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Professor Nicholas Harmer

Professor Nicholas Harmer

Associate Professor in Biochemistry

 5179

 +44 (0)1392 725179

 Living Systems Institute TO3.14

 

Living Systems Institute, University of Exeter, Stocker Road, Exeter, EX4 4QD

 Office hours:

Tuesday 0830-0930. 

Thursday 0830-0930. 

Dr Nic Harmer in the lab

Dr Nic Harmer in the lab

Overview

Enzyme cascades and their applications

Enzymes are nature’s catalysts. They are molecules that make reactions in biology work faster. All the chemical changes needed in living systems rely on enzymes speeding up reactions at the right time. Our work seeks to understand sets of enzymes working together – a “cascade” – to drive desirable reactions. We engineer some enzymes using evolutionary methods. We then apply this understanding to practical problems. Our key examples are: the production of sugars for use in vaccines against bacteria; and chemical transformations for drug manufacture. Our work will help to deliver vaccines or drugs at scale using fewer resources and producing less waste. It will help both with overcoming antimicrobial resistance, and achieving a green future.

 

Research Team

Dr. Sumita Roy (PDRA)

Alice Cross (PhD)

Rhys Cutlan (PhD)

I am a member of the Biochemistry, Chemical Biology and Structural Biology and Microbes and Disease research groups.

Qualifications

Biography

Prof. Harmer trained for his PhD in X-ray crystallography in the laboratory of Prof. Sir Tom Blundell at the University of Cambridge. He spent three further years in Cambridge as a postdoctoral research associate working on growth factors and enzymes, and learning biophysical techniques. He then worked for AstraZeneca in Mölndal, Sweden as a structural biologist for one year to gain an understanding of industry. He joined the University of Exeter in 2007 and established a research programme on the structure and function of enzymes in biological cascades. In 2017 he was amongst the first PIs to join the Living Systems Institute.

Qualifications

2000-2004 PhD Biochemistry, University of Cambridge
1999-2000 MSci Natural Sciences, University of Cambridge
1996-2000 2003 MA Natural Sciences, University of Cambridge

 

Career

2018-present Associate Professor in Biochemistry, Living Systems Institute, University of Exeter, UK

2012-2018 Senior Lecturer in Structural Biochemistry, School of Biosciences, University of Exeter, UK
2007-2012 Lecturer in Structural Biochemistry, School of Biosciences, University of Exeter, UK
2006-2007 Senior Scientist, AstraZeneca R&D Molndal, Sweden
2003-2006 Research Associate, Department of Biochemistry, University of Cambridge, UK

Research group links

Dr Nic Harmer in the lab

Dr Nic Harmer in the lab

Research

Research interests

Enzyme cascades and their applications

Our work aims to understand enzymes as biological catalysts. We seek to understand enzymes individually from a structure-function perspective: we determine the structure of enzymes and align this to function using enzyme assays and complementary methods. Our aim is to understand how enzymes achieve rate enhancement, and how this can be modulated for different functions. Where necessary, we are engineering enzymes using ancestral sequence reconstruction to obtain proteins with novel properties. Key example enzymes are carbohydrate active enzymes, carboxylic acid reductases and prolyl-peptidyl isomerases.

Alongside our studies of individual enzymes, we also aim to understand how groups of enzymes work together to achieve larger transformations. Our particular interest is in modelling groups of enzymes to see whether their individual properties explain their behaviour as a group. Building faithful models of enzyme activity is essential for process upscaling to the quantities required for production levels. We use Python, Matlab or R as appropriate to the experimental problem.

Our enzyme studies are being applied to important problems in life and molecular sciences. Current main projects for the group are the biosynthesis of the Coxiella burnetii O-antigen, and enzyme cascades based around carboxylic acid reductases. Coxiella burnetii infects sheep, goats and cattle across the world, causing abortions and stillbirths, and causes a disease called Q fever in humans. We aim to use our understanding of the O-antigen biosynthesis to help develop a vaccine (funding: BBSRC, Dstl). We are also developing enzyme cascades that can be used to synthesise chiral building blocks for drug manufacture with reduced resources and waste streams (funding: BBSRC, GSK).

Research projects

Current key projects include:

1. Coxiella burnetii O-antigen
Q fever is a disease of ruminant domestic animals, and only a few bacteria are necessary to infect humans. The pathogen is found globally, and is economically important as it can cause abortions in domestic animals. My group is investigating the biosynthesis of the O-antigen of C. burnetii. This is the only polysaccharide of this organism, and is an excellent candidate for novel vaccines. This work is undertaken in collaboration with Prof. Rick Titball (Exeter), Dr. Joann Prior (Dstl), Prof. Brendan Wren and Dr. Jon Cuccui (London School of Hygiene and Tropical Medicine), and Prof. Rob Field (John Innes Centre). This work is funded by BBSRC and Dstl.

2. Enzyme cascades for green chemistry

There is an increasing desire to replace organic chemistry methods with enzymes where possible. This reduces the use of polluting chemicals and solvents. Enzymes also offer the opportunity to generate chiral products with high purity. Using a cascade of enzymes offers further opportunities to reduce side reactions, or to minimise the concentrations of less stable intermediates. We are working on cascades based on the carboxylic acid reductases (CAR). These enzymes reduce acid to aldehydes, producing a reactive substrate for further enzymes. We have developed the most thermostable CAR available to date and aim to use this for biocatalysis at higher temperatures. This work is being undertaken in collaboration with Prof. Jenny Littlechild (Exeter) and Dr. Richard Lloyd (GSK), and is funded by GSK and BBSRC.

3. Chaperones of B. pseudomallei
Chaperones are essential for the correct folding of many proteins in all organisms, and as such they inevitably contribute to the viability and infectivity of micro-organisms. Moreover, chaperones of the FK-506 binding protein family have been identified as significant virulence factors in a range of micro-organisms. My group is aiming to understand the contribution of chaperones to B. pseudomallei infectivity, and determine the potential for novel antimicrobials. This project is being undertaken in collaboration with Dr. Andy Scott (Dstl), Dr. Mitali Sarkar-Tyson (University of Western Australia) and Prof. Ulrike Holzgrabe (University of Würzburg), and is funded by Dstl. It has received further funding from Interreg.

