimer, I.B. Zhulin, N.A. Ekborg, R. Lamed, P.M. Richardson, I. Borovok, S. Hutcheson. 2008. Complete genome squence of the complex carbohydrate-degrading marine bacterium Saccharophagus degradans strain 2-40 T. PLoS Genet. 4: e1000087-. PMID:18516288

C. Dumon, A. Varvak, M.A. Wall, J.E. Flint, R.J. Lewis, J.H. Lakey, C. Morland, P. Luginbuhl, S. Healey, T. Todaro, G. DeSantis, M. Sun, L. Parra-Gessert, X. Tan, D.P. Weiner, H.J. Gilbert. 2008. Engineering hyperthermostability into a GH11 xylanse is mediated by subtle changes to protein structure. J. Biol. Chem. 283: 22557-22564. PMID:18515360

H.J. Gilbert, H. Stalbrand, H. Brumer. 2008. How the walls come crumbling down: recent structural biochemistry of plant polysaccharide degradation. Curr. Opin. Plant Biol. 11: 338-348. PMID:18430603

B.A. Pinheiro, M.R. Proctor, C. Martinez-Fleites, J.A. Prates, V.A. Money, G.J. Davies, E.A. Bayer, C.M. Fontesm, H.P. Fierobe, H.J. Gilbert. 2008. The Clostridium thermocellum provides insights into the mechanism of substrate recognition. J. Biol. Chem. 283: 18422-18430. PMID:18445585

L.E. Tailford, V.A. Money, N.L. Smith, C. Dumon, G.J. Davies, H.J. Gilbert. 2007. Mannose foraging by Bacteroides thetaiotaomicron structure and specificity of the b-mannosidase man2a. J. Biol. Chem. 282: 1191-11299. PMID:18408714

H.J. Gilbert. 2007. Cellulosomes: microbial nanomachines that display plasticity in quaternary structure. Mol. Microbiol. 63: 1568-1576. PMID:17367380

A.L. Carvalho, F.M. Dias, T. Nagy, J.A. Prates, M.R. Proctor, N. Smith, E.A. Bayer, G.J. Davies, L.M. Ferreira, M.J. Romao, C.A.M. Fontes, H.J. Gilbert. 2007. Evidence for a dual binding mode of dockerin modules to cohesins. Proc. Natl. Acad. Sci. USA 104: 3089-3094. PMID:17360613

D.N. Bolam, S. Roberts, M.R. Proctor, J.P. Turkenburg, E.J. Dodson, C. Martinez-Fleites, M. Yang, B.G. Davis, G.J. Davies, H.J. Gilbert. 2007. The crystal structure of two macrolide glycosyltransferases provides a blueprint for host cell antibiotic immunity. Proc. Natl. Acad. Sci. USA 104: 5336-5341. PMID:17376874

T. Nagy, R.B. Tunnicliffe, L.D. Higgins, C. Walters, H.J. Gilbert, M.P. Williamson. 2007. Characterization of a double dockerin from the cellulosome of the anaerobic fungus Piromyces equi. J. Mol. Biol. 373: 612-622. PMID:17869267

L. Cicortas Gunnarsson, C. Montanier, R.B. Tunnicliffe, M.P. Williamson, H.J. Gilbert, E. Nordberg Karlsson, M. Ohlin. 2007. Novel xylan-binding properties of an engineering family 4 carbohydrate-binding module. Biochem. J. 406: 209-214. PMID:17506724

L. McCartney, A.W. Blake, J. Flint, D.N. Bolam, A.B. Boraston, H.J. Gilbert, J.P. Knox. 2006. Differential recognition of plant cell walls by microbial xylan-specific carbohydrate-binding modules. Proc. Natl. Acad. Sci. USA 103: 4765-4770. PMID:16537424

M.R. Proctor, E.J. Taylor, D. Nurizzo, J. Turkenberg, R.M. Lloyd, M. Vardakou, G.J. Davies, H.J. Gilbert. 2005. Tailored catalysts for plant cell-wall degradation: redesigning the exo/endo preference of the Cellvibrio japonicus arabinanse 43A. Proc. Natl. Acad. Sci. USA 102: 2697-2702. PMID:15708971

J. Flint, E. Taylor, M. Yang, D.N. Bolam, L.E. Tailford, C.M. Fleites, E.J.. Dodson, B.G. Davis, H.J. Gilbert, G.J. Davies. 2005. Structural dissection and high-throughput screen of mannosylglycerate synthase. Nature Struct. Mol. Biol. 12: 608-614. PMID:15951819

T. Netherwoods, S.M. Martin-Orue, A.G. ODonnell, S. Gockling, J. Graham, J.C. Mathers, H.J. Gilbert. 2004. Assessing the survival of transgenic plant DNA in the human gastrointestinal tract. Nature Biotechnol. 22: 204-209. PMID:14730317

A.L. Carvalho, F.M. Dias, J.A. Prates, T. Nagy, H.J. Gilbert, G.J. Davies, L.M. Ferreira, M.J. Romao, C.M. Fontes. 2003. Cellulosome assembly revealed by the crystal structure of the cohesin-dockerin complex. Proc. Natl. Acad. Sci. USA 100: 13809-13814. PMID:14623971

D. Nurizzo, J.P. Turkenburg, S.J. Charnock, S.M. Roberts, E.J. Dodson, V.A. McKie, E.J. Taylor, H.J. Gilbert, G.J. Davies. 2002. Cellvibrio japonicus alpha-L-arbinanase 43A has a novel five-blade beta-propeller fold. Nature Struct. Biol. 0: 665-668. PMID:12198486

S.J. Charnock, D.N. Bolam, D. Nurizzo, L. Szabo, V.A. McKie, H.J. Gilbert, G.J. Davies. 2002. Promiscuity in ligand-binding: The three-dimensional structure of a Piromyces carbohydrate-binding module, CBM29-2, in complex with cello- and mannohexaose. Proc. Natl. Acad. Sci. U.S.A. 99: 14077-14082. PMID:12391332

Book Chapters

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