Research grants:

BBSRC - Glycoengineering of Veterinary Vaccines (CoI, Exeter co-PI)

BBSRC/Dstl - Defining the O-antigen biosynthetic pathways in zoonotic Coxiella burnetii (PI)

BBSRC/GSK - Synthetic biology for green chemistry: Building in vivo enzymatic cascades using Carboxylic acid reductases (CARs) – (PI)

BBSRC/ERAnet - HotSolute - Thermophilic bacteria and archaeal chassis for extremolyte production (CoI with Jenny Littlechild)

Research networks

Current external collaborators include Dr. Joann Prior, Dr. Andy Scott (Dstl); Professor Rob Field (University of Manchester); Prof. Brendan Wren and Dr. Jon Cuccui (London School of Hygiene and Tropical Medicine); Prof. Ulrike Holzgrabe (University of Würzburg); Dr. Mitali Sarkar-Tyson (University of Western Australia); Dr. Jiayun Pang (University of Greenwich); Dr. Richard Lloyd (GSK Stevenage).

Links


Publications

Key publications | Publications by category | Publications by year

Key publications


Finnigan W, Cutlan R, Snajdrova R, Adams J, Littlechild J, Harmer NJ (In Press). Engineering a Seven Enzyme Biotransformation using Mathematical Modelling and Characterized Enzyme Parts. ChemCatChem Full text.
Thomas A, Cutlan R, Finnigan W, Van Der Giezen M, Harmer N (2019). Highly thermostable carboxylic acid reductases generated by ancestral sequence reconstruction.  Abstract.  Full text.
Harmer NJ, Vivoli M, Pang J (2017). A half-site multimeric enzyme achieves its cooperativity without conformational changes. Scientific Reports, 7, 16529-16529. Full text.
Finnigan W, Thomas A, Cromar H, Gough B, Snajdrova R, Adams JP, Littlechild JA, Harmer NJ (2016). Characterization of carboxylic acid reductases as enzymes in the toolbox for synthetic chemistry. ChemCatChem, in press Full text.
Rosay T, Bazire A, Diaz S, Clamens T, Blier A-S, Mijouin L, Hoffmann B, Sergent J-A, Bouffartigues E, Boireau W, et al (2015). Pseudomonas aeruginosa Expresses a Functional Human Natriuretic Peptide Receptor Ortholog: Involvement in Biofilm Formation. MBio, 6(4). Abstract.  Author URL.  Full text.
Vivoli M, Isupov MN, Nicholas R, Hill A, Scott AE, Kosma P, Prior JL, Harmer NJ (2015). Unraveling the B. pseudomallei Heptokinase WcbL: from Structure to Drug Discovery. Chemistry and Biology, 22(12), 1622-1632. Abstract.  Full text.

Publications by category


Journal articles

Sheppard EC, Rogers S, Harmer NJ, Chahwan R (In Press). A universal fluorescence-based toolkit for real-time quantification of DNA and RNA nuclease activity.  Abstract.
Cuccui J, Milne TS, Harmer NJ, George AJ, Harding SV, Dean RE, Scott AE, Sarkar-Tyson M, Wren BW, Titball RW, et al (In Press). Characterization of the Burkholderia pseudomallei K96243 Capsular Polysaccharide I Coding Region. Infection and Immunity, 80, 1209-1221. Abstract.
Xu Y, Smith R, Vivoli M, Ema M, Goos N, Gehrke S, Harmer NJ, Wagner GK (In Press). Covalent inhibitors of LgtC: a blueprint for the discovery of non-substrate-like inhibitors for bacterial glycosyltransferases. Bioorganic & Medicinal Chemistry
Barker S, Harding SV, Gray D, Richards MI, Atkins HS, Harmer N (In Press). Drug screening to identify compounds to act as co-therapies for the treatment of pathogenic Burkholderia.  Abstract.
Finnigan W, Cutlan R, Snajdrova R, Adams J, Littlechild J, Harmer NJ (In Press). Engineering a Seven Enzyme Biotransformation using Mathematical Modelling and Characterized Enzyme Parts. ChemCatChem Full text.
Sheppard EC, Rogers S, Harmer NJ, Chahwan R (2019). A universal fluorescence-based toolkit for real-time quantification of DNA and RNA nuclease activity. Sci Rep, 9(1). Abstract.  Author URL.  Full text.
Harmer NJ, Roy S, Vivoli M (2019). Carbohydrate Kinases: a Conserved Mechanism Across Differing Folds. Catalysts, 9, 29-29. Full text.
Thomas A, Cutlan R, Finnigan W, van der Giezen M, Harmer N (2019). Highly thermostable carboxylic acid reductases generated by ancestral sequence reconstruction. Communications Biology, 2(1). Full text.
Bradshaw WJ, Bruxelle J-F, Kovacs-Simon A, Harmer NJ, Janoir C, Péchiné S, Acharya KR, Michell SL (2019). Molecular features of lipoprotein CD0873: a potential vaccine against the human pathogen Clostridioides difficile. J Biol Chem, 294(43), 15850-15861. Abstract.  Author URL.  Full text.
Cutlan R, De Rose S, Isupov MN, Littlechild JA, Harmer NJ (2019). Using enzyme cascades in biocatalysis: Highlight on transaminases and carboxylic acid reductases. Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics, 140322-140322.
Cross AR, Baldwin VM, Roy S, Essex-Lopresti AE, Prior JL, Harmer NJ (2019). Zoonoses under our noses. Microbes Infect, 21(1), 10-19. Abstract.  Author URL.  Full text.
Winter AJ, Williams C, Isupov MN, Crocker H, Gromova M, Marsh P, Wilkinson OJ, Dillingham MS, Harmer NJ, Titball RW, et al (2018). The molecular basis of protein toxin HicA-dependent binding of the protein antitoxin HicB to DNA. J Biol Chem, 293(50), 19429-19440. Abstract.  Author URL.  Full text.
Harmer NJ, Vivoli M, Pang J (2017). A half-site multimeric enzyme achieves its cooperativity without conformational changes. Scientific Reports, 7, 16529-16529. Full text.
Vivoli M, Renou J, Chevalier A, Norville IH, Diaz S, Juli C, Atkins H, Holzgrabe U, Renard P-Y, Sarkar-Tyson M, et al (2017). A miniaturized peptidyl-prolyl isomerase enzyme assay. Anal Biochem, 536, 59-68. Abstract.  Author URL.
Bayliss M, Donaldson MI, Nepogodiev SA, Pergolizzi G, Scott AE, Harmer NJ, Field RA, Prior JL (2017). Structural characterisation of the capsular polysaccharide expressed by Burkholderia thailandensis strain E555:: wbiI (pKnock-KmR) and assessment of the significance of the 2-O-acetyl group in immune protection. Carbohydr Res, 452, 17-24. Abstract.  Author URL.  Full text.
Steinberg G, Harmer NJ, Schuster M, Kilaru S (2017). Woronin body-based sealing of septal pores. Fungal Genet Biol, 109, 53-55. Abstract.  Author URL.
Finnigan W, Thomas A, Cromar H, Gough B, Snajdrova R, Adams JP, Littlechild JA, Harmer NJ (2016). Characterization of carboxylic acid reductases as enzymes in the toolbox for synthetic chemistry. ChemCatChem, in press Full text.
Seufert F, Kuhn M, Hein M, Weiwad M, Vivoli M, Norville IH, Sarkar-Tyson M, Marshall LE, Schweimer K, Bruhn H, et al (2016). Development, synthesis and structure-activity-relationships of inhibitors of the macrophage infectivity potentiator (Mip) proteins of Legionella pneumophila and Burkholderia pseudomallei. Bioorg Med Chem, 24(21), 5134-5147. Abstract.  Author URL.
N'Diaye A, Mijouin L, Hillion M, Diaz S, Konto-Ghiorghi Y, Percoco G, Chevalier S, Lefeuvre L, Harmer NJ, Lesouhaitier O, et al (2016). Effect of Substance P in Staphylococcus aureus and Staphylococcus epidermidis Virulence: Implication for Skin Homeostasis. FRONTIERS IN MICROBIOLOGY, 7 Author URL.  Full text.
Harmer NJ, Chahwan R (2016). Isotype switching: Mouse IgG3 constant region drives increased affinity for polysaccharide antigens. Virulence, 7(6), 623-626. Author URL.  Full text.
sayer C, Finnigan W, Isupov MN, Levisson M, Kengen SWM, van der Oost J, Harmer NJ, Littlechild JA (2016). Structural and biochemical characterisation of Archaeoglobus fulgidus esterase reveals a bound CoA molecule in the vicinity of the active site. Scientific Reports, 6, 25542-25542. Abstract.  Full text.
Blaszczyk M, Harmer NJ, Chirgadze DY, Ascher DB, Blundell TL (2015). Achieving high signal-to-noise in cell regulatory systems: Spatial organization of multiprotein transmembrane assemblies of FGFR and MET receptors. Progress in Biophysics and Molecular Biology, 118(3), 103-111. Abstract.
Blaszczyk M, Harmer NJ, Chirgadze DY, Ascher DB, Blundell TL (2015). Achieving high signal-to-noise in cell regulatory systems: Spatial organization of multiprotein transmembrane assemblies of FGFR and MET receptors. Prog Biophys Mol Biol, 118(3), 103-111. Abstract.  Author URL.
Rosay T, Bazire A, Diaz S, Clamens T, Blier A-S, Mijouin L, Hoffmann B, Sergent J-A, Bouffartigues E, Boireau W, et al (2015). Pseudomonas aeruginosa Expresses a Functional Human Natriuretic Peptide Receptor Ortholog: Involvement in Biofilm Formation. MBio, 6(4). Abstract.  Author URL.  Full text.
Vivoli M, Isupov MN, Nicholas R, Hill A, Scott AE, Kosma P, Prior JL, Harmer NJ (2015). Unraveling the B. pseudomallei Heptokinase WcbL: from Structure to Drug Discovery. Chemistry and Biology, 22(12), 1622-1632. Abstract.  Full text.
Begley DW, Fox D, Jenner D, Juli C, Pierce PG, Abendroth J, Muruthi M, Safford K, Anderson V, Atkins K, et al (2014). A structural biology approach enables the development of antimicrobials targeting bacterial immunophilins. Antimicrobial Agents and Chemotherapy, in press Abstract.
Begley DW, Fox D, Jenner D, Juli C, Pierce PG, Abendroth J, Muruthi M, Safford K, Anderson V, Atkins K, et al (2014). A structural biology approach enables the development of antimicrobials targeting bacterial immunophilins. Antimicrobial Agents and Chemotherapy, 58(3), 1458-1467. Abstract.
Vivoli M, Novak HR, Littlechild JA, Harmer NJ (2014). Determination of protein-ligand interactions using differential scanning fluorimetry. J Vis Exp(91). Abstract.  Author URL.  Full text.
Vivoli M, Ayres E, Beaumont E, Isupov MN, Harmer NJ (2014). Structural insights into WcbI, a novel polysaccharide-biosynthesis enzyme. IUCrJ, 1, 28-38. Full text.
Butt A, Higman VA, Williams C, Crump MP, Hemsley CM, Harmer N, Titball RW (2014). The HicA toxin from Burkholderia pseudomallei has a role in persister cell formation. Biochem J, 459(2), 333-344. Abstract.  Author URL.  Full text.
Butt A, Harmer N, Müller C, Titball RW (2013). Identification of type II toxin-antitoxin modules in Burkholderia pseudomallei. FEMS Microbiol Lett, 338(1), 86-94. Abstract.  Full text.
Cuccui J, Milne TS, Harmer N, George AJ, Harding SV, Dean RE, Scott AE, Sarkar-Tyson M, Wren BW, Titball RW, et al (2012). Characterization of the Burkholderia pseudomallei K96243 capsular polysaccharide I coding region. Infection and Immunity, 80, 1209-1221. Abstract.  Author URL.
Cuccui J, Milne TS, Harmer N, George AJ, Harding SV, Dean RE, Scott AE, Sarkar-Tyson M, Wren BW, Titball RW, et al (2012). Characterization of the Burkholderia pseudomallei K96243 capsular polysaccharide I coding region. Infect Immun, 80(3), 1209-1221. Abstract.  Author URL.
Schuster M, Treitschke S, Kilaru S, Molloy J, Harmer NJ, Steinberg G (2012). Myosin-5, kinesin-1 and myosin-17 cooperate in secretion of fungal chitin synthase. EMBO J, 31(1), 214-227. Abstract.  Author URL.
Norville IH, Harmer NJ, Harding SV, Fischer G, Keith KE, Brown KA, Sarkar-Tyson M, Titball RW (2011). A Burkholderia pseudomallei macrophage infectivity potentiator-like protein has rapamycin-inhibitable peptidylprolyl isomerase activity and pleiotropic effects on virulence. Infect Immun, 79(11), 4299-4307. Abstract.  Author URL.  Full text.
Norville IH, Breitbach K, Eske-Pogodda K, Harmer NJ, Sarkar-Tyson M, Titball RW, Steinmetz I (2011). A novel FK-506-binding-like protein that lacks peptidyl-prolyl isomerase activity is involved in intracellular infection and in vivo virulence of Burkholderia pseudomallei. Microbiology, 157(Pt 9), 2629-2638. Abstract.  Author URL.
Thomas RM, Twine SM, Fulton KM, Tessier L, Kilmury SLN, Ding W, Harmer N, Michell SL, Oyston PCF, Titbal RW, et al (2011). Glycosylation of DsbA in Francisella tularensis subsp. Tularensis. Journal of Bacteriology, 193(19), 5498-5509. Abstract.
Norville I, O'Shea K, Sarkar-Tyson M, Zheng S, Titball RW, Varani G, Harmer NJ (2011). The structure of a Burkholderia pseudomallei immunophilin-inhibitor complex reveals new approaches to antimicrobial development. Biochemical Journal, 437, 413-422. Abstract.
Norville IH, O'Shea K, Sarkar-Tyson M, Zheng S, Titball RW, Varani G, Harmer NJ (2011). The structure of a Burkholderia pseudomallei immunophilin-inhibitor complex reveals new approaches to antimicrobial development. Biochem J, 437(3), 413-422. Abstract.  Author URL.
Harmer NJ (2010). The Structure of Sedoheptulose-7-Phosphate Isomerase from Burkholderia pseudomallei Reveals a Zinc Binding Site at the Heart of the Active Site. JOURNAL OF MOLECULAR BIOLOGY, 400(3), 379-392. Author URL.  Full text.
Goodger SJ, Robinson CJ, Murphy KJ, Gasiunas N, Harmer NJ, Blundell TL, Pye DA, Gallagher JT (2008). Evidence that heparin saccharides promote FGF2 mitogeneisis through two distinct mechanisms. Journal of Biological Chemistry, 283, 13001-13008.
Harmer NJ, King, J.D. Palmer, C.M. Preston, A. Maskell DJ, Blundell TL (2007). Cloning, expression, purification and preliminary crystallographic analysis of the short-chain dehydrogenase enzymes WbmF, WbmG and WbmH from Bordetella bronchiseptica. Acta Crystallographica F, 63(8), 711-715. Full text.
King JD, Harmer NJ, Preston A, Palmer CM, Rejzek M, Field RA, Blundell TL, Maskell DJ (2007). Predicting protein function from structure - the roles of short chain dehydrogenase / reductase enzymes in bordetella O-antigen biosynthesis. Journal of Molecular Biology, 374, 749-763.
Harmer NJ (2007). The fibroblast growth factor (FGF) - FGF receptor complex: Progress towards the physiological state. Topics in Current Chemistry, 272, 83-116. Abstract.
Ryu EK, Cho, K.J. Kim, J.K. Harmer NJ, Blundell TL, Kim, K.H. (2006). Expression and purification of recombinant human fibroblast growth factor receptor in E. coli. Protein Expression and Purification, 49, 15-22.
Harmer NJ (2006). Insights into the role of heparan sulphate in fibroblast growth factor signalling. Biochemical Society Transactions, 34(3), 442-445.
Harmer NJ, Robinson CJ, Adam LE, Ilag LL, Robinson CV, Gallagher JT, Blundell TL (2006). Multimers of the fibroblast growth factor (FGF)-FGF receptor-saccharide complex are formed on long oligers of heparin. Biochemical Journal, 393(3), 741-748.
Blundell TL, Sibanda BL, Montalvao RW, Brewerton S, Chelliah V, Harmer NJ, Worth CL, Davies O, Burke D (2006). Structural biology and bioinformatics in drug design: opportunities and challenges for target identification and lead discovery. Philosophical Transactions of the Royal Society B: Biological Sciences, 361(1467), 413-423.
Harmer NJ, Sivac JM, Amaya E, Blundell TL (2005). 1.15 angstrom crystal structure of the X-tropicalis Spred 1 EVH1 domain suggests a fourth distinct peptide-binding mechanism within the EVH1 family. FEBS Letters, 579(5), 1161-1166.
Robinson CJ, Harmer, N.J. Goodger, S.J. Blundell, T.L. Gallagher JT (2005). Cooperative dimerization of FGF1 upon a single heparin saccharide may drive the formation of 2:2:1 FGF-FGFR-heparin ternary complexes. Journal of Biological Chemistry, 280, 42274-42282.
Harmer NJ, Pellegrini L, Chirgadze D, Fernandez-Recio J, Blundell TL (2004). The crystal structure of fibroblast growth factor (FGF) 19 reveals novel features of the FGF family and offers a structural basis for its unusual receptor affinity. Biochemistry, 43(3), 629-640.
Harmer NJ, Ilag LL, Mulloy B, Pellegrini L, Robinson CV, Blundell TL (2004). Towards a resolution of the stoichiometry of the fibroblast growth factor (FGF) - FGF receptor-Heparin complex. Journal of Molecular Biology, 339(4), 821-834.
Harmer NJ, Chirgadze D, Kim KH, Pellegrini L, Blundell TL (2003). The structural biology of growth factor receptor activation. Biophysical Chemistry, 100, 545-553.
Schuh AC, Watkins, N.A. Nguyen, Q. Harmer, N.J. Lin M, Prosper JY, Campbell K, Sutherland DR, Metcalfe P, Horsfeld W, et al (2002). A tyrosine703serine polymorphism of CD109 defines the Gov platelet alloantigens. Blood, 99, 1692-1698.
Blundell TL, Bolanos-Garcia V, Chirgadze DY, Harmer NJ, Lo T, Pellegrini L, Sibanda BL (2002). Asymmetry in the multiprotein systems of molecular biology. Structural Chemistry, 13(3-4), 405-412. Abstract.
Ouwehand WH, Watkins NA, Nguyen Q, Harmer NJ, Lin M, Prosper JYA, Campbell K, Sutherland DR, Metcalfe P, Horsfall W, et al (2001). A Tyrosine(703) serine polymorphism of CD109 defines the Gov platelet alloantigens. BLOOD, 98(11), 443A-443A. Author URL.
Nagendra HG, Harrington, A.E. Harmer, N.J. Pellegrini, L. Blundell TL, Burke DF (2001). Sequence analyses and comparative modeling of fly and worm fibroblast growth factor receptors indicate that the determinants for FGF and heparin binding are retained in evolution. FEBS Letters, 501, 51-58.

Chapters

Blundell TL, Bolanos-Garcia V, Chirgadze DY, Harmer NJ, Lo T, Pellegrini L, Lynn Sibanda B (2015). Asymmetry in the multiprotein systems of molecular biology. In  (Ed) Science of Crystal Structures: Highlights in Crystallography, 231-237.  Abstract.
Harmer, N.J. (2005). Role of heparan sulfate in fibroblast growth factor signaling. In Garg H, Linhardt R, Hales C (Eds.) Chemistry and Biology of Heparin and Heparan Sulfate, New York: Elsevier.

Conferences

Harmer NJ, Norville I, Zheng S, O'Shea K, Sarkar-Tyson M, Titball RW, Varani G (2011). THE BURKHOLDERIA PSEUDOMALLEI MIP PROTEIN, a VIRULENCE FACTOR AND DRUG TARGET. Society for General Microbiology Spring Conference. 11th - 14th Apr 2011. Abstract.
Norville I, Zheng S, O'Shea K, Sarkar-Tyson M, Titball RW, Varani G, Harmer NJ (2011). THE BURKHOLDERIA PSEUDOMALLEI MIP PROTEIN, a VIRULENCE FACTOR AND DRUG TARGET. SWSBC 2011. 11th - 12th Jul 2011. Abstract.
Harmer NJ (2010). Structure and function of sedoheptulose-7-phosphate isomerase from Burkholderia pseudomallei, an unusual metalloenzyme. Enzymes, Cofactors and Metabolic pathways. 18th - 23rd Jul 2010. Abstract.
Harmer NJ, Norville I, Zheng S, O'Shea K, Sarkar-Tyson M, Titball RW, Varani G (2010). THE BURKHOLDERIA PSEUDOMALLEI MIP PROTEIN, a VIRULENCE FACTOR AND DRUG TARGET. Melioidosis 2010. 30th Nov - 3rd Dec 2010. Abstract.
Robinson CJ, Harmer NJ, Blundell TL, Gallagher JT (2004). Studying the role of heparin in the formation of FGF1-FGFR2 complexes using gel chromatography.  Author URL.

Publications by year


In Press

Sheppard EC, Rogers S, Harmer NJ, Chahwan R (In Press). A universal fluorescence-based toolkit for real-time quantification of DNA and RNA nuclease activity.  Abstract.
Cuccui J, Milne TS, Harmer NJ, George AJ, Harding SV, Dean RE, Scott AE, Sarkar-Tyson M, Wren BW, Titball RW, et al (In Press). Characterization of the Burkholderia pseudomallei K96243 Capsular Polysaccharide I Coding Region. Infection and Immunity, 80, 1209-1221. Abstract.
Xu Y, Smith R, Vivoli M, Ema M, Goos N, Gehrke S, Harmer NJ, Wagner GK (In Press). Covalent inhibitors of LgtC: a blueprint for the discovery of non-substrate-like inhibitors for bacterial glycosyltransferases. Bioorganic & Medicinal Chemistry
Barker S, Harding SV, Gray D, Richards MI, Atkins HS, Harmer N (In Press). Drug screening to identify compounds to act as co-therapies for the treatment of pathogenic Burkholderia.  Abstract.
Finnigan W, Cutlan R, Snajdrova R, Adams J, Littlechild J, Harmer NJ (In Press). Engineering a Seven Enzyme Biotransformation using Mathematical Modelling and Characterized Enzyme Parts. ChemCatChem Full text.

2019

Sheppard EC, Rogers S, Harmer NJ, Chahwan R (2019). A universal fluorescence-based toolkit for real-time quantification of DNA and RNA nuclease activity. Sci Rep, 9(1). Abstract.  Author URL.  Full text.
Thomas A (2019). Ancestral sequence reconstruction as an accessible tool for the engineering of biocatalyst stability.  Abstract.  Full text.
Harmer NJ, Roy S, Vivoli M (2019). Carbohydrate Kinases: a Conserved Mechanism Across Differing Folds. Catalysts, 9, 29-29. Full text.
finnigan W, Cutlan R, Snajdrova R, Adams J, Littlechild J, Harmer NJ (2019). Engineering a Seven Enzyme Biotransformation using Mathematical Modelling and Characterized Enzyme Parts (dataset).  Full text.
Thomas A, Cutlan R, Finnigan W, Van Der Giezen M, Harmer N (2019). Highly thermostable carboxylic acid reductases generated by ancestral sequence reconstruction.  Abstract.  Full text.
Thomas A, Cutlan R, Finnigan W, van der Giezen M, Harmer N (2019). Highly thermostable carboxylic acid reductases generated by ancestral sequence reconstruction. Communications Biology, 2(1). Full text.
Bradshaw WJ, Bruxelle J-F, Kovacs-Simon A, Harmer NJ, Janoir C, Péchiné S, Acharya KR, Michell SL (2019). Molecular features of lipoprotein CD0873: a potential vaccine against the human pathogen Clostridioides difficile. J Biol Chem, 294(43), 15850-15861. Abstract.  Author URL.  Full text.
Sheppard E (2019). Nucleases and histone acetyltransferases in DNA repair and immune diversity.  Abstract.  Full text.
Cutlan R, De Rose S, Isupov MN, Littlechild JA, Harmer NJ (2019). Using enzyme cascades in biocatalysis: Highlight on transaminases and carboxylic acid reductases. Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics, 140322-140322.
Cross AR, Baldwin VM, Roy S, Essex-Lopresti AE, Prior JL, Harmer NJ (2019). Zoonoses under our noses. Microbes Infect, 21(1), 10-19. Abstract.  Author URL.  Full text.

2018

Winter AJ, Williams C, Isupov MN, Crocker H, Gromova M, Marsh P, Wilkinson OJ, Dillingham MS, Harmer NJ, Titball RW, et al (2018). The molecular basis of protein toxin HicA-dependent binding of the protein antitoxin HicB to DNA. J Biol Chem, 293(50), 19429-19440. Abstract.  Author URL.  Full text.

2017

Harmer NJ, Vivoli M, Pang J (2017). A half-site multimeric enzyme achieves its cooperativity without conformational changes. Scientific Reports, 7, 16529-16529. Full text.
Vivoli M, Renou J, Chevalier A, Norville IH, Diaz S, Juli C, Atkins H, Holzgrabe U, Renard P-Y, Sarkar-Tyson M, et al (2017). A miniaturized peptidyl-prolyl isomerase enzyme assay. Anal Biochem, 536, 59-68. Abstract.  Author URL.
Bayliss M, Donaldson MI, Nepogodiev SA, Pergolizzi G, Scott AE, Harmer NJ, Field RA, Prior JL (2017). Structural characterisation of the capsular polysaccharide expressed by Burkholderia thailandensis strain E555:: wbiI (pKnock-KmR) and assessment of the significance of the 2-O-acetyl group in immune protection. Carbohydr Res, 452, 17-24. Abstract.  Author URL.  Full text.
Steinberg G, Harmer NJ, Schuster M, Kilaru S (2017). Woronin body-based sealing of septal pores. Fungal Genet Biol, 109, 53-55. Abstract.  Author URL.

2016

Finnigan W, Thomas A, Cromar H, Gough B, Snajdrova R, Adams JP, Littlechild JA, Harmer NJ (2016). Characterization of carboxylic acid reductases as enzymes in the toolbox for synthetic chemistry. ChemCatChem, in press Full text.
Seufert F, Kuhn M, Hein M, Weiwad M, Vivoli M, Norville IH, Sarkar-Tyson M, Marshall LE, Schweimer K, Bruhn H, et al (2016). Development, synthesis and structure-activity-relationships of inhibitors of the macrophage infectivity potentiator (Mip) proteins of Legionella pneumophila and Burkholderia pseudomallei. Bioorg Med Chem, 24(21), 5134-5147. Abstract.  Author URL.
N'Diaye A, Mijouin L, Hillion M, Diaz S, Konto-Ghiorghi Y, Percoco G, Chevalier S, Lefeuvre L, Harmer NJ, Lesouhaitier O, et al (2016). Effect of Substance P in Staphylococcus aureus and Staphylococcus epidermidis Virulence: Implication for Skin Homeostasis. FRONTIERS IN MICROBIOLOGY, 7 Author URL.  Full text.
Harmer NJ, Chahwan R (2016). Isotype switching: Mouse IgG3 constant region drives increased affinity for polysaccharide antigens. Virulence, 7(6), 623-626. Author URL.  Full text.
sayer C, Finnigan W, Isupov MN, Levisson M, Kengen SWM, van der Oost J, Harmer NJ, Littlechild JA (2016). Structural and biochemical characterisation of Archaeoglobus fulgidus esterase reveals a bound CoA molecule in the vicinity of the active site. Scientific Reports, 6, 25542-25542. Abstract.  Full text.

2015

Blaszczyk M, Harmer NJ, Chirgadze DY, Ascher DB, Blundell TL (2015). Achieving high signal-to-noise in cell regulatory systems: Spatial organization of multiprotein transmembrane assemblies of FGFR and MET receptors. Progress in Biophysics and Molecular Biology, 118(3), 103-111. Abstract.
Blaszczyk M, Harmer NJ, Chirgadze DY, Ascher DB, Blundell TL (2015). Achieving high signal-to-noise in cell regulatory systems: Spatial organization of multiprotein transmembrane assemblies of FGFR and MET receptors. Prog Biophys Mol Biol, 118(3), 103-111. Abstract.  Author URL.
Blundell TL, Bolanos-Garcia V, Chirgadze DY, Harmer NJ, Lo T, Pellegrini L, Lynn Sibanda B (2015). Asymmetry in the multiprotein systems of molecular biology. In  (Ed) Science of Crystal Structures: Highlights in Crystallography, 231-237.  Abstract.
Rosay T, Bazire A, Diaz S, Clamens T, Blier A-S, Mijouin L, Hoffmann B, Sergent J-A, Bouffartigues E, Boireau W, et al (2015). Pseudomonas aeruginosa Expresses a Functional Human Natriuretic Peptide Receptor Ortholog: Involvement in Biofilm Formation. MBio, 6(4). Abstract.  Author URL.  Full text.
Vivoli M, Isupov MN, Nicholas R, Hill A, Scott AE, Kosma P, Prior JL, Harmer NJ (2015). Unraveling the B. pseudomallei Heptokinase WcbL: from Structure to Drug Discovery. Chemistry and Biology, 22(12), 1622-1632. Abstract.  Full text.

2014

Begley DW, Fox D, Jenner D, Juli C, Pierce PG, Abendroth J, Muruthi M, Safford K, Anderson V, Atkins K, et al (2014). A structural biology approach enables the development of antimicrobials targeting bacterial immunophilins. Antimicrobial Agents and Chemotherapy, in press Abstract.
Begley DW, Fox D, Jenner D, Juli C, Pierce PG, Abendroth J, Muruthi M, Safford K, Anderson V, Atkins K, et al (2014). A structural biology approach enables the development of antimicrobials targeting bacterial immunophilins. Antimicrobial Agents and Chemotherapy, 58(3), 1458-1467. Abstract.
Vivoli M, Novak HR, Littlechild JA, Harmer NJ (2014). Determination of protein-ligand interactions using differential scanning fluorimetry. J Vis Exp(91). Abstract.  Author URL.  Full text.
Vivoli M, Ayres E, Beaumont E, Isupov MN, Harmer NJ (2014). Structural insights into WcbI, a novel polysaccharide-biosynthesis enzyme. IUCrJ, 1, 28-38. Full text.
Butt A, Higman VA, Williams C, Crump MP, Hemsley CM, Harmer N, Titball RW (2014). The HicA toxin from Burkholderia pseudomallei has a role in persister cell formation. Biochem J, 459(2), 333-344. Abstract.  Author URL.  Full text.

2013

Butt A, Harmer N, Müller C, Titball RW (2013). Identification of type II toxin-antitoxin modules in Burkholderia pseudomallei. FEMS Microbiol Lett, 338(1), 86-94. Abstract.  Full text.

2012

Cuccui J, Milne TS, Harmer N, George AJ, Harding SV, Dean RE, Scott AE, Sarkar-Tyson M, Wren BW, Titball RW, et al (2012). Characterization of the Burkholderia pseudomallei K96243 capsular polysaccharide I coding region. Infection and Immunity, 80, 1209-1221. Abstract.  Author URL.
Cuccui J, Milne TS, Harmer N, George AJ, Harding SV, Dean RE, Scott AE, Sarkar-Tyson M, Wren BW, Titball RW, et al (2012). Characterization of the Burkholderia pseudomallei K96243 capsular polysaccharide I coding region. Infect Immun, 80(3), 1209-1221. Abstract.  Author URL.
Schuster M, Treitschke S, Kilaru S, Molloy J, Harmer NJ, Steinberg G (2012). Myosin-5, kinesin-1 and myosin-17 cooperate in secretion of fungal chitin synthase. EMBO J, 31(1), 214-227. Abstract.  Author URL.

2011

Norville IH, Harmer NJ, Harding SV, Fischer G, Keith KE, Brown KA, Sarkar-Tyson M, Titball RW (2011). A Burkholderia pseudomallei macrophage infectivity potentiator-like protein has rapamycin-inhibitable peptidylprolyl isomerase activity and pleiotropic effects on virulence. Infect Immun, 79(11), 4299-4307. Abstract.  Author URL.  Full text.
Norville IH, Breitbach K, Eske-Pogodda K, Harmer NJ, Sarkar-Tyson M, Titball RW, Steinmetz I (2011). A novel FK-506-binding-like protein that lacks peptidyl-prolyl isomerase activity is involved in intracellular infection and in vivo virulence of Burkholderia pseudomallei. Microbiology, 157(Pt 9), 2629-2638. Abstract.  Author URL.
Thomas RM, Twine SM, Fulton KM, Tessier L, Kilmury SLN, Ding W, Harmer N, Michell SL, Oyston PCF, Titbal RW, et al (2011). Glycosylation of DsbA in Francisella tularensis subsp. Tularensis. Journal of Bacteriology, 193(19), 5498-5509. Abstract.
Harmer NJ, Norville I, Zheng S, O'Shea K, Sarkar-Tyson M, Titball RW, Varani G (2011). THE BURKHOLDERIA PSEUDOMALLEI MIP PROTEIN, a VIRULENCE FACTOR AND DRUG TARGET. Society for General Microbiology Spring Conference. 11th - 14th Apr 2011. Abstract.
Norville I, Zheng S, O'Shea K, Sarkar-Tyson M, Titball RW, Varani G, Harmer NJ (2011). THE BURKHOLDERIA PSEUDOMALLEI MIP PROTEIN, a VIRULENCE FACTOR AND DRUG TARGET. SWSBC 2011. 11th - 12th Jul 2011. Abstract.
Norville I, O'Shea K, Sarkar-Tyson M, Zheng S, Titball RW, Varani G, Harmer NJ (2011). The structure of a Burkholderia pseudomallei immunophilin-inhibitor complex reveals new approaches to antimicrobial development. Biochemical Journal, 437, 413-422. Abstract.
Norville IH, O'Shea K, Sarkar-Tyson M, Zheng S, Titball RW, Varani G, Harmer NJ (2011). The structure of a Burkholderia pseudomallei immunophilin-inhibitor complex reveals new approaches to antimicrobial development. Biochem J, 437(3), 413-422. Abstract.  Author URL.

2010

Harmer NJ (2010). Structure and function of sedoheptulose-7-phosphate isomerase from Burkholderia pseudomallei, an unusual metalloenzyme. Enzymes, Cofactors and Metabolic pathways. 18th - 23rd Jul 2010. Abstract.
Harmer NJ, Norville I, Zheng S, O'Shea K, Sarkar-Tyson M, Titball RW, Varani G (2010). THE BURKHOLDERIA PSEUDOMALLEI MIP PROTEIN, a VIRULENCE FACTOR AND DRUG TARGET. Melioidosis 2010. 30th Nov - 3rd Dec 2010. Abstract.
Harmer NJ (2010). The Structure of Sedoheptulose-7-Phosphate Isomerase from Burkholderia pseudomallei Reveals a Zinc Binding Site at the Heart of the Active Site. JOURNAL OF MOLECULAR BIOLOGY, 400(3), 379-392. Author URL.  Full text.

2008

Goodger SJ, Robinson CJ, Murphy KJ, Gasiunas N, Harmer NJ, Blundell TL, Pye DA, Gallagher JT (2008). Evidence that heparin saccharides promote FGF2 mitogeneisis through two distinct mechanisms. Journal of Biological Chemistry, 283, 13001-13008.

2007

Harmer NJ, King, J.D. Palmer, C.M. Preston, A. Maskell DJ, Blundell TL (2007). Cloning, expression, purification and preliminary crystallographic analysis of the short-chain dehydrogenase enzymes WbmF, WbmG and WbmH from Bordetella bronchiseptica. Acta Crystallographica F, 63(8), 711-715. Full text.
King JD, Harmer NJ, Preston A, Palmer CM, Rejzek M, Field RA, Blundell TL, Maskell DJ (2007). Predicting protein function from structure - the roles of short chain dehydrogenase / reductase enzymes in bordetella O-antigen biosynthesis. Journal of Molecular Biology, 374, 749-763.
Harmer NJ (2007). The fibroblast growth factor (FGF) - FGF receptor complex: Progress towards the physiological state. Topics in Current Chemistry, 272, 83-116. Abstract.

2006

Ryu EK, Cho, K.J. Kim, J.K. Harmer NJ, Blundell TL, Kim, K.H. (2006). Expression and purification of recombinant human fibroblast growth factor receptor in E. coli. Protein Expression and Purification, 49, 15-22.
Harmer NJ (2006). Insights into the role of heparan sulphate in fibroblast growth factor signalling. Biochemical Society Transactions, 34(3), 442-445.
Harmer NJ, Robinson CJ, Adam LE, Ilag LL, Robinson CV, Gallagher JT, Blundell TL (2006). Multimers of the fibroblast growth factor (FGF)-FGF receptor-saccharide complex are formed on long oligers of heparin. Biochemical Journal, 393(3), 741-748.
Blundell TL, Sibanda BL, Montalvao RW, Brewerton S, Chelliah V, Harmer NJ, Worth CL, Davies O, Burke D (2006). Structural biology and bioinformatics in drug design: opportunities and challenges for target identification and lead discovery. Philosophical Transactions of the Royal Society B: Biological Sciences, 361(1467), 413-423.

2005

Harmer NJ, Sivac JM, Amaya E, Blundell TL (2005). 1.15 angstrom crystal structure of the X-tropicalis Spred 1 EVH1 domain suggests a fourth distinct peptide-binding mechanism within the EVH1 family. FEBS Letters, 579(5), 1161-1166.
Robinson CJ, Harmer, N.J. Goodger, S.J. Blundell, T.L. Gallagher JT (2005). Cooperative dimerization of FGF1 upon a single heparin saccharide may drive the formation of 2:2:1 FGF-FGFR-heparin ternary complexes. Journal of Biological Chemistry, 280, 42274-42282.
Harmer, N.J. (2005). Role of heparan sulfate in fibroblast growth factor signaling. In Garg H, Linhardt R, Hales C (Eds.) Chemistry and Biology of Heparin and Heparan Sulfate, New York: Elsevier.

2004

Robinson CJ, Harmer NJ, Blundell TL, Gallagher JT (2004). Studying the role of heparin in the formation of FGF1-FGFR2 complexes using gel chromatography.  Author URL.
Harmer NJ, Pellegrini L, Chirgadze D, Fernandez-Recio J, Blundell TL (2004). The crystal structure of fibroblast growth factor (FGF) 19 reveals novel features of the FGF family and offers a structural basis for its unusual receptor affinity. Biochemistry, 43(3), 629-640.
Harmer NJ, Ilag LL, Mulloy B, Pellegrini L, Robinson CV, Blundell TL (2004). Towards a resolution of the stoichiometry of the fibroblast growth factor (FGF) - FGF receptor-Heparin complex. Journal of Molecular Biology, 339(4), 821-834.

2003

Harmer NJ, Chirgadze D, Kim KH, Pellegrini L, Blundell TL (2003). The structural biology of growth factor receptor activation. Biophysical Chemistry, 100, 545-553.

2002

Schuh AC, Watkins, N.A. Nguyen, Q. Harmer, N.J. Lin M, Prosper JY, Campbell K, Sutherland DR, Metcalfe P, Horsfeld W, et al (2002). A tyrosine703serine polymorphism of CD109 defines the Gov platelet alloantigens. Blood, 99, 1692-1698.
Blundell TL, Bolanos-Garcia V, Chirgadze DY, Harmer NJ, Lo T, Pellegrini L, Sibanda BL (2002). Asymmetry in the multiprotein systems of molecular biology. Structural Chemistry, 13(3-4), 405-412. Abstract.

2001

Ouwehand WH, Watkins NA, Nguyen Q, Harmer NJ, Lin M, Prosper JYA, Campbell K, Sutherland DR, Metcalfe P, Horsfall W, et al (2001). A Tyrosine(703) serine polymorphism of CD109 defines the Gov platelet alloantigens. BLOOD, 98(11), 443A-443A. Author URL.
Nagendra HG, Harrington, A.E. Harmer, N.J. Pellegrini, L. Blundell TL, Burke DF (2001). Sequence analyses and comparative modeling of fly and worm fibroblast growth factor receptors indicate that the determinants for FGF and heparin binding are retained in evolution. FEBS Letters, 501, 51-58.

nic_harmer Details from cache as at 2019-12-07 06:01:20

Refresh publications

External Engagement and Impact

Committee/panel activities

Research Council Committees

BBSRC Panel D Core Member (since 2015)
BBSRC Pool of Experts (2014-2015)

Dr Nic Harmer in the lab

Dr Nic Harmer in the lab

Teaching

I currently teach Year 2 Analytical Techniques in Biochemistry (BIO2090) and Metabolism (BIO2086), and Year 3 Horizons of Biochemical Research (BIO3085).

Modules

2019/20


Supervision / Group

Postdoctoral researchers

Postgraduate researchers

  • Alice Cross
  • Rhys Cutlan

Alumni

  • Victoria Baldwin
  • Will Finnegan
  • Tara Macey
  • Adam Thomas

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